PASTEUR, LOUIS

(b. Dole, Jura, France, 27 December 1822; d. Chateau Villeneuve-l’Ètang, near Paris, France, 28 September 1895)

crystallography, chemistry, microbiology, immunology.

Pasteur and His Place in History. If Pasteur was a genius, it was not through ethereal subtlety of mind. Although often bold and imaginative, his work was characterized mainly by clearheadedness, extraordinary experimental skill, and tenacity–almost obstinacy–of purpose. His contributions to basic science were extensive and very significant, but less revolutionary than his reputation suggests. The most profound and original contributions are also the least famous. Beginning about 1847 Pasteur carried out an impressive series of investigations into the relation between optical activity, crystalline structure, and chemical composition in organic compounds, particularly tartaric and paratartaric acids. This work focused attention on the relationship between optical activity and life and provided much inspiration and several of the most important techniques for an entirely new approach to the study of chemical structure and composition. In essence, Pasteur opened the way to a consideration of the disposition of atoms in space, and his early memoirs constitute founding documents of stereochemistry.

From crystallography and structural chemistry Pasteur moved to the controversial and interrelated topics of fermentation and spontaneous generation. If he did more than anyone to promote the biological theory of fermentation and to discredit the theory of spontaneous generation, his effect was due less to profound conceptual originality than to experimental ingenuity and polemical virtuosity. He did broach and contribute fundamentally to important questions in microbial physiology–including the relationship between microorganisms and their environment–but he was readily distracted from such basic issues by more practical concerns–the manufacture of wine, vinegar, and beer, the diseases of silkworms, and the etiology and prophylaxis of diseases in general.

To an extent, Pasteur’s interest in practical problems evolved naturally from his basic research, especially that on fermentation, for the biological theory of fermentation contained obvious implications for industry. By insisting that each fermentative process could be traced to a specific living microorganism, Pasteur not only drew attention to the purity of the causative organism and the amount of oxygen employed, but also suggested that the primary industrial product could be preserved by appropriate sterilizing procedures, called “pasteurization” almost from the outset. Furthermore, the old and widely accepted analogy between fermentation and disease made any theory of the former immediately relevant to the latter. Pasteur’s biological theory of fermentation virtually implied a biological or “germ” theory of disease made any implication was more rapidly developed by others, particularly Joseph Lister; but Pasteur also perceived it from the first and devoted his last twenty years almost exclusively to the germ theory of disease.

No one insisted more strongly than Pasteur himself on the degree to which his pragmatic concerns grew out of his prior basic research. He saw the progression from crystallography through fermentation to disease as not only natural but virtually inevitable; he had been “enchained,” he wrote, by the “almost inflexible logic of my studies.”¹ This view, however enduring and widely accepted, has not gone entirely unchallenged. Rene Dubos has emphasized how Pasteur’s work could have taken many other directions with equal fidelity to the internal logic of his research.² To some extent Pasteur chose, or at least allowed himself to pursue, the practical consequences of his work at the expense of his potential contributions to basic science. Without disputing the immense value and fertility of the basic research he did accomplish, it is fascinating to speculate on what might have been. Late in life, Pasteur indulged in similar speculation and expressed regret that he had abandoned his youthful researches before fully resolving the relationship between asymmetry and life. Had he contributed as much as he had once hoped toward this problem, he would surely have fulfilled his ambition of becoming the Newton or Galileo of biology.

By taking another direction, however, Pasteur revealed the enormous medical and economic potential of experimental biology. He himself developed only one treatment directly applicable to a human disease– his treatment for rabies–but his widely publicized and highly successful efforts on behalf of the germ theory were immediately credited with saving much money and many lives. It is for this reason above all that he was recognized and honored during his lifetime and that his name remains a household word.

As his letters make clear, Pasteur chose his path under the impulse of complex and mixed motives. Apart from the internal logic of his research, these motives included ambition for fame and imperial favor, his wish to serve his country and humanity, and his concern for financial security (more for the sake of his work and his family than for himself). In the highly competitive academic life of mid-nineteenth-century France, he was unabashedly ambitious and opportunistic. Not yet thirty, he consoled his rather neglected wife by telling her that he would “lead her to posterity.”³ Pasteur’s correspondence is filled with references to academic politics and with appeals for support from his influential friends–notably Biot and Dumas at the outset of his career, and later a number of important ministers and government officials, including Emperor Louis Napoleon and Empress Eugenie.

Pasteur sometimes complained bitterly of the neglect of science by the French state; but once his concern with practical problems became manifest, he had remarkable success in getting what he sought–a new laboratory, additional personnel, a larger research budget, a national pension for himself, even railroad passes for himself and his assistants. His support, although not spectacular in comparison with that provided to some scientists in German universities, was unusually generous by French governmental standards.

To supplement it, Pasteur competed actively for awards from private societies and foreign governments. Here too he enjoyed considerable success. For his work on racemic acid, for example, he received a prize of 1,500 francs from the Société de Pharmacie de Paris in 1853; and for his efforts to aid the silkworm industry, he was awarded 5,000 florins by the Austrian government. By far the most spectacular award for which Pasteur completed–in this case unsuccessfully –was a prize of 625,000 francs offered in 1887 by the government of New South Wales for practical measures to reduce the rabbit population. As unpublished correspondence makes clear,⁴ Pasteur sought this fortune partly for the sake of his family and partly to support the projected Institut Pasteur, toward the creation of which a widely publicized the highly successful drive had been launched. The fame of Pasteur’s treatment for rabies attracted donors throughout the world, and the value of their contributions surpassed 2 million francs by November 1888,⁵ when the Institut Pasteur was officially inaugurated. The French National Assembly had already voted him two national recompenses–one in 1874 with an annual value of 12,000 francs and another in 1883 that increased his life annuity to 25,000 francs and made it transferable upon his death to his wife and then to his children.⁶

Pasteur secured yet other revenues from patents or licenses for products and processes that resulted from his research. In 1861 he patented his method of making vinegar; and he later received patents or licenses for his methods of preserving wine and manufacturing beer, for a bacterial filter (the Chamberland-Pasteur filter), and for his vaccines against fowl cholera, anthrax, and swine crysipelas. No adequate account exists of the fate of these patents and licenses, but some were allowed to enter the public domain or were otherwise unexploited, while those for the filter and vaccines apparently yielded large revenues, most of which seem to have gone to the state or to the Institut Pasteur. Apparently at the urging of his wife and family, Pasteur accepted some unknown amount of the income from his patents. His will reveals only that the left his wife “all that the law allows.”⁷ Apparently Pasteur amassed no large personal fortune. Although exaggerated, his insistence that he worked solely for the love of science and country and the standard portrayal of him as a “savant desinteresse” carry more conviction than attempts to depict him as a scientific prostitute. Compared, for example, with Liebig, he was a model of commercial restraint.⁸

Pasteur displayed no comparable restraint in controversy. Combative and enormously self-assured, he could be devastating to the point of cruelty. He so offended, one opponent, an eighty-year-old surgeon, that the latter challenged him to a duel.⁹ Although often counseled to spend his energy more productively, Pasteur was constitutionally incapable of suffering criticism in silence. A few debates, notably on spontaneous generation, did stimulate valuable work and produce important clarifications, but most were barren. Sharing with many contemporary scientists a zealous concern for his intellectual property, he spent considerable time and effort to establish the priority of concepts and discoveries, particularly his process for preserving wines. Pasteur generally gave credit to others only grudgingly and mistrusted those who claimed to have reached similar views independently. He also shared a rather simpleminded and absolutist notion of scientific truth, rarely conceding the possibility of its being multifaceted and relieve. By appeal to public demonstrations–notably in the sensational vaccination experiments at Pouilly-le-Fort–and by frequent recourse to “judiciary” commissions of the Académie des Sciences, Pasteur almost invariably won public and quasi-official sanction for his views.¹⁰

Although in some ways unfortunate, Pasteur’s polemical inclinations and talents were a major factor in his success. Intuitively at least, he perceived that the essential measure of a scientist’s achievement is the degree to which he can persuade the scientific community of his views. By this measure, Pasteur was enormously successful, thanks in part to his tendency toward self-advertisement. The most obvious factor contributing to his success was his tremendous capacity for work; equally important was his ability to concentrate intensely on one problem for remarkably long periods. Other factors, especially obvious in his early work in crystallography, were his powerful visual imagination and highly developed aesthetic sense. Perhaps the most surprising factor invoked to explain Pasteur’s success was his myopia, which reportedly enhanced his close vision so that, in an object under the microscope or between his hands, he saw things hidden to those around him.¹¹

His father’s constant concern for his health suggests that Pasteur had never been robust, and excessive physical and mental exertion further undermined his constitution. On 19 October 1868, in the midst of silkworm studies, Pasteur suffered a cerebral hemorrhage that completely paralyzed his left side. Treated with leeches and later by electricity and mineral waters, he improved somewhat but retained a lifelong hemiplegia that impaired his speech and prevented his performing most experiments. He continued to design and direct experiments with his usual care and ingenuity, but their execution was often left to collaborators. For nearly twenty years Pasteur’s health remained fairly stable; but in the autumn of 1886 he began to experience cardiac deficiency and in October 1887 he suffered another stroke that further impaired his speech and mobility. His strength fading steadily, Pasteur was visibly feeble when he moved into the Institut Pasteur in 1889. In 1892 he expressed a brief enthusiasm for Charles Brown-Sequard’s controversial testicular injections, but in 1894 he suffered what was probably a third stroke.¹² At his death was almost completely paralyzed.

Virtually obsessed with science and its applications, Pasteur devoted little thought to political, philosophical, or religious matters. His beliefs in these areas were basically visceral or instinctive. His close association with the Second Empire reflects his political instincts. Despite a youthful flirtation with republicanism during the Revolution of 1848, Pasteur was essentially conservative, not to say reactionary. He considered strong leadership, firm law enforcement, and the maintenance of domestic order more important than civil liberty or even democracy, which he distrusted lest it lead to national mediocrity or vulgar tyranny. Yearning for the past glory of France, which he traced to Napoleon, he believed that Louis Napoleon might somehow restore it.¹³

From the coup d’état of 2 December 1851, by which Louis Napoleon dissolved the Constituent Assembly, Pasteur declared himself a “partisan” of the new leader.¹⁴ Partly through Dumas, whom Napoleon III named a senator, Pasteur developed personal relations with the imperial household, to which he sent copies of his works on fermentation and spontaneous generation. Especially after 1863, when Dumas presented him to Louis Napoleon, Pasteur openly sought to attract imperial interest to his research. He dedicated his book on wines (1866) to the emperor and his book on silkworm diseases (1870) to the empress, who had encouraged him during the difficult early stages of this work.¹⁵

Louis Napoleon’s deposition in 1870 nullified an imperial decree of 27 July 1870 by which Pasteur would have been awarded a national pension and made a senator. In 1868 the emperor had promoted Pasteur to commander of the Legion of Honor, and in 1865 had invited him to Compiegne, the most elegant imperial residence. During a week there Pasteur, in giddy letters to his wife, betrayed his awe of, and fascination with, imperial power, pomp, and wealth.¹⁶ No mere political opportunist, however, he continued to acknowledge his association with and indebtedness to the empress after the abdication—in the face of advice that it could be politically imprudent to do so.¹⁷

However firm Pasteur’s loyalty to the Second Empire, his general patriotism was even stronger. In 1871, despite tempting offers from Milan and Pisa, Pasteur remained in France, partly because of his wife’s unwillingness to expatriate but especially because he felt it would be an act of desertion to leave his country in the wake of its crushing defeat by Prussia.¹⁸ That defeat and the excesses of the Prussian army so aroused Pasteur that he vowed to inscribe all of his remaining works with the words. “Hatred toward Prussia. Revenge! Revenge!“¹⁹ Also in 1871 he returned in protest an honorary M.D. awarded in 1868 by the University of Bonn. In an exchange of letters with the dean of the faculty of medicine there, which he published asa brochure, Pasteur cried out in rage at the “barbarity” being visited upon his country by Prussia and its king. In another brochure of 1871, “Some Reflections on Science in France,” Pasteur emphasized the disparity between the state support of science in France and in Germany, and traced the defeat of France in the war to its excessive tolerance toward the “Prussian canker [chancre]“ and to its neglect of science during the preceding half-century.

During the war and, later, the Commune, Pasteur withdrew to the provinces and launched his studies on beer-his explicit object being to bring France into competition with the superior German breweries. In 1873, when he patented the process that resulted from these studies, Pasteur stipulated that beer made by his method should bear in France the name “Bieres de la revanche nationale” and abroad the name “Bieres francaises.”²⁰ Chauvinism undoubtedly played some part in his refusal to grant permission to translate his Études sur la biere into German and in his bitter and protracted controversy with Robert Koch in the 1880’s Even on the eve of his death, Pasteur’s memories of the war remained so strong that he declined the Prussian Ordre Pour le Merite.²¹

In 1875 Pasteur was asked by friends in Arbois to run for the Senate. Saying that he had no right to a political opinion because he had never studied politics, he nonetheless consented to run as a conservative. Presenting himself as the candidate of science and patriotism, he rehearsed his published explanations for the fall of France in the Franco-Prussian War and made his central political pledge “never [to] enter into any combinations the goal of which is to upset the established order of things.”²² Although Pasteur’s strong commitment to scientific professionalism probably struck some as elitist, the main issues against him were his conservatism, his links with the Second Empire, and his suspected Bonapartist loyalties. In response, Pasteur reported that the emperor had died owing him 4,000 francs and disclaimed any link with organized Bonapartist groups. He was soundly defeated, receiving only 62 votes, nearly 400 less than each of the two successful candidates (both republicans). Although asked at least twice during the 1880’s to run again for the Senate, Pasteur declined while his strength for scientific work remained. By then he referred to politics as ephemeral and sterile compared with science, a view that can only have been reinforced by his hostile reception on a visit to Arbois in 1888.²³ In 1892, no longer strong enough for research, Pasteur began soliciting support for a place in the Senate but eventually withdrew.²⁴

At the center of Pasteur’s public views on religion and philosophy lay his insistence on an absolute separation between matters of science and matters of faith or sentiment.²⁵ Although he was reared and died a Catholic, religious ritual and sectarian doctrine held little attraction for him. He cared as little for formal philosophy. By 1865 he had read only a few “absurd passages” in Comte, and he described his own philosophy as one “entirely of the heart.²⁶ Throughout his life he disdained materialists, atheists, freethinkers, and positivists. In 1882, in his inaugural address to the Académie Francaise, Pasteur found wanting the positivistic philosophy of Emile Littre, whom he was replacing. For Pasteur, the failures of positivism included its lack of real intellectual novelty, its confusion of the true experimental method with the “restricted method” of observation, and above all its disregard for “the most important of positive notions, that ofǀ the lnfinite,” one form of which is the idea of God. Pasteur never doubted the existence of the spiritualrealm or of the immortal soul. In that sense, and in his opposition to philosophical materialism, he was a spiritualist. Indeed, in his inaugural address he spoke of the service his research had rendered to the “spiritualistic doctrine, much neglected elsewhere, but certain at least to find a glorious refuge in your ranks.”²⁷

Pasteur’s chief contribution to the “spiritualist doctrine” was his campaign against spontaneous generation, the religiophilosophical consequences of which he emphasized in an address at the Sorbonne in 1864 while fervently denying that these broader issues had influenced his actual research. To the extent that any question was truly scientific, he argued, neither spiritualism nor any other philosophical school had a place in it. The “experimental method” alone could arbitrate scientific disputes. And while limited hypotheses played an essential role in the experimental method, speculation on the ultimate origin and end of things was beyond the realm of science. Despite this public posture, Pasteur sometimes speculated on the origin of life and attempted to create it experimentally, as he finally confessed in 1883.²⁸ And while the results of his work on fermentation, spontaneous generation, and disease may point toward a vitalistic rather than a mechanistic position, it would be misleading if not erroneous to label Pasteur a vitalist.

Pasteur was frank, stubborn, prodigiously self-confident, intensely serious—almost somber—and rather aloof toward those outside his select circle. Obsessed with his work, he brooked no interference with it. Sincerely kind to children, he could be insensitive and exploitative to others. His passion for tidiness and cleanliness approached the eccentrc, and fear of infection allegedly made him wary of shaking hands or of eating without first wiping the dinnerware and scrutinizing his food.²⁹ Pasteur tended to be highly secretive about the general direction of his current work, even with his most trusted assistants; and his insistence on absolute control of his laboratory reportedly extended even to the recording of experimental notes and the labeling of animal cages.³⁰

An innovative administrator and fastidious organizer, Pasteur showed a legendary devotion to detail. As director of scientific studies at the École Normale Supreriere, he proposed procedural and structural reforms, notably with regard to the agrégé-préparateurs (laboratory assistant who were graduates of the school); founded a journal, Annales scientifiques de ’École normale superieure; and raised the standards and reputation of the scientific section so that it began to challenge the École Polytechnique. On the other hand, Pasteur’s handling of student discipline betrayed an inflexible and rather authoritarian spirit. His relations with students were described as “hardly frequent” but “often disagreeable.”³¹ He dealt summarily, unsympathetically, and sometimes arbitrarily with student complaints about food and rules; and by 1863 he was openly appalled by what he considered student insubordination. In 1867 Pasteur was removed from his post as administrator and director of scientific studies precisely because of his rigid and unpopular stand against a student protest involving free speech and anti-imperial sentiment.³²

Pasteur was considered an excellent teacher, and his lectures were beautifully organized if not spellbinding. During the last two decades of his life, however, he taught only by precept and example in the laboratory and only those few who could simultaneously contribute to his own work and meet his exacting standards. He therefore trained very few students directly, but several of them—notably Emile Duclaux and Emile Roux—transmitted the spirit of his work to others who established and staffed the more than 100 medical institutes and scientific centers that now bear Pasteur’s name. Despite his tendency to be as demanding of others as he was of himself, Pasteur inspired tremendous loyalty. If any assistant-collaborator felt that his contributions were being unduly appropriated to Pasteur’s name, none ever expressed that feeling publicly.

In realizing most if not all of his ambitions, Pasteur became a national hero and “benefactor of humanity” to many while arousing the envy and hostility of others. A portion of the medical profession and of what he denigrated as the “so-called scientific press” vilified him as an intolerant representative of “official” science, an egomaniacal and greedy opportunist, and a would-be suppressor of dissident views. Some fervently denied that his work had brought the immense industrial, agricultural, or medical benefits claimed for it. In addition to debates over the safety and efficacy of Pasteur’s treatment for rabies, there were questions about the degree of success of his other vaccines, preservative processes, and remedies.³³ These questions deserve more detailed were generally so exaggerated and badly argued that they fail now, as then, to persuade others of the residue of truth they contain.

Early Life and Education . Until the late seventeenth century the Pasteurs were simple laborers or tenant farmers in the Franche-Comte, on the eastern border of France. Then, for two generations, Pasteur’s ancestors were millers at Lemuy, in service to the count of Udressier. About the middle of the eighteenth century his great-grandfather migrated to Salins-les-Bains, where he became a tanner and, by payment to and “special grace” of the count of Udressier, achieved independence for himself and his posterity. Pasteur’s grandfather, Jean-Henri Pasteur (1769–1796), moved to Besancon, where he too worked as a tanner. His only son, Jean-Joseph Pasteur, was Louis Pasteur’s father.

Born in 1791, Jean-Joseph Pasteur was drafted into the French army in 1811. As a member of the celebrated Third Ragiment of Napoleon’s army, he served with distinction in the Peninsular War during 1812–1813. By 1814, when he was discharged he had attained the rank of sergeant major and had been awarded the cross of the Legion of Honor. Upon his return to civilian life Jean-Joseph also became a tanner, initally at Besancon. In 1816 he married Jeanne-ètiennette Roqui daughter ofa gardener from a family of the Francehe-Comte. They moved to Dole, where the first four of their five children were born. Louis, their third child, was preceded by a son who died in infancy and by a daughter born in 1818; two daughters were born later. About 1826 the family moved to Marnoz, the native village of the roqui family and in 1827 to the neighboring town of Arbois, on the Curisance River, where a tannery had become available for lease. It was in Arbois, a town of about 8,000 inhabitants, that Louis grew up and to which he returned periodically.

From his parents Louis absorbed the traditional petit bourgeois values: familial loyalty, moral earnestness, respect for hard work, and concern for financial security. Jean-Joseph, who had received little education wished only that his son should join the faculty of a local Lycée. Louis who at one time apparently shared this goal gradually directed his vision toward the scientific elite in paris. Jean-Joseph’s modest ambitions for his son seem entirely in keeping with Louis’s early performance at school. In 1831, after two years in the associated École Primaire, Louis entered the Collège d’Arbois as a day pupil; he was for several years considered only a slightly better-than-average student. Until quite near the end of his secondary schooling nothing in his record presaged his later success and fame. Only his genuine, in immature, artistic talent seemed to promise anything exceptional. Several early portraits of friends, teachers, and acquaintances have been preserved; two sensitive character sketches of his parents reveal a talent quite beyond the ordinary.

If Louis ever seriously considered an artistic career, he was dissuaded by his pragmatic father and by Bousson de Mairet, a family friend and headmaster of the Collège d’Arbois until 1837. Under Bousson and his successor, Romanet, Louis’s scholarly enthusiasm was at last aroused; and he swept the school prizes during the academic year 1837–1838. Bousson and Romanet also awakened his ambition to prepare for the École Normale Superieure. Apparently with this end in view, it was arranged that he enter the preparatory school in Paris headed by M. Barbet, himself a Franc-Comtois. Louis arrived in Paris in October 1838; less than a month later, overwhelmed by homesickness, he returned to Arbois. His superb performance that year at the Collège d’Arbois inspired him to prepare again for the École Normale.

Because the Collège d’Arbois had no class in philosophy leading to the baccalaureate in letters, Louis was compelled to continue his studies elsewhere. On 29 August 1840 he received his bachelor’s degree in letters from the Collège Royal de Besancon. He received a mark of “good” in all subjects except elementary science, in which he received a “very good.” Consumed with the ambition of entering the science section of the École Normale, he had first to obtain a bachelor’s degree in science. His family’s financial burdens were eased by his appointment as “preparation master’ or tutor at the Collège Royal de Besancon. After two years in the class of special mathematics there, Pasteur received his baccalaureate in science on 13 August 1842, although in physics he was considered merely passable and in chemistry “mediocre”. two weeks later he was declared admissible to the École Normale, but he was dissatisfied with declined admittance. Having also considered a career as a civil engineer, pasteur took the entrance examination for the École Polytechnique in September but failed.³⁴ He decided to spend another year preparing emphasized the importance of study in paris; and in October 1842 he returned to Barbet’s boarding school.

Like all students at Barbet school pasteur attended the classes of the Lycée st. Louis but he also went to hear Jean-Baptiste Dumas, professor of chemistry at the sorbonne, whose fervent admirer he quickly became. At the end to the academic year 1842–4843, he took first prize in physics at the Lycée st. Louis sixth “accessit” in physics in the annual general competition, and admitted fourth on the list of candidates to the science section of the École Normale, which he entered in the autumn of 1843.

Until November 1848 pasteur studied and worked at the École Normale. Before he could join even a secondary school faculty, he had to pass the license examination and to compete in the annual agregation. In the license examination, which he took in 1845, Louis placed seventh. In September 1846 he placed third in the annual aggregation in the physical sciences. His appointment in October as preparateur in chemistry to Antoine Jerome Balard at the École Normale enabled pasteur to continue toward his doctorate, which he received in August 1847 with dissertations in both physics and chemistry. While awaiting an appropriate post, he continued to work as preparateur at the École Normale and launched those studies on optical activity which were to make his early reputation.

Optical Activity, Asymmetry, Crystal Structure. By the time he completed his dissertation in physics, pasteur’s interest in optical activity had emerged. Already attracted to crystallography by the lectures of Gabriel Delafosse, processor of mineralogy at the École Normale, he found his interest intensified by his association with Auguste Laurent, who worked in the same laboratory form late in 1846 until April 1847. In his dissertation pasteur also expressed indebtedness to Biot, whose Owen polarimeter pasteur had used and whose pioneering papers on the optical activity of organic liquids had served as a guide. Essentially a preliminary methodological study, pasture’s dissertation focused in the relation between isomorphism and optical activity. The results, based on two pairs of isomorphic substances, supported Laurent’s view that substances of the same crystalline form possess the same optical activity in solution. One of these isomorphic pains belonged to the tartrates, and pasteur’s other references to the tartrates and paratartrates suggest that he had already begun a systematic study of them.

Ordinary tartaric acid had been known since the eighteenth century. Prepared from salts of the tartar deposited as a by-product in wine vats, it had become especially important in medicine and in dyeing. Racemic or paratartaric acid had come to the attention of chemists only in the 1820’s when Gay-Lussac established that it possessed the same chemical composition as ordinary tartaric acid. Because of their importance for the emerging concept of isomerism, the two acids had thereafter attracted considerable notice. The studies of Biot and Eilhard Mitscherlich had established that aqueous solutions of tartaric acid and its derivatives rotated the plane of polarized light to the right, while aqueous solutions of racecmic acid and its derivatives exerted no effect on it. Indeed, in a brief note of 1844 Mitscherlich had claimed that in one case—the sodium-ammonium double salts—the tartrates and paratartrates were identical in every respect, including crystalline form and atomic arrangement, except for this difference in optical activity.

Pasteur later emphasized the seminal role of Mitscherlich’s note in his work. He had been deeply disturbed, he said, by the notion that “two substances could be as similar as claimed by Mitscherlich without being completely identical³⁵. Pasteur’s approach to the problem reflects his tutelage under Delafosse, who had made a special study of hemihedrism and naturally emphasized it in his lectures.³⁶ Through him pasteur learned of the earlier work of Hauy, Biot, and John Herschel on crystallized quartz. Hauy had shown that some quartz crystals are hemihedral to the left, while others are hemihedral to the right. Biot had shown that some quartz crystals rotate the plane of polarized light to the left, while others of the same thickness rotate it an equal amount to the right. Herschel in 1820 had established a causal connection between the asymmetrical crystalline forms and the direction of optical activity. Because quartz displays optical activity only in he crystallized state and loses it when dissolved, it had been recognized that only the quartz crystal as a whole, and not its constituent molecules, is asymmetrical. But Biot had also found a number of natural organic substances—oil of turpentine, camphor, sugar, tartaric acid—that were optically active in aqueous solutions or in the fluid state. As he emphasized, optical activity in such cases—unlike that of quartz-must depend on an asymmetry in the form of the constituent molecules.

Obviously prepared in part by the ideas of Delafosse and Laurent, Pasteur became convinced that the molecular asymmetry of optically active liquids ought to fine expression in an asymmetry or hemihedrism in their crystalline form. In May 1848—having published several related papers on isomorphism and dimorphism in various compounds—pasteur announced the discovery of small hemihedral facets on the crystals of all nineteen tartrate compounds he had studied. In all of them the hemihedral facts inclined in the same direction, and the direction of optical activity was the same. In the optically inactive paratartrates Pasteur expected to find perfectly symmetrical crystals. This expectation was confirmed with the notable exception of the sodium-ammonium paratartrate on which Mitschoerlich’s claims specifically rested. At first disappointed when he found hemihedrism in these crystals, Pasteur soon noticed that certain crystals inclined to the right, others to the left. Pasteur meticulously separated them by hand, dissolved them, and found that solutions of the right-handed crystals rotated the plane of polarized light in one direction while solutions of the left-handed crystals rotated it in the opposite direction to approximately the same degree. When equal weights of the two kinds of crystals were dissolved separately and then combined, the result was an optically inactive sodium-ammonium paratartrate.

Similar results were obtained with the acids from which the sodium-ammonium salts had been derived. Right-handed salts gave a right-handed acid identical to ordinary tartaric acid. Left-handed salts gave a hitherto unknown acid identical to tartaric acid except for the left-handed direction of both its hemihedrism and optical activity. Combinations of equal weights of the left-handed and right-handed acids yielded an acid identical to racemic or paratartaric acid. Pasteur now concluded that the optical inactivity of paratartaric acid (and hence of its derivatives) resulted from its being a combination of two optically active acids that were mirror images of each other, the separate optical activities of which, in opposite directions, compensated for or canceled each other.

These results, quickly confirmed by Biot and further developed by Pasteur in a series of papers between 1848 and 1850, bear striking testimony to the fertility of an admittedly a prior conception. Indeed, so powerful was Pasteur’s conviction that tartrates and other optically active substances must possess hemi-hedral facets that he was able not only to see subtle distinctions that had eluded earlier observers, but in a sense even to produce them by appropriate adjustments in the conditions of crystallization. The hemi-hedral forms of sodium-ammonium paratartrate appear only under quite special and delicate conditions, especially with regard to temperature, a circumstance that leads some to assign luck a rather large role in Pasteur’s first great discovery.³⁷ His decision to begin with the tartrates and paratartrates seems at least as fortunate, for in no other optically active compounds is the relationship between molecular asymmetry and crystalline structure so clear or straightforward; and Pasteur soon had to contend with several “exceptions” to his “law of hemihedral correlation”.

Meanwhile, his credentials having been established, Pasteur was appointed professeur suppleant in chemistry at the Faculty of Sciences in Strasbourg on 29 December 1848. On 29 May 1849 he married Marie Laurent, daughter of the rector of the Strasbourg Academy. Devoted to her husband and his career, tolerating his intense absorption in his work.³⁸ and often serving as his stenographer or secretary, she bore him three daughters who died before reaching maturity, a son,Jean-Basptiste(b. 1851), who became a diplomat and a fourth daughter, Marie-Louise (b.1858), who in 1879 married Rene Vallery-Radot, later Pasteur’s biographer.

At Strasbourg, Pasteur continued and greatly extended his work on optical activity and molecular asymmetry despite expanding teaching duties. During 1850 and 1851 he turned to asparagine and its derivatives (aspartic acid, malic acid, the aspartates and malates,) which were among the very few optically active compounds from which crystals could be obtained in sizes and amounts adequate for his investigations. Most of these compounds, too, display hemihedral facets as well as optical activity and, at least in this respect, fulfilled Pasteur’s expectations. Indeed, malic acid shares so many analogies with tartaric acid (with which it occurs naturally in the grape) that Pasteur was led to postulate a common atomic grouping for the two and to predict the existence of a hitherto unknown left-handed malic acid and of an optically inactive malic acid analogous to, and appearing naturally with, recemic acid. Several of the asparates and palates do not, however, conform to Pasteur’s conclusions concerning the tartrates and paratartrates. Certain compounds, for example, rotate the plane of polarized light in a direction contrary to the direction of their hemihedrism. A few display hemihedrism in the absence of optical activity, while others display optical activity in the absence of hemihedral crystals. Even in cases where the relationship between optical activity and crystalline form does seem to conform to Pasteur’s “law,“ the evidence is more ambiguous. Similar difficulties emerged when other groups of optically active compounds were investigated.

Some of these difficulties escaped Pasteur, who naturally sought confirmation and not refutation of his earlier conclusions. His response to those “exceptions” which he did recognize was sometimes brilliant, sometimes evasive, but always ingenious. For cases of hemihedrism in the absence of optical activity, he had a ready explanation derived from the case of quartz. Like quartz he argued, such substances must possess not true molecular asymmetry but merely a fortuitous asymmetry in the form of their crystal as a whole. More generally and more importantly, he suggested that minor aspects of the conditions of crystallization could mask the existence of a clear and consistent correlation between molecular and crystalline asymmetry; and he even managed in several cases to adjust the crystallizing medium and conditions so as to produce the “hidden” hemihedral facets he sought.³⁹ This bold achievement perhaps accounts for the confidence with which Pasteur announced as late as 1856 that the only legitimate exception to his law was one which he himself had discovered; amyl alcohol which shared with a few other compounds the property of being optically active in the absence of crystalline asymmetry but which also displayed in its mode of crystallization unique features that convinced Pasteur that any “hidden” asymmetry could never be revealed.⁴⁰

By 1860, as the number of apparent “exceptions” multiplied, Pasteur had subtly shifted the emphasis of his position so that optical activity became the primary index of molecular asymmetry, while crystalline form was relegated to a secondary although still important position.⁴¹ Never, it seems, did he fully and openly abandon his basic conviction that optical activity (and hence molecular asymmetry) must somehow find expression in crystalline form.⁴²

In speculating on the kind of atomic arrangements that could produce molecular asymmetry, pasteur suggested tentatively in 1860 that the atoms of a right-handed compound, for example, might be “arranged in the form of a irregular tetrahedron,”⁴³ But he never developed these suggestions, and it was left to others-notably Le Bel and van’t Hoff in 1874—to link his work with KeKule’s theory of the tetrahedral carbon atom. From this linkage emerged the concept of the asymmetrical carbon atom, which underlies all subsequent development in stereochemistry. Besides adding precision and clarity to pasteur’s earlier investigations of molecular asymmetry, these developments in stereochemistry raised further doubts about the validity of some of his principles.

Asymmetry and Life . In the meantime, Pasteur’s preconceptions had opened a fertile new territory to him. But scarcely had he entered it when he committed himself firmly and permanently to another guiding idea—that optical activity was somehow intimately associated with life and could not be produced artificially by ordinary chemical procedures. The precise origin and basis of this idea are the subject of some controversy;⁴⁴ but pasteur’s commitment to it seems undeniable by 1852, and he may have held it implicitly from the outset of his career. Even then, evidence existed (especially from the work of Biot and Laurent) that optical activity was generally present in organic products and uniformly absent from inorganic substances. In any case, Pasteur’s conviction of an association between molecular and crystalline asymmetry.

Quite probably because of this conviction, pasteur reacted dramatically to the work of Victor Dessaignes, who announced in 1850 that he had prepared aspartic acid by heating optically inactive starting materials (maleic and fumaric acids). Since the only known aspartic acid was optically active, Dessaignes’s discovery seemed to constitute the artificial creation of optical activity. Upon hearing of this work, pasteur went immediately to Dessaignes’s laboratory in Vendome to obtain samples of the new acid. As he expected, it proved to be a hitherto unknown inactive aspartic acid, as did the malic acid prepared from it. The possibility remained, however, that these newly discovered inactive acids were “racemic“ that is, that they owed their optical inactivity to a compensation between left-handed and right-handed forms. Initially, in a memoir of 1852, pasteur rejected this possibility on the ground that such “racemic” acids could be synthesized only from “racemic” starting materials, while the available evidence suggested that neither the maleic nor the fumaric acid with which Dessaignes had begun could possess such a constitution.

Having rejected this explanation for the inactivity of Dessaignes’s aspartic and malic acids, pasteur boldly suggested that they belonged to an entirely new class of compounds—those the original asymmetry of which had been “untwised” so that they had become inactive by total absence of any asymmetry, “inactive by nature” rather than “inactive by compensation.” The existence of such compounds (subsequently designated by the prefix “meso“) was quickly confirmed by pasteur’s preparation of “mesortartaric” acid, a compound he predicted on the basis of his belief that all forms of malic acid should have counterpart forms of tartaric acid. His hypothetica; “mesomalic” acid has never been found, however, and it now seems certain that Dessaignes’s synthetic malic acid was in fact “racemic” or “inactive by compensation.” That pasteur did not recognize it as such has led to the assumption that he operated under the sway of preconceived ideas—an assumption that gains immense force from pasteur’s remark of 1860 that if Dessaignes’s malic acid were inactive by compensation between left-handed and right-handed forms, he would have performed the remarkable feat of producing not just one but two optically active substances from inactive starting materials.⁴⁵

A similar interpretation can be given to Pasteur’s trip of October 1852 through the tartaric acid factories of Germany and Austria. His explicit aim was to find the origin of and new sources for paratartaric or racemic acid, which had become scarce and which resisted attempts to produce it in the laboratory. For these reasons the Société de pharmacies in 1851 had established a prize of 1,500 francs for the resolution of two questions; Does racemic acid preexist in certain tartrates? How can racemic acid be produced from tartaric acid?

Another chemist might have sought the answers solely within the laboratory, but pasteur’s conviction that asymmetry could not be produced chemically suggested another approach. Since racemic acid is a combination of right- and left- handed tartaric acids, its production from ordinary (right-handed) tartaric acid implied the transformation of a portion of right-handed tartaric acid into its left-handed form. By 1852 pasteur had become convinced that such a transformation was chemically impossible and that racemic acid might best be sought by tracing it to its natural origin. He therefore visited the tartaric acid factories where racemic acid had once appeared or was now believed to appear, in order to compare the sources and natures of the tartars they used as well as their modes of manufacture. A survey of factories in Saxony, Vienna, and Prague revealed a correlation between the appearance of racemic acid and the use of crude that racemic acid preexisted naturally to varying degrees in crude tartars and resulted not from some accidentally discovered industrial procedure. Since most manufacturers used semirefined rather than crude tartars, Pasteur asked one of them to switch back to crude Italin tartars, with the expected result that racemic acid soon reappeared in the factory. In addition he persuaded two manufactures to seek racemic acid by treating the mother liquids left from the initial purification of their semirefined tartars, and this effort too had rapid success.

During this journey Pasteur met a German industrial chemist who claimed to have achieved what Pasteur then considered impossible—the chemical transformation of tartaric into racemic acid. Although he soon confirmed his belief that this particular claim was inaccurate, Pasteur unexpectedly achieved the transformation in May 1853 by heating cinchonine tartrate at 170°C. for five to six hours. This procedure also yielded a small amount of inactive “mesotartaric” acid, the existence of which Pasteur had predicted the year before and in search of which he had apparently undertaken the experiment. In the memoir (1 August 1853) in which he announced these two discoveries, Pasteur disclosed a new method for separating racemic acid into its left- and right- handed components. His original method, involving the manual separation of the crystals, was laborious and extremely limited in applicability. The central feature of the new method was the chemical combination of racemic acid with optically active bases. Under appropriate conditions they affected the solubility of the resulting paratartrates in such a way as to favor the crystallization of only one of the two forms that together compose the paratartrate. Although introduced by Pasteur only for the case of racemic acid, this new method clearly had wider applicability and was soon used to separate the left- and right- handed components in other “racemic” substances (substances inactive by compensation)

In November 1852, immediately after his foreign tour, Pasteur was promoted to professeur titulaire at Strasbourg. For his work on racemic acid and crystallography he received the prize of 1,500 francs from the Société de pharmacie (1853), membership in the Legion of Honor, and the Rumford Medal of the Royal Society (1856). In December 1857, having moved to Lille and become deeply involved in the study of fermentation, Pasteur announced in preliminary fashion the discovery of a third method for separating racemic acid. If the first method is considered as manual and the second as chemical, then the new method was biological or physiological. In essence, it depended on the capacity of certain microorganisms to “discriminate” between left-and righthanded forms and selectivly to metabolize one or the other.

The particular example that Pasteur described grew out of his study of the fermentation of ammonium paratartrate. Following this fermentation with a polarimeter, he found that the fermenting fluid displayed increasing optical activity to the left. Eventully, the fluid yielded form originally present in the paratartrate had been selectivly attacked during the fermentation, while the left-handed form had been left alone. Pasteur linked this discriminatory action with the nutritional needs of a living microorganism presumed to be responsible for the fermentation. Initially vague about its nature, he showed in 1860 that a specific mold, penicillium glaucum, selectively metabolized the right-handed form in a solution of ammonium paratartrate containing a little phosphate. Later qualified, modified, and generalized by others, Pasteur’s new method become applicable to the separation of leftand right-handed forms in a number of compounds. Another method of wide applicability was discovered in 1868 by Desire Gernez, one of Pasteur’s assistants. He showed that a single crystal of either the left-or the right-handed form, when sown into a supersaturated solution of a paratartrate, induced the selective crystallization of the form sown.

Pasteur retained a lifelong conviction that asymmetry and life are intimately associated. To do so, however, he had to refine, qualify, and even deny some aspects of his original position, especially in the face of accumulating evidence that racemic acid and other racemic substances could be produced from optically inactive compounds by ordinary chemical procedures. Ultimately Pasteur merely insisted that the artificial production of racemic substances should in no way be compared with the production of a single active substance unaccompanied by its inverse form. Ascribing the latter faculty to nature alone, he perceived in it the last barrier between organic and inorganic phenomena.⁴⁶

If this mode of thought seems to stamp Pasteur as a vitalist, a slightly different perspective can make him seem a mechanist, for he spoke not of “vital forces“ but of “asymmetrical forces.” While emphasizing that these asymmetrical forces were not deployed in ordinary chemical procedures, he nonetheless connected them with, and sought them among, physical forces at work in the cosmos. In particular, he suggested that the earth is asymmetrical, in the sense that when it turns on its axis, its mirror image rotates in a different direction. And if an ether moving with the rotating earth presides over electrical and magnetic phenomena, the latter must be considered asymmetrical in the same sense. Solar light, too, presents an asymmetrical aspect, for it strikes the earth (and its organisms) at an angle which would be inverted in a mirror. Somehow, Pasteur believed, these or other asymmetrical forces must generate asymmetry (and thus life) in matter.

Not content merely to harbor such boldly speculative ideas, Pasteur sought experimental evidence for them. As early as 1853, while still at Strasbourg, he tried to bring asymmetrical forces to bear upon crystallization by means of powerful magnets built to his specifications. At Lille he tried to modify the normal character of optically active substances by using a large clockwork mechanism to rotate a plant continuously in alternate directions and by using a reflector-and-heliostat arrangement to reverse the natural movement of solar rays directed on a plant from its moment of germination. Biot and others discouraged such experiments as a waste of physical and mental resources, and Pasteur admitted that he must have been a “little mad” to undertake them.⁴⁷ Nonethless, despite his lack of success, Pasteur never abandoned hope that life might someday be created, or at least profoundly modified, in the laboratory under the influence of such asymmetric forces. It seems a remarkable paradox that he could retain this hope while attacking all attempts by others to achieve spontaneous generation.⁴⁸ In any case, all subsequent research has supported Pasteur’s convictions that optical activity and life are somehow intimately associated and that the production of a single active substance unaccompanied by its mirror image is indeed nature’s prerogative except under highly exceptional and basically “asymmetrical” conditions.

Fermentation: The Background . In December 1854 Pasteur was named professor of chemistry and dean of the newly established Faculty of Sciences at Lille. Located at the center of the most flourishing industrial region in France, it was designed in part to bring science to the service of local industry. While resisting any emphasis on applied subjects at the expense of basic science, Pasteur strongly supported this goal and sought to link industry and the Faculty of Sciences in his own courses and activities. For instance, he taught the principles and techniques of bleaching, of extracting and refining sugar, and especially of fermentation and the manufacture of beetroot alcohol, an important local industry. During 1856, he went regularly to the beetroot alcohol factory of M. Bigo, seeking the cause of and remedies for recent disappointments in the quality of that product. For this reason especially, Pasteur’s interest in fermentation has often been traced to the brewing industry in Lille.

Pasteur, however, traced his interest to 1849, when Biot informed him that amyl alcohol displayed optical activity.⁴⁹ For a brief period during that year, he apparently tried to study the compound, but the problem of securing pure amyl alcohol in adequate quantities led him to abandon the topic. His transfer to Lille may well have reactivated his intention to continue these studies, for amyl alcohol was readily available as a by-product of several industrial fermentations. By August 1855 Pasteur had published a paper showing that the crude amyl alcohol found in industrial fermentations was composed of two isomeric forms, one optically active and the other optically inactive. A careful study of the two forms and their derivatives convinced him by June 1856 that he had found the first legitimate exception to his “law of hemihedral correlation.”His determination to investigate this exception thoroughly probably helped to direct his attention to fermentations.

Once attracted to the study of fermentation, Pasteur naturally pondered the source of asymmetry in its optically active products, notably amyl alcohol. The prevailing view traced the optical activity of amyl alcohol to the sugar (also optically active) that served as the starting material in fermentations. Pasteur, however, believed that the molecular structure of amyl alcohol differed too greatly from that of sugar for its optical activity to originate there. His tendency to associate asymmetry and optical activity with life may then have brought him to the view that fermentation depends on the activity of living microorganisms. In taking this view Pasteur defied the dominant chemical theory of fermentation, but his basic position was by no means novel or obscure. Since 1837 several observers—notably Charles Cagniard de Latour and Theodor Schwann—had insisted that alcoholic fermentation depended on the vital activity of brewer’s yeast. This view had been ridiculed and eventually overwheimed by Liebig and Berzelius, who insisted that the process was chemical rather than vital or biological. Their position drew impressive support from indisputably chemical processes considered analogous to fermentation—most notably the action of the soluble digestive “ferments” (enzymes) diastase and pepsin. But the alternative biological theory had also been founded and developed on the basis of persuasive evidence that must have given Pasteur enormous comfort when he launched his campaign against the chemical theory.

Lactic Fermentation. The opening salvo in that campaign was a short memoir on lactic fermentation, presented in August 1857 to the Society of the Sciences, Agriculture, and the Arts in Lille. Emile Duclaux has suggested that two factors induced Pasteur to focus first on the relatively unimportant lactic fermentation (most familiar as the process producing sour milk) rather than alcoholic fermentation: (1) a large quantity of amyl alcohol is produced during lactic fermentation and (2) alcoholic fermentation had already been thoroughly investigated without seriously threatening the dominant chemical theory. In a sense, unless and until living organisms were implicated in other fermentations, advocates of the chemical theory could continue to doubt the essential role of living yeast in alcoholic fermentation.⁵⁰

Pasteur’s memoir expressed the basic approach and point of view which informed all of his subsequent work on fermentation. After a historical introduction he began by claiming that “just as an alcoholic ferment exists–namely, brewer’s yeast–which is found wherever sugar breaks down into alcohol and carbonic acid–so too there is a special ferment–a lactic yeast–always present when sugar becomes lactic acid.” In an ordinary lactic fermentation, this “lactic yeast” appeared as a gray deposit the central role of which could be demonstrated by isolating and purifying it. To do this Pasteur took the soluble extract from brewer’s yeast, added to it some sugar and some chalk, and then sprinkled in a trace of the gray deposit from an ordinary lactic fermentation. In this way he invariably produced a lively and indisputably lactic fermentation, with the gray deposit increasing in amount as the fermentation progressed. Viewed macroscopically, this deposit resembled ordinary pressed or drained brewer’s yeast. Under the microscope it seemed to be composed of “litle globules or very short segmented filaments, isolated or in clusters, which form irregular flakes resembling those of certain amorphous precipitates.” An extremely small amount of the deposit sufficed to decompose a large amount of sugar. Although smaller and harder to see than brewer’s yeast, the lactic ferment seemed to Pasteur so analogous to it that he supposed the two “yeasts” might belong to closely related species or families.

Throughout the memoir Pasteur more nearly assumed than proved that lactic yeast “is a living organism,…that its chemical action on sugar corresponds to its development and organization,” and that the nitrogenous substances in the fermenting medium served merely as its food. Nonetheless, his convictions were firm and his conception of fermentation was already remarkably complete. Nothing demonstrates this more forcefully than his discussion of the conditions essential for good fermentations, which include not only a pure and homogeneous ferment but also an appropriate nutrient medium, well adapted to the “individual nature” of the ferment. “In this respect,” he wrote, “it is important to realize that the circumstances of neutrality, alkalinity, acidity, or chemical composition of the liquids play a great part in the predominant growth of…a ferment, for the life of each does not adapt itself to the same degree to different states of the environment.” Acidity, for example, favors the development of the alcoholic over the lactic fermentation, while in neutral or slightly alkaline media the situation is reversed. Furthermore, the purity of the fermentation is greatly enhanced by protecting it from air and by the method of sowing pure ferments, for both prevent the invasion of “foreign vegetation or infusoria.” An unsown fermentable medium, like an unseeded plot of land, “soon becomes crowded with various plants and insects that are mutually harmful.” Pasteur even referred to the capacity of “the essential oil of onion” to inhibit the development of both brewer’s yeast and infusoria without affecting the growth of the lactic ferment–a remark to which some have traced the concept of antibiotics.

With two striking exceptions this memoir contains the central theoretical and methodological features of all of Pasteur’s work on fermentation–the biological conception of fermentation as the result of the activity of living microorganisms; the view that the substances in the fermenting medium serve as food for the causative microorganism and must therefore be appropriate to its nutritional requirements; the notion of specificity, according to which each fermentation can be traced to a specific microorganism; the recognition that particular chemical features of the medium can promote or impede the development of any one microorganism in it; the notion of competition among different microorganisms for the aliments contained in the media; the assumption that air might be the source of the microorganisms that appear in fermentations; and the technique of directly and actively sowing the microorganism presumed responsible for a given fermentation in order to isolate and purify it. The two missing features, which soon completed Pasteur’s basic conception, were the technique of cultivating microorganisms (and thereby producing fermentations) in a medium free of organic nitrogen and his notion of fermentation as “life without air.”

In October 1857, two months after presenting his memoir on the lactic fermentation, Pasteur left Lille for the École Normale in Paris, where he had been named director of scientific studies and administrator, his duties including “the surveillance of the economic and hygienic management, the care of general discipline, intercourse with the families of the pupils and the literary or scientific establishments frequented by them.”⁵¹ Because these positions included neither laboratory nor allowance for research expenses, Pasteur was obliged to make frequent appeals to governmental agencies for financial support. Although he considered such appeals “antipathetic to the character of a scientist worthy of the name,”⁵² he made them with sufficient success to secure his own research laboratory, which consisted at first of two rooms in an attic of the École Normale. By December 1859 he had gained possession of a small pavilion, which was expanded considerably in 1862. In these surroundings Pasteur pursued his study of fermentation and quickly extended his basic conclusions on lactic fermentation to various others, notably the tartaric, butyric, and acetic as well as alcoholic.

Alcoholic Fermentation. In December 1857 Pasteur published the first in a series of abstracts, notes, and letters on alcoholic fermentation that culminated in a long and classic memoir of 1860. Divided into two major sections, dealing respectively with the fate of sugar and of yeast in alcoholic fermentation, it inflicted on the chemical theory what Duclaux called “a series of blows straight from the shoulder, delivered with agility and assurance.”⁵³ Pasteur established that alcoholic fermentation invariably produces not only carbonic acid and ethyl alcohol–as was well known–but also appreciable quantities of glycerin and succine acid as well as trace amounts of cellulose, “fatty matters,” and “indeterminate products.” On the basis of these results, Pasteur emphasized the complexity of alcoholic fermentation and attacked the tendency of chemists since Lavoisier to depict it as the simple conversion of sugar into carbonic acid and alcohol. If the alleged simplicity of the process had formerly been seen as evidence of its chemical nature, he argued, then its actual complexity ought now to be seen as evidence of its dependence on the activity of a living organism. In truth, the complexity of alcoholic fermentation was such as to prevent the writing of a complete equation for it, a fact which was only to be expected, since chemistry was “too little advanced to hope to put into a rigorous equation a chemical act correlative with a vital phenomenon.”

However impressive this line of attack against the chemical theory, an even more decisive mode of argument derived from Pasteur’s ability to produce yeast and alcoholic fermentation in a medium free of organic nitrogen. To a pure solution of cane sugar he added only an ammonium salt and the minerals obtained by incineration of yeast, then sprinkled in a trace of pure brewer’s yeast. Although the experiment was difficult and not always successful, this method could produce an alcoholic fermentation accompanied by growth and reproduction in the yeast and the evolution of all the usual products. If any one constituent of this medium were eliminated, no alcoholic fermentation took place. Obviously, argued Pasteur, the yeast must grow and develop in this mineral medium by assimilating its nitrogen from the ammonium salt, its mineral constituents from the yeast ash, and its carbon from the sugar. In fact, it is precisely the capacity of yeast to assimilate combined carbon from sugar that explains why it can decompose sugar into carbonic acid and alcohol. Above all, there is in this medium none of the “unstable organic matter” required by Liebig’s theory.

When this memoir on alcoholic fermentation appeared, Pasteur had already begun to exploit more widely his new method of cultivating microorganisms in a medium free of organic nitrogen. Described initially in a note of December 1858, this method had been applied to the lactic ferment by February 1859. Indeed, “Pasteur’s fluid“–a solution of sugar, yeast ash, and ammonium salt–proved far more conducive to the growth of the lactic ferment than to that of brewer’s yeast. Sometimes, the lactic fermentation appeared “spontaneously” in this medium, even when only brewer’s yeast had been sown. From similar events in ordinary crude alcoholic fermentations, some chemists had concluded that lactic acid was a normal by-product of alcoholic fermentation. Pasteur showed, however, that the appearance of lactic acid in such cases could be associated with an accidental contamination of the fermenting medium by the lactic ferment. To ensure the uncontaminated growth of the lactic ferment itself, it was necessary only to add calcium carbonate to the solution of sugar, yeast ash, and ammonium salt.

Fermentation and Putrefaction as “Life Without Air.” In November 1860 Pasteur described the successful cultivation of Penicillium “or any mucedinous fungus” in a medium of pure water, cane sugar, phosphates, and an acid ammonium salt. By February 1861 he had isolated a specific butyric ferment and had produced butyric fermentation in a similar medium. In two respects this new butyric ferment greatly suprised him: (1) unlike brewer’s yeast and the lactic ferment, it was motile and thus, presumably, a member of the animal kingdom; and (2) while examining microscopically the liquid from a butyric fermentation, he noticed that the rodlike “infusoria” lost their motility and vitality at the margins of the slide glass but remained active in the center. Assuming that this phenomenon depended on the presence of atmospheric air at the margins of the slide glass, Pasteur passed a current of ordinary air through a butyric fermentation. Within an hour or two the butyric fermentation had ceased and all the motile rods had been killed. Carbonic acid gas, on the other hand, exerted no appreciable effect on their life and reproduction. Pasteur concluded that the butyric ferment is an infusorium and that this infusorium lives without free oxygen gas. This was, he believed, the first known example of an animal ferment and of an animal capable of living without free oxygen.

From the beginning naturalists challenged Pasteur’s belief that the butyric ferment was an animal, because for many of them motility had ceased to be an automatic index of animality. More specifically, the genus Vibrionia, to which Pasteur assigned his new ferment, had been identified as vegetable in 1854 by Ferdinand Cohn, who had linked it with the algae and bacteria. Not surprisingly, then, an English translator immediately suggested that Pasteur’s supposed butyric “infusorium” probably belonged instead among the algae.⁵⁴ Cohn later placed it among the bacteria (Bacillus subtilis).⁵⁵ Although Pasteur quickly qualified his assertion of the animality of the new ferment, he demonstrated little concern about the taxonomic issue and little serious interest in the literature of the naturalists, whom he seemed sometimes to despise. This attitude and Pasteur’s inadequacies as a naturalist led to some confusion about and hostility toward his work–and by no means solely in the case of the butyric ferment. In later years Pasteur became some-what more sensitive to taxonomic issues and emphasized the importance of physiological characters as a taxonomic criterion; but his generally casual attitude toward microbial morphology and nomenclature helped to exacerbate some of the debates over spontaneous generation, the transformation of microbial species, and the germ theory of disease. Cohn and Koch, among others, chastised Pasteur severely for his lack of rigor in these areas.

Pasteur’s discovery of the butyric ferment and of its death in air gave a new direction to his studies on fermentation. He quickly investigated the effect of free oxygen on other ferments and moved gradually toward a new definition of fermentation as “life without air.” In June 1861 he reported that the activity of brewer’s yeast depended fundamentally on the degree of free oxygen available to it. Like ordinary fungi or infusoria, it grew and reproduced with great vigor in the presence of air. As a ferment, however, it was virtually powerless under such circumstances; only in the absence of free oxygen did it display a significant capacity to ferment sugar. For Pasteur the explanation was obvious: when deprived of free oxygen, the yeast of necessity attacked the sugar in order to extract its combined oxygen.

In March 1863 Pasteur announced that calcium tartrate fermented in a medium free of organic nitrogen by the action of a motile infusorium analogous to the butyric ferment. Like the butyric, the new ferment lived only in the absence of air and belonged to the genus Vibrionia, although its external form differed greatly from the butyric ferment. In a medium exposed to the air, the new ferment developed only when protected by organisms that consumed free oxygen at the surface of the medium, while the ferment lived and developed at lower, oxygen-free levels. Fermentation, Pasteur now suggested, is merely “nutrition without the consumption of free oxygen gas.” In this conception, he believed, lay the key to “the secret and mysterious character of all true fermentations and, possibly, that of many normal and abnormal actions in the organization of living things.”

Among these “normal and abnormal actions” was putrefaction, generally defined as the decomposition of vegetable or animal matter with the evolution of fetid gases. In April and June 1863, on the basis of rather sketchy evidence, Pasteur extended to the phenomena of putrefaction the central conclusions of his work on fermentation. Like fermentation, he insisted, putrefaction can be traced to the vital activity of living ferments. Indeed, except for the action of microorganisms, the constituents of dead plants and animals could be considered “relatively indestructible.” To express the matter in more poetic terms, “life takes part in the work of death in all its phases,” for the decomposition associated with death depends on the development and multiplication of microorganisms. Moreover, death is as essential to the cycle of life as life is to the phenomena of death. For it is only as a consequence of death and putrefaction that carbon, nitrogen, and oxygen become available as nutrients to support the life of other organisms. Thus, in an eternal cycle, life stems from death and death from life.

Within this cosmic perspective, reformulated and reemphasized on other occasions, Pasteur developed a more prosaic analysis of the nature and action of the microorganisms involved in the decomposition of dead substances. These organisms are of two kinds: (1) the oxidative microorganisms–the mycodermas and their relatives–which in the course of their vital activity transfer atmospheric oxygen to the dead organic substances and thereby enormously increase the rate of combustion and (2) the putrefactive ferments perse, which (like the butyric ferment) belong to the genus Vibrionia and live only in the absence of air. Putrefaction and fermentation are, therefore, analogous processes, for both involve the decomposition of substatances by organisms living in the absence of air. In fact, putrefaction is merely the fermentation of substances containing a relatively high proportion of sulfur, and the release of this sulfur in gaseous form produces the fetid odors commonly associated with putrefaction.

In other words, Pasteur emphasized, a putrescible liquid exposed to atmospheric air experiences two distinct sorts of chemical decomposition correlative with the life and development of two distinct sorts of microscopic organisms. On the one hand the anaerobes—purtrefactive ferments living below the surface, in the absence of air—determine “acts of fermentatiaon They transform nitrogenous materials into simpler but still complex substances. On the other hand the aerobes” oxodative microorganisms living at the surface, in the presence of air—can assimilate these intermediate products and transform them into the “simplest binary combinations” —water, ammonia, and carbonic acid. Bulloch has traced the concept of anaerobism or “life without air” to Leeuwenhoek and Spallanzani.⁵⁶ Their work in this regard having been completely forgotten, however, pastuer has alwasys been recognized as the architect of the idea.

Studies on Acetic Fermentation and Vinegar. By the time he publihsed his papers on putrefaction, Pasteur was deeply involved in the study of acetic fermentation and the manufacture of vinegar. Beginning in July, 1861 he proudced a series of papers on acetic fermentation that linked theory with industrial practice and culminated in a long memoir (1864) and in Études sur le vinaigre (1868) When he began this work, acetic fermentation was widely viewed as a chemical, catalytic process, comparable with the wellknown oxidation of alcohol to aldehyde and acetic acid in the presence of finely divided platinum. This conception seemded in accord with the German method of manufacturing vinegar, in which the fermenting medium consisted of a dilute alcohol solution, a trace of acetic acid, and some “unstable organic matter” such as sharp wine or acid beer. When this liquid trickled through a hollow column of wine casks containing loosely piled beechwood shavings, the alcohol was oxidized to acetic acid with the release of heat and the production of an upward current of air that constantly renewed the supply of oxygen. As Liebig interpreted this method, the “unstable organic matter” initiated fermentation and the beechwood shavings facilitated the oxidation process while remaining un altered (that is, they acted as a catalyst). In all of this there was no hint of biological action.

Pasteur approached acetic fermentation fully confident that he would find in this case, too, that a microorganism was esential to the process. The relative ease with which he succeeded can be partly ascribed to the character of the French method of vinegar production, for which the leading center was Orleans. This method differed markedly from the German method. In Orleans vinegar was produced by the slow oxidation of wine in covered casks stacked on end about one-third empty and exposed to the air by an opening or window” above the surface of the fermenting liquid. On the surface of the liquid, which consisted of a mixture of finihsed vinegar and new wine, there appeared a delicate pelliche—long known as “mother of vinegar”— the presence of which was recognized as essential to the process. From his earlier studies of fermentation, Pasteur knew that such pellicles could be formed by microorganisms. Moreover, several observes had already suggested that the “mother of vinegar” consisted of living organism. In 1822 persoon had named it “mycoderma” precisely to suggest that it was a fungal skin. And in 1837 Friedrich Kutzing had drawn a connection between the life of this skin and the production of vinegar—as indeed, in the same year he had also connected the life of yeast with the production of alcohol in ordinary alcoholic fermentation. As in alcoholic fermentation, pasteur could draw inspiration from a tradition that viewed fermentation as a vital process. His task was to present this case so persuasively as to override the dominant authority and agruments of Liebig.

To do so, Pasteur resorted again to media free of organic nitrogen. By July 1862 he had succeeded in cultivating Mycoderma aceti in a medium of dilute alcohol, ammonia, and mineral salts. When sown into such a medium, Mycoderma aceti consistently produced acetic acide; and Pasteur again emphasized the ability of a microorganism to yeild fermentation in the absence of the “unstable organic matter” required by Liebig’s theory. Moreover, he was able to detect a thin film of Mycoderma aceti on the beechwood shavings so important in the German method of vinegar production. Protected from or deprived of the Mycoderma, the shavings lost their capacity to produce acetic acid. Their only role, Pasteur insisted was to provide a site for the growth and development of Mycoderma aceti. In his view Mycoderma aceti acted by transmitting the “combustive action” of atmospheric oxygen to alcohol and thus oxidizing it to acetic acid. If no alcohol remained in the fermenting medium, the Mycoderma could attack the acetic acid it had produced and compelte the oxidation to water and carbonic acid. Mycoderma aceti also ceased to produce acetic acid if submerged; only at the surface of the fermenting medium, in the presence of abundant Oxygen, did it support acetic fermentation. Although this latter fact posed an obvious difficulty for his concept of fermentation as “life without air,” Pasteur made no attempt to resolve the issue at the time.

From the beginning of his research on acetic fermentation, Pasteur recongized its industrial significance; and in July 1861 he took out a patent “for the manufacture of vinegar or acetic acid by means of molds in particular Mycoderma vini and Mycoderma aceti⁵⁷ To a considerable extent Pasteur’s interpretation of acetic fermentation merely provided a rationale for industrial practices that had already been introduced empirically, although it did allow somewhat greater confidence in and control over them. Perhaps the most important advantage that Pasteur ascribed to his method of manufacturing vinegar was that it permitted the process to be directed at will. No longer was it necessary to await the “spontaneous” appearance of the mycodermic pellicle, which sometimes took several weeks. Manufacturers could now produce acetification quickly and reliably by direct sowing of Mycoderma aceti. Moreover, he claimed his method produced acetic acid three to five times as rapidly as the OrlÉans method and greatly reduced the losses by evaporation experienced in the German method. By 1868, when he publihsed his Études sur le vinaigre, Pasteur could appeal by analogy to his recent studies on the “diseases” of wine in order to discuss the diseases of vinegar, all of which (like the disease of wine) could be prevented by heating finished vinegar to about 55°C.

Studies on Wine. In December 1863 Pasteur published the first of the papers that culminated in his Études sur le vin (1866; 2nd ed. 1873). In that first paper, dealing with the role of atmospheric oxygen in vinification, he sought to establish that the aging of wine resulted from the slow penetration of atmospheric oxygen through the porous wook casks into which new wine was decanted. By virtue of this slow oxidation, he claimed, new wine grows less harsh and acid to the taste as it becomes clearer and lighter from the to the taste as it becomes clearer and lighter from the precipation of dark coloring matters. In his second paper (January 1864) Pasteur examined the “alterations” or “diseases of wine, especially wine from the Jura, his native department. Reviewing the familiar disease of “turned,” “acid” “ropy” or “oily “ wine, he associated each with a microscopic organism. He summarized the results of his first two papers by nothing that “wine, which is proudced by a cellular vegetation acting as a ferment [namely, yeast], is altered only by the influence of other vegetations of the same order; and once removed from the effects of their parasitism, it is made or matured principally by the action of atmospheric oxygen penetrating slowly through the staves of the casks.”

Since the diseases of wine are due to the development of foreign orgnaisms, which are present before the wine becomes sensibly “sick” and the germs of which are bottled with the wine, the crucial task was to find a way of killing these germs without damaging the taste or other qualities of wine. On 1 May 1865 Pasteur told the Académie des Sciences that his attempts to cure diseased wines with chemical antiseptics had been less than satisfying, but that he had found a perfectly reliable and practical procedure for preserving healthy wine: by heating it in closed vessels for an hour or two at a temperature between 60° and 100° C. As a result of small-scale preliminary trials, Pasteur progressively lowered the temperature to between 50° and 60° C. Within this range, he claimed, wine could be perfectly protected from disease at minimum risk to its taste, bouquet, and color.

As soon as pasteur publicy disclosed this method. which he patented in April 1865, alternative claims began to appear. In a series of letters and notes published between 1865 and 1872, nearly all of which were reproduced or incorporated into the two editions of his Études sur le vin Pasteur repeatedly defended his priority rights, even as he became increasingly informed of the Long history of “emprical” attempts to preserve wine. Eventually he admitted that he had been anticipated by Nicolas Appert, who had specifically proposed the applicaitons to wine of his method of preserving foodstuffs by heating them in closed vessels. nonetheless, he insisted that he had rescued from oblivion and established on the basis of regiorous scientific experiments what had been only a poorly tested and entirely empirical technique.

In support of the practicability of his method, Pasteur cited a series of commission the members of which generally preferred the taste of heated to untreated wine. One commission was appointed by the French navy in 1868 to test the feasibility of applying Pasteur’s process to wines destined for the fleet and the French colonies. The results were impressive enough for the navy to adapt pasteur’s process. Further evidence of the value of his method was reflected in the grand prize awarded pasteur by the jury of the Exposition Universelle (1867); the use abroad of the word “pasteurization” to denote the heating of wine; and the prizes from agricultural socieities and from the Société Encouragement pour I’Indusrie Nationale for the best apparaturs for heating wine (fifteen examples of which pasteur described and illustrated in the second edition of (Études sur le vin)

Spontaneous Generation: The Background. Almost from the beginning of his work on fermentation and despite attempts by Biot and Dumas to dissuade him, Pasteur became embroiled in the controversial issue of spontaneous generation. Although advanced in several more or less sophisticated versions, the doctrine of spontaneous generation rests at bottom on the notion that living organisms can arise independently of any immediate living parent, whether form inorganic substances (abiogenesis) or from organic debris (heterogenesis). In his classic paper of 1861, “Mémoire sur les corpuscules organisés qui existent dasn l’atmosp phére… “Pasteur included a fairly substantial historical introduction, which seems greatly to have influenced subsequent histories of the debate. To accounted for the modern rise of the doctrine—following its apparent destruction in the seventeenth century by Francesco Redi’s experiments on the generation of insects—Pasteur empahsized the influence of the microscope. By revealing a teeming world of hitherto unseen living organisms of dubious or unknown parentage, the microscope gave the doctrine a new lease on life and led to a celebrated eighteenthcentury dispute between Spallanzani and Needham. Spallanzani seemed largely to carry the day by showing that infusions boiled for forty-five minutes in closed vessels (to destroy any organisms they might already contain) thereafter remained free of alteration and microbial life. But his technique was open to the objection that the air in his sealed flasks might have been altered in such a way as to render spontaneous generation impossible. In the early nineteenth century this objection took special force from Gay-Lussa’s study of the role of oxygen in fermentaion and putrefaction. Having found that oxygen was absent from substances preserved by Appert’s canning process, and that grapes crushed under mercury in a bell jar fermented only upon the introduction of air. Gay-Lussac concluded that oxygen was essential to the onset of fermentation and putrefaction (and hence to the appearance of any microorganisms associated with these alterations).

As Pasteur emphasized, Gay-Lussac’s experiments made it imperative to remove any doubts about the possible alteration of air in Spallanzani’s flasks Toward this end Theodor Schwann made “a great step forward” in 1837 by showing that boiled meat infusions could be preserved from alteration in flasks in which the air was continually renewed, provided only that the added air had been heated or “calcined” before entering the flasks. Schwann’s experiement extended that of Franz Schulze, who in 1836 had achieved similar results by drawing the added air through potassium hydroxide and sulfuric acid; it also helped to set the stage for the work of Heinrich Schroder and Theodor von Dusch, who in the 1850’s exposed alterable substances to ordinary air filtered through cotton. By these means Schwann, Schulze, schroder, and Dusch prevented putrefaction, fermentation, and microbial life in many alterable substances—including meat infusions, beer, must, starch paste, and the constituents of milk taken separately—and tended to suppose that they had done so by eliminating airborne germs. But in the case of other substances—notably milk, egg yolk, and dry meat—their experiments often failed and helped to sustain the view that something like spontaneous generation could occur.

Moreover, Pasteur insisted, even those experiments which seemed to contradict spontaneous generation did so only in the sense of showing that an unknown something in atmospheric air was essential to life in organic infusions. This unknown principle seemed often to be eliminated by heat, cotton, or certain chemical reagents; but insofar as Schwann and others tended to suppose that atmospheric germs had thus been killed or eliminated, they “had no more proofs for their opinion,” wrote Pasteur, “than those who believed that [the unknown principle] might be a gas, fluid, noxious effluvia, etc., and who consequently were inclined to believe in spontaneous generation.” There, according to Pasteur, the issue lay when Fleix Pouchet launched his attempt to establish the doctrine of spontaneous generation on the basis of irrefutable experiments. Pouchet, a respected naturalist from Rouen and a corresponding member of the Académie des Sciences, published in 1859 his long and controversial heterogene ou traite de la generation spontanee, which created a sensation in France and probably stimulated the Académie des Sciences to institute the Alhumbert Prize in 1860 for the best “attempt, by well conducted experiments, to throw new light on the question of so-called spontaneous generations.”

Pasteur won this competition with his “Memoire sur les corpuscles…” By ifnoring a wide range of other factors that helped to discredit spontaneous generation (notably studies of cell division and the debate, by then resolved, over the origin of parasitic worm⁵⁸ it magnified the importance of his own contributions and nearly all subsequent accounts have followed suit. At the end of his historical introduction, Pasetur traced his interest in spontaneous generation to his work on fermentation, and particularly to his recognition that the ferments were living organisms:

Then, I said to myself, one of two things must be true. The true ferments being living organisms, if they are produced by the contact of albuminous materials with oxygen alone, considered merely as oxygen, then they are spontaneously generated. But if these living feremtns are not of spontaneous origin, then it is not just the oxygen as such that intervences in their production—the gas acts as a stimulant to a germ carried

with it or already existing in the nitrogenous or fermentable materials. At this point, to which my study of fermentation brought me, I was thus obliged to form an opinion on the question of spontaneous generation. I thought I might find here a powerful support for my ideas on those fermentations which are properly called fermentations.

As this passage suggests, it is perhaps artificial to separate Pasteur’s study of spontaneous generation from his work on fermentation, especially since some of his adversaries contended that microorganisms could appear as a result of fermentation rather than as its cause. The question of the origin of the ferments was therefore crucial, and Pasteur’s concern with it is apparent from his earliest paper on fermentation.

In 1858, in his initial paper of fermentation, Pasteur wrote that the lactic ferment “originates spontaneously, with as much facility as brewer’s yeast, whenever conditions are favorable,” but immediately emphasized in a footnote that he used the word “spontaneously” merely to “describe the fact, leaving entirely aside any judgment on the question of spontaneous generation.” In February 1859 he addressed the issue somewhat more directly, asserting that in his experiments the lactic ferment always came “uniquely by way of the atmospheric air.” If he boiled his medium and then removed it from all contact with air or exposed it only to previously calcined air, no microbial life or fermentation of any kind appeared. “On this point,” he wrote, “the question of spontaneous generation has made an advance.”

Spontaneous Generation, 1860–1861. Beginning in February 1860, Pasteur presented to the Académie des Sciences a series of notes focusing specifically on spontaneous generation. In the first and most importent of these papers, he began by examining the solid particles of the air, which he collected by aspirating atmospheric air through a tube plugged with guncotton. When this guncotton was dissolved in a sedimentation tube containing an alcohol-ether mixture, the solid particles trapped by it settled at the bottom. Although this method killed any germs or microorganisms in the trapped particles, microscopic examination always revealed a variable number of corpuscles, the form and structure of which closely resembled those of living organisms. But were these

“organized corpuscles” in fact the “fecund germs” of the microorganisms which appeared in alterable media exposed to the air? In search of an answer, Pasteur employed three distinct methods. With the first, involving the use of a pneumatic trough filled with mercury, he obtained somewhat dubious or inconsistent results and abandoned it in favor of a second method, which he characterized as “unassailable and decisive.” In a flask of about 300 cubic centimeters, he placed 100 to 150 cubic centimeters of sugared yeast water, which he boiled for a few minutes. After the flask had cooled, he filled it with calcined air (by means of a neck connected to a red-hot platinum tube) and then sealed it in a flame. The liquid in such a flask, deposited in a stove at 28–32° C., could remain there indefinitely without alteration.

Having thus far only repeated the experiments of Schwann and others. Pasteur now introduced an important modification. After a month to six weeks he removed the flask from the stove and connected it to an elaborate apparatus so arranged that small wad of guncotton previously charged with atmospheric dust could be made to slide into the hitherto sterile liquid in the flask (see Figure 1). In twenty-four to thirty-six hours, the liquid swarmed with familiar microorganism. Thus, Pasteur concluded, the dust of the air, sown in an otherwise sterile medium, produces organisms of the same sort and in the same period of time as would appear if the liquid were freely exposed to ordinary air. Finally, to counter the objection that these microorganisms arose not from germs in the atmospheric dust but “spontaneously” from the organic matter in the guncotton, Pasteur replaced the guncotton with dust-charged asbestos, a mineral substance, and obtained the same results. With dust-free or precalcined asbestos, on the other hand, no growths appeared in the flask.

To confirm and extend these conclusions on the role of atmospheric dust, Pasteur employed a third method, perhaps the most influential by virtue of its elegant simplicity: the famous “swan-necked” flask. After preparing a series of flasks in the same manner as in the second method, he drew their necks out into very narrow extensions, curved in various ways and exposed to the air by an opening one to two millimeters in diameter (see Figure 2). Without sealing these flasks, he boiled the liquid in most of them for several minutes, leaving three or four unboiled to serve as controls. If all the flasks were then placed in calm air, the unboiled liquids became covered with various molds in twenty-four to forty-eight hours, while the boiled flasks remained unaltered indefinitely despite their exposure. Moreover, if one of the curved necks were detached from a hitherto sterile flask and placed upright

in it, vegetative growths appeared in a day or two. Pasteur concluded that the “sinuosities and inclinations” of his swan-necked flasks protected the liquids from growths by capturing the dusts that entered with the air. In fact, Pasteur insisted, nothing in the air—whether gases, fluids, electricity, magnetism, ozone, or some unknown or occult agent—constitutes a condition of microbial life except the germs carried by atmospheric dusts.

According to Duclaux, the swan-necked flask method was suggested to Pasteur by Balard; and Pasteur admitted that Chevreul had already done “similar experiments” in his chemistry lectures.⁵⁹ But if in this case, as in his experiments with calcined air, Pasteur borrowed importantly from the techniques of his predecessors, he also developed and exploited them with greater effect and influence. By the force of its conclusions and the variety and ingenuity of its experimental techniques, his paper of 6 February 1860 propelled Pasteur to preeminence among the opponents of spontaneous generation. All of his subsequent work in this field can be seen as an extension, elaboration, and defense of the principles and methods set forth here.

By May 1860, as promised at the end of his February paper. Pasteur had extended his conclusions to media other than albuminous sugar water—namely, to urine and milk, two substances highly susceptible to alteration in air. Deprived of atmospheric dust, Pasteur claimed, boiled urine could be stored indefinitely without alteration, even at the temperature most favorable to its putrefaction. But the addition of dustcharged asbestos to a previously sterile flask of urine resulted in the appearance of various microorganisms and an abundant deposit of phosphates and urates. One of the microorganisms could be identified as the “true ferment of urine,” responsible for the production of ammoniacal urine. Its germ, like those of the infusoria and molds that appeared with it, could have entered the flask only by way of the atmospheric dust.

Unlike urine and sugared yeast water, milk boiled for two minutes and then protected from atmospheric dusts did not remain unaltered. Instead, it invariably coagulated within three to ten days, this coagulation being associated with the appearance and development of vibrios. By no means, however, did this alteration imply that spontaneous generation had taken place. For if the duration of boiling were increased, the number of flasks in which milk coagulated decreased proportionately. And if the temperature were increased to 110° or 112°C., no vibrios appered and the milk did not coagulate. Obviously, Pasteur concluded, a temperature of 100°C. does not entirely destroy the fecundity of the vibrio germs, while a temperature of 110° to 112° C. does.

In September and November 1860, Pasteur described another famous set of experiments in which he exposed alterable liquids to the natural atmosphere of different locations and altitudes, hoping thereby to discredit the belief that any quantity of ordinary air, however minute, is sufficient for the production of organized growths in any kind of infusion. In his view this belief enjoyed currency chiefly because of Gay-Lussac’s analysis of Appert’s preserves and his experiment with grapes crushed under mercury, for these studies led him to associate fermentation or putrefaction with the presence of oxygen, even in minute quantities. On this basis the partisans of spontaneous generation had elaborated a seemingly impressive argument against the notion of airborne germs. For if the most minute quantity of air can produce the microorganisms appropriate to any infusion, and if these organisms are supposed to derive from preexistent germs, then the air must be so loaded with a multitude of different germs as to be foggy at least, if not as dense as iron.

Pasteur’s approach to this problem was deceptively simple. After boiling sugared yeast water in sealed flasks, he broke the necks to admit the surrounding air, immediately resealed the flasks in a flame, and stored them in a stove at a temperature favorable to the development of microorganisms. Under these conditions the liquids in the flasks sometimes remained entirely unaffected a “simple and unobjectionable proof” that a limited quantity of ordinary air does not invariable produce infusorial growths. On the other hand, the result accorded well with the notion of the variable dissemination of germs in the air. The latter notion received further support from the fact that it was easy to alter the proportion of flasks in which microbial life appeared merely by exposing them to the air in various locations or altitudes. In the vaults of the Paris observatory, for example, the proporation of exposed flasks that later showed infusorial growths was much lower than in Pasteur’s laboratory at the École Normale. This proportion also decreased with increased altitude. Thus, of twenty flasks opened at the foot of the Jura plateau, eight later showed vegetative growths; of twenty exposed on one of the Jura mountains, 850 meters above sea level, five produced growths; and of twenty opened on a glacier at Montanvert, 2,000 meters above sea level, only one flask underwent subsequent alteration. For Pasteur such results authorized the conclusion that germs are variably disseminated in the air, their relative abundance depending on locality, altitude, and other environmental circumstances.

In January 1861, in his fifth paper on spontaneous generation, Pasteur described the influence of temperature on the fecundity of fungal spores. Spallanzani had found that fungal spores could survive boiling in water at 100° C. and—without assigning a precise upper limit—had claimed that they could even resist the heat of a furnace when dry. Pasteur denied that this upper limit was as high as Spallanzani had supposed and criticized his experimental technique for its failure to ensure that any observed fungi derived solely from the spores he had sown and not from additional spores in the air or on the experimental apparatus. His own method, which seemed to Pasteur “beyond reproach,” was a modification of the technique he had used to sow dust-charged asbestos into sterile media in an atmosphere of calcined air. In this case the asbestos was charged with fungal spores and then heated to determined temperature before sowing. Pasteur found that in a vacuum or in dry air, such spores could remain fecund even after being heated at 120–125° C. for as long as an hour. On the other hand, their fecundity was completely destroyed by heating them at a temperature of 127–130° C. for twenty to thirty minute. These results also offered a means of proving that fungal spores spores exist in the atmospheric dust, for the sowing of such dust at 120–125° C. produced fungi, while none appeared when the dust was sown at 125–130° C.

The Memoir of 1861. In May 1861, at a meeting of the Société Chimique de Paris, Pasteur presented the major results of his work on spontaneous generation in a lecture later expanded into his prize-winning memoir. Although this memoir is essentially a restatement of his earlier papers on the topic, it is richer in detail and contains some new material, including the historical introduction. The appearance under the microscope of atmospheric dust and of the organisms found in infusions received considerable attention, as did the role of contaminated mercury as a source of error in the experiments of Pouchet and others. Pasteur had barely hinted at the latter possibility in his initial paper of 6 February 1860 and had made it explicit in a note of September 1860. Pouchet’s experimental case for spontaneous generation rested chiefly on his ability to produce microbial life by adding germ-free air to boiled hay infusions under mercury. Pasteur admitted that Pouchet’s precautions seemed to eliminate every source of possible contamination by living germs with one exception—the mercury. But this exception was crucial, Pasteur argued, since ordinary laboratory mercury often contains germs. As proof he cited the following comparative experiments. If a globule of ordinary mercury is dropped into an alterable liquid in an atmosphere of calcined (and hence germ-free) air, microbial life appears within two days. But if the mercury is previously calcined, not a single living organism will appear. Indeed, so thoroughly did Pasteur mistrust experiments with the mercury trough that he insisted that this mode of experimentation be banished from the field.

The most important new material in the 1861 memoir concerned the effect of the alkalinity of a medium on the heat-resistance of germs in it. Pasteur identified the alkalinity of milk as the chief reason why boiling at 100° C. failed to protect it from subsequent alteration. As evidence he noted that sugared yeast water—ordinarily protected by boiling at 100° C.—must be heated at 105–110° if its alkalinity is increased by the addition of chalk.

This memoir seriously damaged the doctrine of spontaneous generation, but the blow was far from fatal and many unresolved issues remained. In Pasteur’s mind the most obvious weakness of his work on spontaneous generation was its exclusive reliance on experiments involving heated substance—“organic matters which are not only dead but which have also been carried to the temperature of boiling.” To all such experiments, partisans of spontaneous generation could object that so high a temperature profoundly modified organic substances and perhaps destroyed a “Vegetative force” or some other condition essential for spontaneous generation. For this reason Pasteur long sought to extend his conclusions to “natural organic substances, not previously heated”—in short, to “natural substances such as life elaborates them.” In April 1863 he announced that he had found a way to take fresh blood and urine directly from healthy, living organisms and to preserve both substances from putrefaction without preliminary boiling. He immediately asserted that these results “carry a final blow to the doctrine of spontaneous generation,” and he attached enormous importance to them in all subsequent debates over spontaneous generation and the germ theory of disease.

The Pasteur-Pouchet Debate. Pasteur’s work on spontaneous generation created as great a sensation in France as had Pouchet’s Hétérogénie (1859), and in neither case was the sensation confined to scientific circles. The wide public interest in the debate stemmed from its presumed religiophilosophical and even political implications, for the issue of spontaneous generation formed part of the general debate raging in France between materialism and spiritualism. Pouchet’s results were invoked in support of materialism, evolutionism, and radical politics, while Pasteur’s opposing results were used to support spiritualism, the Biblical account of creation, and conservative politics. In April 1864, in a lecture at the Sorbonne, Pasteur emphasized that the doctrine of spontaneous generation (like materialism in general) threatened the very concept of God the Creator. And although he insisted that he had approached the issue without preconceived ideas, and would willingly have announced in favor of spontaneous generation had “experiment imposed the view on me,” there is reason to believe that he wanted a priori to deny the existence of spontaneous generation at least as fervently as Pouchet wanted to affirm it.⁶⁰ For Pasteur’s position in the debate was in keeping both with his conservative religious and political convictions and with certain aspects of his concept of fermentation—notably the idea of specificity, which implied the transmission of hereditary characters and led to a belief in an ordinary kind of generation among microorganisms. That Pasteur was influenced by such a priori convictions seems clear from his tendency automatically to suspect error in any experiment—including his own—which might be used in support of spontaneous generation and from the eagerness with which he accused Pouchet and other heterogeneticists of technical errors without having repeated their experiments carefully.

Perhaps partly for this reason, as well as the public notoriety of Pasteur’s experiments on the glacier at Montanvert, Pouchet decided to expose his usual hay infusions to the atmosphere at high altitude, following Pasteur’s procedure and without using mercury. In November 1863 Pouchet and two collaborators, Nicolas Joly and Charles Musset, announced that the results of their experiments, conducted in the Spanish Pyrenees, contradicted Pasteur’s results at Montanvert. For when they exposed their flasks to the air, all subsequently showed microbial growths, as one would expect if the organic material in infusions required only oxygen to organize itself spontaneously into living organisms. In his contemptuous reply to this announcement, Pasteur criticized Pouchet and his collaborators for using a short file instead of long pincers to break the necks of their flasks and for limiting their flasks to so small a number as eight.

In January 1864 the Académie des Sciences named a commission to adjudicate the dispute. When the commission proposed that the participants in the debate repeat their principal experiments before it in March, Pouchet and his collaborators asked that the meeting be delayed until the summer, on the ground that warm weather was conducive to the success of their experiments. In June the commission met with Pasteur and his adversaries, but the latter objected to the program as arranged by the commission and withdrew without repeating their experiments. The commission then observed a series of Pasteur’s experiments and verified their exactitude in a report that scarcely veiled its contempt for the opposite side.⁶¹

As Duclaux has emphasized, this episode might have had a different outcome had Pouchet and his collaborators maintained their nerve in the face of Pasteur’s self-assurance and the contempt of the commission.⁶² For although no one seemed to realize it immediately, there was a curcial difference between the experiments of Pasteur and those of Pouchet—namely, that Pasteur used yeast water as his alterable medium, while Pouchet used hay infusions. And while boiling easily kills the microorganisms common to yeast water, decoctions of desiccated hay often contain heatresistant bacilli endospores which can survive high heat and subsequently develop in the presence of oxygen. For this reason Pouchet’s flasks could have given microbial life and could have been used in support of spontaneous generation. Only after 1876, especially as a result of the work of Ferdinand Cohn and John Tyndall, did the heat-resistant hay bacillus endospore become fully recognized. Ironically, Pasteur had briefly considered a possibility of this sort in his Sorbonne lecture of 1864, but his attention seems to have been diverted by his zeal to ascribe technical errors to Pouchet. Thus, even though Pasteur had examined the heat resistance of fungal spores and had recognized the role of heat resistance in other cases, the full complexity and importance of the issue became clear to him only during his debate with Henry Charlton Bastian in the 1870’s and in the wake of work by Cohn, Tyndall, Koch, and others.

The Silkworm Problem: The Background. On 8 December 1862, three weeks before he won the Alhumbert Prize, Pasteur had been elected to membership in the mineralogy section of the Académie des Sciences, succeeding in his third formal campaign for the honor. His often active participation in the weekly meetings of the Academy regularly took him away from his laboratory and administrative tasks. So did his lectures at the École des Beaux-Arts, where from November 1863 to October 1867 he was the first professor of geology, physics, and chemistry in their application to the fine arts, and where he introduced laboratory procedures oriented toward the problems of art and its materials. Pasteur also found time to write historical articles on Lavoisier in 1865 and on his friend Claude Bernard in 1866. But the most exhausting demand on his time from 1865 through 1870 was the silkworm problem, which took him away from Paris for several months each year.

By 1865 French sericulturists had become almost frantic about a blight which had afflicted their silkworms for the past fifteen to twenty years—a disease so disastrous as to reduce silk production over this period by a factor of six. In Alais [now Alés] alone, the center of French sericulture, the revenue loss was estimated at 120 million francs for the fifteen years before 1865.⁶³ The gravity of the situation aroused the concern of the ministry of agriculture and of Dumas, Pasteur’s mentor and patron, who was from Alais. In May 1865 Dumas asked Pasteur to study the silkworm blight. Confessing utter ignorance of the problem and noting that he had never even touched a silkworm,⁶⁴ Pasteur nonetheless acceded to Dumas’s request and immersed himself in the relevant literature, notably Quatrefage’s 1859 work.

According to most authorities, the blight resulted from a disease called pébrine (pepper) by Quatrefages because of the small black spots frequently seen on sick worms. Its symptoms included stunted or interrupted growth, sluggishness, loss of appetite, and premature death. A general association had also been established between pébrine and the existence of microscopic “corpuscles” within the internal organs of diseased worms. Although considerable controversy surrounded the precise role and nature of these corpuscles, several authorities considered them to be the cause of the disease. Those who did tended to suppose that the corpuscles were living parasites, a position that drew support from Agostino Bassi’s pioneering studies in the 1830’s of another major silkworm disease, muscardine, which he had traced to a fungal parasite. Unfortunately the microscopic corpuscles of pébrine could sometimes be found in apparently healthy broods, while their absence failed to guarantee either healthy worms or good silk cocoons. Nonetheless, in 1859, after detecting the corpuscles even in silkworm eggs, where they increased in size and number as hatching time approached, Marco Osimo had tried to establish a preventive measure based on the rejection of corpuscular eggs and pupae. Preliminary trials of Osimo’s method were unimpressive, however, and the problem remained obscure.

Pasteur’s Early Silkworm Studies. Pasteur’s initial firsthand experience with pébrine disposed him to doubt both its contagiousness and the causative role of the corpuscles. On his first trip to Alais, in June 1865, he observed two neighboring cultures or broods the opposite fates of which seemed to refute the supposed connection between pébrine and the internal corpuscles. The first brood, a successful one, had already spun its cocoons and had therefore entered the pupa stage of its life cycle; the second brood, which had proceeded sluggishly and poorly, as if diseased, had not yet made its passage from silkworms to pupae. Surprisingly, the pupae and moths of the successful brood contained corpuscles in abundance, while the worms of the poor brood contained almost none. Similar cases appeared in other silkworm nurseries around Alais. Some of the surprise abated as the second brood continued to pass through its life cycle. The previously rare corpuscles became increasingly frequent in the pupae, and eventually every moth contained them in profusion. Nonetheless, from the rarity of corpuscles in the sick worms of the second brood, Pasteur concluded that pébrine must be a constitutional, hereditary disease, existing prior to and independently of the corpuscles. These corpuscles he supposed to be products of the disease, perhaps resulting from tissue disintegration. Since both broods displayed corpuscles, both must have been diseased; but presumably the first brood had been attacked only late in its life cycle (and thus without serious damage to its silk crop), while the second brood had suffered more severely since an earlier stage.

This conception led Pasteur to essentially the same preventive remedy proposed by Osimo—the selection of eggs from noncorpuscular moths and the rejection of those from corpuscular moths. That Pasteur could advocate this method of egg selection while denying the causative role of the corpuscles becomes less paradoxical if the corpuscles are regarded as an index of the severity of the disease. In Pasteur’s view corpuscular moths were obviously in an advanced state of the disease; and although noncorpuscular moths might also be sick, they must be less seriously so and thus less likely to produce diseased offspring. This method of egg selection, which Pasteur announced only two weeks after his arrival in Alais, remained at the core of his remedial proposals even as his conception of the silkworm plague underwent a dramatic change.

For various reasons this change took place with almost agonizing slowness. In the first place, the tentative conclusions drawn from one year’s silk culture could be overturned by the results of the next year, and no way existed to circumvent fully this prolonged natural delay. Moreover, if the material selected happened to fail for reasons unconnected with the prevailing blight, it became useless as a guide to the disease. Personal tragedies and burdens further frustrated Pasteur’s efforts. During his first brief trip to Alais, toward the end of the silkworm season of 1865, his father died. The studies of the following year were briefly interrupted by the death of his two-year-old daughter. Immediately after the 1867 season he became the focus of the student protest which ended with his dismissal from the administration of the École Normale. His activities during the 1869 and 1870 seasons were restricted by his debilitating stroke of October 1868.

But the most fundamental obstacle lay in the inherent complexity of the task. Only gradually did it become clear that the silkworm plague involved at least two independent diseases, which differed in ways precisely calculated to confuse students of the problem. Under the weight of these burdens, Pasteur leaned heavily on the moral support of Dumas and Empress Eugénie, and—beginning in 1866—on the companionship and assistance of his loyal collaborators Désiré Gernez, Maillot, Jules Raulin, and Émile Duclaux. For about five months of every year through 1870, one or more of these collaborators joined Pasteur and his wife at Pont-Gisquet, near Alais, where in an abandoned orangery they arranged a makeshift laboratory and carried out of the experiments which the master had designed.

From the outset Pasteur’s basic experimental strategy was to compare carefully the results of cultures from relatively corpuscular moths with those from relatively noncorpuscular moths. These painstaking studies established the following general conclusions: (1) the more corpuscular the parent moths, the less successful the resulting crop of silk cocoons; (2) while the offspring from partially corpuscular moths sometimes gave a good first crop, they never gave a good second crop; (3) in any brood, however corpuscular the eggs from which it derived, some noncorpuscular moths could always be found. If this third result offered hope that healthy moths (and hence cultures) could always appear even in the midst of disease, the first two tended to emphasize the connection between the corpuscles and the disease and to reinforce the value of selecting eggs from noncorpuscular moths. Indeed, this method had so won Pasteur’s confidence by the end of the 1866 season that he began to rely on it to make bold public prophecies. In a letter to the mayor of St.-Hippolyte-du-Fort he predicted the fate during the 1867 season of fourteen batches of eggs he had examined there the year before. In twelve of the fourteen cases, the results conformed closely to his predictions.⁶⁵

None of these results, however, really demonstrated either that the corpuscles caused the disease or that they were living parasites. Nor did a clear answer emerge from preliminary feeding experiments conducted by Pasteur in 1866. For when he fed healthy worms mulberry leaves smeared with corpuscles— to see ifPébrine could be transmitted in this way —many of the young worms died without becoming corpuscular. On the other hand, similar feeding experiments by Gernez seemed strongly to support the parasitic theory of pébrine. Besides establishing a general association between a corpuscular diet and Pébrine, Gernez showed more precisely that the time at which the corpuscles of Pébrine appeared in a brood depended directly on the time at which the corpuscular diet had been introduced. Pasteur, however, was not yet convinced. When he reported the results of Gernez’s experiments in November 1866, he focused chiefly on those which showed that broods from noncorpuscular months gave good silk crops—in other words, he reemphasized the practical value of his method of egg selection.

By now, it seems, Pasteur’s collaborators were thoroughly convinced both that the corpuscles caused Pébrine and that they were living parasites. His reluctance to accept this view greatly surprised them, and Duclaux went so far as to accuse him of obstinacy.⁶⁶ Pasteur’s hesitation is indeed remarkable, not only in view of Gernez’s persuasive results but more emphatically in view of his abiding faith in the pathological implications of the germ theory of fermentation—a faith which ought presumably to have disposed him toward a parasitic etiology for pébrine. Nonetheless, his initial observations in 1865, and the evidence which he knew best from his own research, conflicted in some respects with the parasitic theory. As late as January 1867, he listed four major objections to a parasitic etiology for pébrine: (1) the disease is certainly constitutional in a number of circumstances and precedes the appearance of corpuscles; (2) the feeding of corpuscular matter often kills young worms without corpuscles appearing in their bodies; (3) I have been unable thus far to discover a mode of reproduction for the corpuscles; (4) their mode of appearance resembles a transformation of tissues.”⁶⁷

These objections depended in part on Pasteur’s inadequate knowledge of protozoan reproduction and on his then defective technique for detecting corpuscles. But they derived in larger measure from a general confusion between pébrine and another disease, mortsflats or flacherie, the complex etiology of which was even more obscure than that of Pébrine. Perhaps partly because he shared this confusion with so many other because he shared this confusion with so many other authorities on Pébrine, Pasteur resisted a rapid and careless extension of the germ theory to the diseases of silkworms. Indeed, no other work by Pasteur displays greater sensitivity to the complex relationships between heredity, environment, and parasitism; and Duclaux—while accusing Pasteur of obstinacy—wrote that he did not know a “more beautiful example of scientific investigation” than Pasteur’s study of the silkworm problem.⁶⁸

The Silkworm Season of 1867. The silkworm season of 1867 marked a watershed in Pasteur’s investigations. Before it ended, he had become a convert to the parasitic theory of pébrine and had come to recognize that morts-flats or flacherie—which most authorities linked with pébrine—was an independent disease, with its own character and etiology.⁶⁹ His conversion to the parasitic theory of pébrine depended chiefly on mounting evidence of its contagiousness. To establish this characteristic, it was necessary to discredit the notion that the disease arose in consequence of a mysterious epidemic environment. Pasteur rejected this notion on the ground that broods derived from noncorpuscular moths—of which he had secured a large supply—usually remained sound and noncorpuscular even in the midst of the allegedly epidemic environment. This result helped to clear the way for further feeding experiments, for it undermined the objection that worms which became sick on a corpuscular diet might owe their disease to an epidemic environment having no connection with their diet.

Against this background Pasteur and his collaborators repeated on a large scale Gernez’s feeding experiments and supplemented them with experiments in which healthy silkworms were directly inoculated with corpuscles through surface punctures. In both ways, although especially by corpuscular diets, otherwise healthy worms contracted Pébrine and became highly corpuscular. Having reached this point, Pasteur seems to have encountered little difficulty in discovering a mode of reproduction for the corpuscles, a mode strikingly different from the budding and binary fission of the microorganisms which he knew best but a mode familiar to protozoologists.

While these studies seemed, therefore, to establish the contagiousness of Pébrine, with parasitic corpuscles as its cause, they raised another question: If pébrine is contagious, of what use is the method of egg selection as a remedy? In the first place, Pasteur replied, the corpuscles of diseased parent moths can be transmitted directly to their eggs; and in this sense pébrine is simultaneously hereditary and contagious. Moreover, if the offspring of noncorpuscular moths later contract pébrine—whether by eating corpuscular leaves or by inoculation—the incubation period is long enough to ensure that all, or virtually all, the worms will spin cocoons and yield a silk crop. And since the corpuscles lose their fecundity and pathogenicity from one silkworm season to the next, the only effective source of contagion in each season must be the corpuscles contained in the eggs produced by corpuscular moths. If, therefore, all the eggs from corpuscular moths are rejected, Pébrine ought to disappear quickly. In this way Pasteur developed a new and more impressive rationale for his method of egg selection, but his hope that it could lead to total elimination of pébrine was doomed by the fact that the corpuscle enjoys hosts other than the silkworm.⁷⁰

Studies on Flacherie, 1867–1870. Pasteur’s recognition of flacherie as an independent disease can be traced at least in part to his confidence in the method of egg selection, undoubtedly reinforced by his new conviction of the parasitic nature of pébrine. For what especially alerted him to the independence of flacherie was the failure during the 1867 season of entire broods descended from noncorpuscular moths. Most of these unsuccessful broods, which appeared in Pasteur’s cultures as well as those of several breeders to whom he had sent the eggs, displayed neither the corpuscles nor the black external sports of pébrine. Instead, nearly all the worms died with the familiar symptoms of flacherie —symptoms different enough from those of pébrine to have received a separate name, although most authorities (including Pasteur) had hitherto supposed that these symptoms merely represented a special stage or effect of pébrine. That flacherie represented a well-defined and independent hereditary disease now seemed clear not only from the absence of corpuscles in these diseased broods but also from the way it attacked all of the offspring of certain batches of eggs, even though these eggs had been cultivated in widely different environments.

Although these events aroused great practical concern, they also helped to clarify much of the apparently contradictory evidence. In the case of Pasteur’s work, it now seemed clear that his initial observations at Alais, as well as his preliminary experiments with corpuscular diets, had miscarried through the intervention of flacherie. Because, in both cases, he had observed death and disease in the absence of corpuscles, he had supposed that pébrine must be a constitutional disease. The events of the 1867 season strongly suggested that such a constitutional disease did exist, but that this disease was flacherie rather than pébrine. Compared with pébrine, flacherie had contributed rather little to the ruinous silkworm blight; but its character and etiology demanded great attention because it threatened the method of egg selection on which Pasteur had based his hopes for the rejuvenation of French sericulture. At first Pasteur merely advised the rejection of eggs from broods which displayed high mortality, languor, or any other symptom of flacherie. Then, during the silkworm seasons of 1868 to 1870, he sought to unravel the etiology of flacherie from that of pébrine and to find a prophylactic method for it as reliable as the method of egg selection he had devised for péebrine.

At the outset of these studies on flacherie, two striking phenomena arrested Pasteur’s attention: (1) the strongly hereditary aspect of the disease, as revealed by the almost constant and devastating appearance of flacherie in descendants of broods which had shown some symptoms of the disease before spinning their cocoons and laying their eggs; and (2) the abundant presence of microorganisms in the intestinal canals of worms attacked by flacherie. Notable among these microorganisms, which were virtually absent from healthy worms, were vibrions (bacilli) and a “petit ferment en chapelets de grains” (a micrococcus), which resembled an organism he had already associated with certain fermentations.⁷¹ As with the corpuscles of pébrine, Pasteur at first supposed that these microorganisms were a consequence of the disease rather than its cause, their chief significance being diagnostic rather than etiological.⁷² More specifically, he conceived of flacherie as a sort of hereditary susceptibility to indigestion, in consequence of which ingested mulberry leaves underwent fermentation in the intestinal canal. On this view the microorganisms associated with intestinal fermentation, and especially the small ferment in chains, served as a physical index of a late stage in the disease. But even while thus denying the intestinal microorganisms a direct causative role in flacherie, Pasteur put them at the center of his efforts to develop a prophylactic measure against it. In brief, he counseled the rejection of pupae the stomachs of which contained the small ferment in chains, since they were certain to transmit the hereditary predisposition to their offspring.

During the silkworm season of 1869, Pasteur considerably modified his conception of flacherie.⁷³ As in the case of pébrine, feeding experiments seem to have been chiefly responsible for this shift. On a diet of leaves smeared with excrement from worms with flacherie, previously healthy worms fell sick with the disease. Thus flacherie, like pébrine, was contagious as well as hereditary. Unlike pébrine, however, flacherie owed its hereditary character not to the direct transmission of a microorganism from the parent moths to the eggs but to a constitutional weakness of which there was no immediately visible sign. While thus retaining part of his original conception of the disease, Pasteur now perceived—however dimly—that this hereditary weakness involved a susceptibility not so much to indigestion per se as to the germs of the microorganisms later seen in the intestinal canal. Henceforth he identified the intestinal microorganisms as the proximate cause of flacherie. Unlike the corpuscles of pébrine, these microorganisms are common and universally distributed. They must therefore become pathogenic in silkworms only under special cirumstances. Hereditary susceptibility to them in certain silkworms clearly forms one of these special circumstances; but other such conditions must exist, for flacherie sometimes appears “accidentally” or “spontaneously” in a brood without any hereditary predisposition. In such cases, Pasteur suggested, unusual conditions of temperature, humidity, or ventilation in the nursery must either promote the multiplication of the causative microorganisms on the leaves or lower the resistance of the silkworms to the ingested germs. To prevent or reduce all forms of flacherie, therefore, it was necessary not only to reject infected pupae but also to monitor and to control as far as possible the environmental conditions in the nursery.

According to René Dubos, the etiology of flacherie is even more complex than Pasteur realized.⁷⁴ Among other things, the susceptibility of silkworms to the bacteria of flacherie seems to depend on the intervention of a filterable virus. However that may be, Pasteur had attained a remarkably keen insight into the essential features of pébrine and flacherie. He recognized the subtlety and importance of the questions this work raised about the interaction of parasite, host, and environment in the production of disease; and he later advised young physicians to study his Études sur la maladie des vers a soie (1870) as an introduction to such issues.⁷⁵ But Pasteur had grown increasingly tired of this work, especially as he became confident that he had provided the basis for a practical solution to the problems of French sericulture. In fact, between 1868 and 1870 study of the etiology of flacherie occupied him less fully and directly than his efforts to establish and proselytize his practical measures against the silk worm blight. Toward this end he engaged in an enormous correspondence with sericulturists and their trade journals, distributed vast quantities of eggs for industrial trials, and became a practical sericulturist. These efforts brought Pasteur recognition and testimonials from commissions and sericulturists, many of whom adopted his methods. If his success was less than total, it was certainly considerable and he did not lose confidence even during a serious depression in French sericulture from 1879 to 1881, which he ascribed not to a failure of his methods but to bad weather and to the comparatively low prices of Oriental silk.⁷⁶

Debates Over Fermentation, 1871–1876. From 1865 to 1870, while Pasteur was preoccupied with the silkworm problem, his theory of fermentation enjoyed increasing favor, especially abroad. What criticism did appear during that period failed to distract him from his central task. In 1871, however, the Annales de chimie et de physique published a French translation of a wide-ranging critique by Liebig, who had broken a long silence on the issue in two lectures (1868, 1869). In a reply of almost arrogant brevity, Pasteur discussed only two aspects of Liebig’s critique, both of which involved direct challenges to experimental claims made a decade before by Pasteur: (1) that pure yeast and a simple alcoholic fermentation could be produced in a medium free of organic nitrogen and (2) that acetic fermentation required the intervention of Mycoderma aceti. Pasteur responded by challenging Liebig to submit the dispute to a commission of the Académie des Sciences. Before this commission, Pasteur boldly predicted, he would prepare, in a medium free of organic nitrogen, as much beer yeast as Liebig might reasonably demand and would demonstrate the existence of Mycoderma aceti on the surface of the beechwood shavings used in the German method of acetification.⁷⁷

Although Liebig died in 1873 without accepting Pasteur’s challenge, some aspects of his critique were adopted in France by Edmond Frémy and Auguste Trécul, among others. These critics earned the scorn and ridicule of Pasteur who went so far as to impugn the patriotism of those who dared to defend a “German theory” against a “French theory” after the Franco-Prussian War.⁷⁸ Despite their often personal and repetitive character, the ensuing debates nonetheless contributed to Pasteur’s understanding and articulation of the issues surrounding fermentation and spontaneous generation. Insofar as the debated concerned fermentation as such, their chief value was to induce Pasteur to clarify his views on the role of oxygen in the process, to extend to all living cells his theory of fermentation without air, and to begin at last to face directly and explicitly the ambiguities of his definition of fermentation.

In his papers of the 1860’s Pasteur had implied that oxygen played no role in fermentation, unless to impede it. In fact, some brewers supposed that he advocated the total elimination of air during brewing, a natural enough conclusion from his theory of fermenttin as “life without air.”⁷⁹ Only gradually, under prodding from such critics as Frémy, Oscar Brefeld, and Moritz Traube, did Pasteur begin to emphasize that oxygen played an essential, if strictly limited, role. In the face of Frémy’s repeated insistence that some contact with oxygen was essential to the fermentation of grape juice, Pasteur finally acknowledged in 1872 that this view contained a kernel of truth, in that yeast—the true agent of fermentation—did require some oxygen in order to germinate.⁸⁰ In 1875 he responded in essentially similar fashion to the objections of Brefeld and Traube, whose careful experiments suggested that yeast deprived of free oxygen either could not live at all or else provoked at most a very feeble and incomplete fermentation. In his reply Pasteur suggested that they had been misled by using contaminated yeast or yeast too old and “exhausted” to germinate in an oxygen-free environment.⁸¹ In his Études sur la biere (1876), in which he also described a new and perfected method of preparing pure yeast, Pasteur emphasized that yeast occasionally required small quantities of oxygen in order to retain its “youth” and its capacity to germinate in oxygen-free environments. Having now achieved a new appreciation for the importance of oxygen in brewing, and especially the advantages of aerated wort, he insisted only that air should be carefully limited and freed of foreign germs rather than entirely eliminated.

In the meantime Pasteur had extended his theory of fermentation to all living cells, a development that Dumas believed might well mark “an epoch in the history of general physiology.”⁸² Beginning in October 1872, Pasteur set forth and elaborated the view that because fermentation is a manifestation of life in the absence of free oxygen, and because every living cell can survive at least temporarily under such conditions, “all living things are ferments in certain conditions of their life.” As evidence he cited experiments showing that Mycoderma vini and Penicillium glaucum, ordinarily aerobic organisms that comsume free oxygen, can live for a time in the absence of free oxygen—when forcibly submerged in a sugared liquid medium, for example. Under these anaerobic conditions the Mycoderma and Penicillium become ferments: they decompose the sugar in order to extract its combined oxygen and carbon, producing alcohol in the process. Similarly, intact grapes, prunes, plums, and other fruits give off a small quantity of alcohol in an oxygen-free environment. In the latter case the cells of the fruit decompose the sugar in the fruit to obtain carbon and oxygen and thus the heat (or energy) required for physiological processes. As early as 1861 Pasteur had described in preliminary fashion a converse phenomenon—the capacity of yeast, ordinarily an anaerobic organism, to become adapted to a more or less aerobic existence, in which case its power as a ferment decreased or disappeared. In August 1875 he specified the conditions under which yeast could become a fully aerobic plant, living exactly like common molds. The essential task was to germinate the yeast on a liquid of large surface area in the presence of abundant oxygen. Under these circumstances it consumed free oxygen and did not produce fermentation.⁸³

In several respects these ideas confused Pasteur’s contemporaries, and some of his opponents thought he had unwittingly exposed fundamental flaws in his germ theory of fermentation. By revealing the protean character of yeast and other lower organisms—which might live as either anaerobes or aerobes, as ferments or not—he seemed to undermine his insistence on the specificity and peculiarity of fermentative microorganisms. More directly, his suggestion that fruit cells could produce alcohol—without the intervention of living microorganisms—struck some as an outright contradiction of his earlier views and the entire germ theory of fermentation. While responding to such confusion and criticism, Pasteur finally emphasized and clarified several points hitherto largely implicit or otherwise submerged in his work. Above all, he revealed how much his theory of fermentation depended on his carefully circumscribed definition of the process.

The Circularity of Pasteur’s Theory of Fermentation. From the beginning of his work on fermentation, Pasteur had restricted the germ theory to “fermentations proprement dites” (“fermentations properly so called”). When, in February 1872, Fremy demanded to know what he meant by this expressions, “so vague and so elastic,” Pasteur said that he applied it to “the fermentations that I have studied and which include all the best characterized fermentations, those which are as old as the world, those which give bread, wine, beer, sour milk, ammoniacal urine, etc., etc., those in which the ferments are, according to my researches, living beings which arise and multiply during the act of fermentation.”⁸⁴ On the other hand, processes such as the so-called diastatic fermentation, by which starch was converted into sugar, did not merit inclusion among the fermentations “properly so-called,” because they involve a soluble chemical ferment (an enzyme) rather than a living microorganism. In other words, Pasteur excluded from his definition of fermentation those processes of decomposition which he admitted to be chemical rather than biological.

But Pasteur also excluded from the list of true fermentations certain processes of decomposition that he had identified as biological. He probably acted intentionally, for example, when he omitted acetic fermentation from the list of the “best characterized fermentations” that he had studied. This obvious omission can be explained by supposing that Pasteur defined as “fermentations properly so-called” only those processes associated with anaerobic microorganisms. Because acetification depended on Mycoderma aceti, an aerobic organism, it must be excluded from the true fermentations, even though it met two other fundamental criteria—it was microbial and it involved the decomposition of a weight of substance vastly greater than the weight of the responsible microorganism. Along somewhat similar lines, Pasteur differentiated between alcoholic fermentation “properly so-called” and the nonmicrobial production of alcohol by fruit cells in the absence of free oxygen. By itself, he insisted, the production of alcohol is no index of true alcoholic fermentation, for the latter process also yields glycerin, succinic acid, and other substances. This process is called “alcoholic fermentation” only by abbreviation; to be precise, one ought to designate it by its complete equation, the complexity of which reflects its dependence on living yeast.

As these examples make clear, Pasteur’s theory of fermentation reduced to a virtual tautology, for any process which failed to conform to that theory in every respect automatically failed to qualify as a fermentation “properly so-called.” In similar fashion Liebig might have maintained an unassailable chemical theor; of fermentation had he been willing to exclude from his definition of fermentation those processes which Pasteur associated with microorganisms. In so doing, however, Liebig would have excluded many of the decomposition processes traditionally regarded as fermentations—most notably ordinary alcoholic fermentation, which had always been considered the archetypal fermentative process. The fertility and power of Pasteur’s theory derived precisely from its applicability to these familiar processes, and he seemed remarkably unconcerned that it did not also apply to those processes associated with such soluble chemical ferments as diastase, emulsin, or pepsin, By admitting, or at least implying, that his theory also failed to apply to certain biological process—including acetification and the nonmicrobial production of alcohol by fruit cells—Pasteur invited confusion and threatened his own attempt to generalize the theory to all living cells. That his study of fermentation nonetheless produced valuable insights, both theoretical and practical, illustrates forcefully that not all circles are vicious.

The Issue of a Soluble Alcoholic Ferment . In retrospect, the most intriguing feature of the debate between Pasteur and Liebig is the extent to which they seemed ultimately to approach a mutually acceptable conception of fermentation. By 1869, at least, Liebig was prepared to admit the possibility that alcoholic fermentation depended in part of the life of yeast. Adopting a hypothesis by no means original with him, he suggested that living yeast cells might secrete a soluble chemical ferment, analogous to diastase or pepsin, which then induced the decomposition of sugar into alcohol and carbonic acid. This hypothesis drew particular support from the knowledge that yeast did produce at least one other soluble ferment, ferment glycosique or invertase, responsible for inverting cane sugar.

Pasteur made no immediate objection to Liebig’s suggestion; indeed, in his memoir of 1860 on alcoholic fermentation, he had mentioned the possibility that yeast might act by secreting a soluble ferment. In 1875, two years after Liebig’s death, Pasteur suggested that the process resulting from soluble ferments might someday be reunited with the true fermentations “in some way as yet unknown.”⁸⁵ In July 1876 he conceded that the ammoniacal fermentation of urine, which he had ascribed since 1860 to a living microorganism, could be traced more immediately to a soluble chemical ferment produced by the living ferment. When his opponents tried to exploit this concession, Pasteur emphasized that for twenty years he had devoted himself chiefly to demonstrating that the agents of fermentations were microorganisms. The precise mechanism by which these agents acted was a problem of a different order and required further investigation.⁸⁶

From this perspective the debate between Pasteur and Liebig seems to have ended as an essentially semantic dispute, a disagreement born of their approach to the phenomena of fermentation at different levels, with Liebig seeking its proximate cause and Pasteur content to establish more remote correlations. As Duclaux emphasized, however, the two position implied strikingly different experimental strategies.⁸⁷ Because this difference was reinforced by long-standing disagreements over experimental results, and by personal and national antagonisms, Pasteur and Liebig found it difficult to make concessions; and their potential rapproachement remained largely submerged in mutual hostility.

Even in the absence of these difficulties, Pasteur and Liebig might never have achieved a fully compatible conception of fermentation, for some of the issues which divided them reemerged in Pasteur’s debate with Marcelin Berthelot, the leading French advocate of the modified chemical theory of fermentation. Like Liebig, Berthelot had initially opposed Pasteur’s attempt to implicate living organisms in fermentation and had then moved to the view that living yeast might act by secreting a soluble alcoholic ferment. His views on fermentation derived particular authority from his having isolated from yeast the soluble ferment responsible for the inversion of cane sugar. In 1878 Berthelot arranged for the posthumous publication of manuscript notes in which Claude Bernard criticized Pasteur’s theory of fermentation and claimed to have isolated a soluble ferment capable of producing alcoholic fermentation independently of living yeast.

The publication of this manuscript placed Pasteur in an awkward position, for Bernard had long contributed his immense authority and support to Pasteur’s cause. To some extent Pasteur adopted the strategy of impugning Berthelot’s motives rather than the work of the revered Bernard, who had neither authorized the publication of his manuscript notes nor described their contents to Pasteur. Nonetheless, in a full-length critique of Bernard’s manuscript (1879), Pasteur attacked in devastating fashion the experiments by which Bernard believed he had destroyed Pasteur’s theory of fermentation as life without air. By carefully repeating these experiments and comparing them with his own, Pasteur went a long way toward justifying his claim that Bernard’s results were mistaken, dubious, or badly interpreted. In this task Pasteur benefited from the patently crude and preliminary character of Bernard’s experiments (at least as they were represented in the manuscript notes) and from their author’s inability to reply or defend himself. While expressing reluctance about taking advantage of these circumstances, Pasteur justified his action on methodological grounds. In his view Bernard’s manuscript offered a dramatic example of the danger of “systems” and “preconceived ideas,” a danger which Bernard himself had done so much to expose in his Introduction à l’étude de la médicine expérimentale (1865).

Saying that Bernard had somehow forgotten his own wise precepts, Pasteur suggested that he had been led astray by an a priori conviction of a fundamental opposition between organic syntheses, which he supposed to be peculiarly vital phenomena, and organic decompositions (including fermentation, combustion, and putrefaction), which he supposed to be physicochemical rather than vital processes. Because his theory of fermentation linked life and organic syntheses with a process of organic decomposition, Pasteur continued, it conflicted with Bernard’s general conception of life and thereby earned his rejection. From this perspective it was easy to understand why Bernard not only embraced the view that the immediate cause of fermentation was a soluble alcoholic ferment but also claimed that this soluble ferment existed—independently of yeast cells—in the juice of grapes at a certain stage of their maturity. By this claim Bernard sought even Liebig and Berthelot were willing to concede that it might be essential for the production of the hypothetical soluble ferment. Unfortunately for Bernard, said Pasteur, his claim was refuted by the fact that grapes of any degree of maturity never fermented when carefully protected from yeast germs.

If this version of Bernard’s “preconceived ideas” was less than fair or accurate—as Duclaux suggests⁸⁸ —Pasteur may have been driven to it by the extravagance of Bernard’s views. But it is clear from his critique of Bernard, and from the associated debate with Berthelot, that he was also suspicious of the more moderate attempts by Berthelot and Liebig to incorporate his “physiological” theory of fermentation into the modified chemical theory that yeast acted by secreting a soluble alcoholic ferment. Even as he insisted that he would be neither surprised nor disturbed by the discovery of such a chemical ferment—indeed, he reportedly sought it himself by grinding and plasmolyzing yeast cells⁸⁹—Pasteur asserted that the role of soluble ferments would one day be eclipsed by that of life without air.⁹⁰

Until his death Pasteur could retain this hope as he surveyed a long tradition of unsuccessful attempts to isolate a soluble alcoholic ferment. In 1897, however, while engaged in apparently unrelated immunological research, Eduard Buchner achieved this goal and thereby cast Pasteur’s physiological theory of fermentation into the shade. Even then, however, the phenomenon known as the “Pasteur effect”—the inhibition of fermentation in the presence of free oxygen—remained as real as it was inexplicable. More recently, the physiological and chemical theories of fermentation have come to be seen as complementary rather than opposed. If, at some level, Pasteur perceived this possibility, he never explained precisely how the notion of a soluble alcoholic ferment could be reconciled with the doctrine of fermentation as life without air. He sought instead to defend the conclusions he had already reached and challenged the wisdom or necessity of invoking the concept of a soluble alcoholic ferment. For him this concept remained a gratuitous and unproved assumption. For his opponents, and particularly and Berthelot, the concept of life without air was an equally gratuitous, unproved and unnecessary hypothesis. In short, if our present conception of fermentation suggests that the debate was largely semantic and capable of easy resolution, its participants were unable to see it that way.

Studies on Beer. During the late 1860’s the “pasteurization” of wine and vinegar became increasingly common. The process found a new application in Austria and Germany, where the practice of heating bottled beer to 55° C. became widespread following the publication of Pasteur’s Études sur le vin (1866). Beginning in May 1871, largely under the stimulus of the Franco-Prussian War, Pasteur launched a study of beer in hopes of serving “a branch of industry in which Germany is superior to us.”⁹¹ This effort, begun in Émile Duclaux’s laboratory at Clermont-Ferrand, led to a series of patents and to Pasteur’s Études sur la bière (1876). Meanwhile, Pasteur had become embroiled in a series of debates over fermentation and spontaneous generation; and the book on beer consists for the most part of a sometimes oddly organized and largely tedious rehearsal of those debates.

Only two chapters in the book were directed specifically toward the practical problems of brewing. In the first chapter Pasteur sought to demonstrate that the alterations or “diseases” of beer depend on the appearance and development of foreign microorganisms, “not at this time a new idea,” according to Duclaux.⁹² In the last chapter Pasteur described his process for manufacturing beer, which emphasized the use of pure yeast and carefully limited quantities of pure air. As in his books on vinegar and wine, he gave considerable space to descriptions and drawings of the industrial apparatus his new method would require. Perhaps because of its wide adoption in the German brewing industry, the method of preserving beer by heat received only passing and skeptical attention.⁹³

Among the advantages that Pasteur claimed for his new method of manufacturing beer, the most important were the elimination or reduction of costly cooling techniques (introduced empirically, but now explicable as a means of impeding the development of pathogenic organisms) and the protection of finished beer from disease. Nonetheless, Pasteur admitted that his process had “not yet been practically adopted,”⁹⁴ a result he ascribed chiefly to the costly retooling it would require. If attempts were ever made to exploit Pasteur’s patents on beer, their fate has yet to be described. Nonetheless, his more general contributions to the study of brewing attracted the attention and admiration of some industrial brewers, notably J. C. Jacobsen, founder of the Carlsberg brewery in Denmark. In the late 1870’s Jacobsen gave 1.5 million francs for the creation of a magnificent laboratory at his Carlsberg brewery. For this laboratory, which soon became a leading center of biochemical research, he commissioned a bust of Pasteur, who responded by dedicating his 1879 critique of Bernard to Jacobsen.⁹⁵

Pasteur and Spontaneous Generation, 1871–1879. If Pasteur believed that his triumph over Pouchet would silence the partisans of spontaneous generation, he was soon disappointed. The issue remained a subject of lively debate, especially in England and Germany, where Pasteur’s critics had rather less to fear from the judiciary proceedings of the Académie des Sciences and from the presumed association of spontaneous generation with Darwinian evolution and radical politics. When Pasteur rejoined the controversy in 1871 his chief French opponents were those who simultaneously challenged his theory of fermentation—notably Frémy and Trécul. In France the debate on spontaneous generation now focused on the origin of the alcoholic yeasts, although attention was also paid to the origin of the microorganisms found in putrefying eggs and in human abscesses. Bound up with these specific concerns were the broader issues of the transmutation of microbial species, the nature and distribution of germs, and the distinction between aerobic and anaerobic life. From July 1876 to July 1877 Pasteur also engaged in a celebrated controversy with the English naturalist H. Charlton Bastian, who claimed he could produce microorganisms spontaneously in neutral or alkaline urine. From this debate—the most productive in the series—Pasteur emerged with a firmer grasp of the relative distribution of germs in air, in water, and on solid objects, and—most important— with a greater appreciation for the heat resistance of certain microorganisms.

Pasteur rejoined the spontaneous generation controversy by attacking Frémy’s claim that the yeasts of vinification arose internally and spontaneously from grape juice upon contact with the air. In 1872, in an attempt to make his point decisively, Pasteur showed that a drop of unheated natural grape juice, aspirated from the interior of a ripe grape, would neither ferment nor give yeasts in germ-free air.⁹⁶ He took great delight in this delicate experiment, which he often linked with his earlier demonstrations that natural urine and blood could be preserved in germ-free air even without preliminary heating. Although Frémy and Trécul managed to find objections against even this experiment, Pasteur disposed of them quite readily and continued to cite the experiment as definitive proof against the internal, spontaneous origin of yeasts.

When Frémy then sought support for spontaneous generation in Pasteur’s demonstration that fruits could remain intact (hence closed to external germs) and yet produce alcohol in an oxygen-free environment, Pasteur was obliged to emphasize that no microorganisms participated in this process; it was a case of the fruit cells themselves acting as “ferments” under anaerobic conditions.

But Pasteur went much further. Denying that the yeasts of wine originated spontaneously within the grape, he sought to establish their precise external origin and to clarify their more general properties. By 1876, when he reported his results in his Études sur la bière, he felt confident that he had established the following generalizations about the alcoholic yeasts: (1) a great many yeasts exist, differing in form, physiological properties, and in the taste and other qualities that they impart to the fermenting liquid; (2) the yeasts of wine derive from germs that are particularly abundant on the wood of the grape cluster, somewhat less abundant on the surfaces of the grapes themselves, and rare in ordinary atmospheric air; (3) these germs gradually decrease in number and fecundity during the winter and are entirely absent from the surfaces of immature grapes; (4) these germs increase in number and fecundity as the grapes mature and as the time of the vintage approaches (so that when the ripe grapes are crushed, no yeasts need be sown, as they must in brewing beer); (5) these germs require oxygen to retain their vitality and thus their capacity to produce fermentation; and (6) the species of yeast are distinct, are not transformed one into the other, and do not represent special developmental forms of another plant.⁹⁷

In 1878, after Bernard’s manuscript on fermentation had revived the notion of an internal origin for the yeast of wine, Pasteur confirmed under natural conditions the central conclusions of his Études sur la bière. In July of that year, immediately after reading Bernard’s manuscript, he ordered the construction of several glass hothouses, with which he intended to cover some of the still immature vines in his own vineyard near Arbois. This plan had been executed by early August, before any yeast germs had appeared on the grape clusters. As a further precaution he wrapped some of the clusters within the hothouses in sterile cotton. By 10 October all the grapes had ripened and the time of vintage had arrived. As Pasteur expected, the exposed grapes easily and rapidly fermented when crushed, while those protected from yeast germs by the hothouses did not, except in one case. The grapes wrapped in cotton within the hothouses never fermented when proper precautions were taken. On the other hand, if these grapes were subsequently exposed in the open air, they soon fermented when crushed with the yeast germs that they had in the meantime received.⁹⁸

By these experiments Pasteur went a long way toward a definitive demonstration of the external origin of the yeast of wine. He had by then reached an equally firm position on the issue of the transmutation of microbial species. From the 1840’s to the early 1870’s, an increasing number of botanists claimed that they had observed the transformation of one microbial species into another; and their claims had been enlisted in support of Darwinian evolution and spontaneous generation. In 1861 Pasteur specifically challenged several presumed cases of microbial transmutation— notably of Penicillium glaucum into beer yeast—and his more general opposition to the doctrine seems implicit in his work on fermentation and spontaneous generation, with its dependence on the specificity and hereditary continuity of microorganisms. Nonetheless, Pasteur gave little explicit attention to the issue before the 1870’s; and his general position had been obscured by his claim of 1862 that he had observed the transformation of Mycoderma vini into the alcoholic yeast of wine under anaerobic conditions, more specifically when submerged in a fermentable liquid. For the next decade, as he continued to hold this view, Pasteur used it in support of his theory of fermentation as life without air. Then quite suddenly, in October and November 1872, he reconsidered and abandoned his earlier claim.⁹⁹

By Pasteur’s own account, this change of view had its origin in two sorts of observational evidence. First, even when he had sown only Mycoderma vini into the fermentable liquid, he sometimes found cells of Mucor mucedo or racemosus as well as yeast cells among the submerged mycodermic pellicle. Assuming that this Mucor could have entered the medium only from the surrounding air, he began to wonder if the air could not also be the source of the yeast cells he had hitherto supposed to be the transformed cells of Mycoderma vini. Second, yeast cells sometimes failed to appear in the submerged pellicle, even when the experimental conditions seemed identical. Why should the presumed transmutation fail to take place in these cases? To resolve his doubts Pasteur modified his swan-necked flasks in such a way as to permit the comparative study of the same microorganism under anaerobic conditions (when submerged) and under aerobic conditions (on the surface of a shallow liquid) without exposing the liquid medium to the ambient air or to any other external source of germs. Under these conditions Pasteur never again observed the supposed transformation of Mycoderma vini into yeast, and he never again wavered in his opposition to the notion of direct microbial transmutation.

If Pasteur felt any embarrassment about rejecting his original belief in the transmutability of Mycoderma vini, he probably found more than adequate consolation in the circumstance that his theory of fermentation not only remained intact but also acquired a new extension and generality. For his rejection of the transmutability of Mycoderma vini coincided with, and perhaps depended upon, the extension to all living cells of his theory of fermentation as life without air. In the light of this generalized version of his theory, he could and did ascribe fermentative power directly to the cells of Mycoderma vini under anaerobic conditions, without needing to suppose that they acquired this power by virtue of a transformation into yeast cells. Pasteur may also have been encouraged to take this position and to reassert his general opposition to microbial transformism by the influential work of the German botanists Anton de Bary and Ferdinand Cohn. Certainly he was not alone in his opposition to immediate microbial transformism; and de Bary, Cohn, and others contributed more than he to the general rejection of the doctrine.

With regard, finally, to Pasteur’s general position on the transmutation of species, it should be emphasized that he did not directly and explicitly repudiate Darwinian evolutionary theory per se. Although clearly skeptical of the theory and suspicious of its popularity—which he ascribed to its failure to require “rigorous experimentation” or “profound observations”¹⁰⁰—Pasteur insisted only that no one had demonstrated the immediate transformation of one microbial species into another.

The Pasteur-Bastian Debate. By July 1876, when Pasteur locked horns with H. Charlton Bastian, that influential English advocate of spontaneous generation had already established his reputation through his long and controversial The Beginnings of Life (1872) and had engaged the attention and opposition of the English physicist John Tyndall. Although Bastian’s advocacy of spontaneous generation depended on a wide range of experimental evidence and theoretical considerations, his dispute with Pasteur focused very narrowly on one issue: whether microorganisms can originate spontaneously in neutral or alkaline urine. Pasteur seems publicly to have ignored Bastian’s work until the latter sent a note to the Académie des Sciences in which he claimed that microorganisms appeared under carefully specified conditions in urine that had been boiled and subsequently protected from atmospheric germs. According to Bastian, the requisite physicochemical conditions were the intervention of potash and oxygen and a storage temperature of 50° C. On the assumption that the boiling killed any organism in the urine, Bastian claimed to have produced spontaneous generation.

Within a week Pasteur had repeated Bastian’s experiment and had confirmed in most cases his central result—boiled urine rendered alkaline by aqueous potash did indeed yield microbial life in germ-free air. With Bastian’s interpretation of this result, however, Pasteur profoundly disagreed. In his view Bastian’s result merely proved “that certain inferior germs resist 100° C. in neutral or slightly alkaline media, no doubt because their envelopes are not penetrated by water under these conditions as they are…[in] slightly acid media.”¹⁰¹ He referred Bastian to his memoir of 1861 on organized corpuscles in the atmosphere, in which he had discussed the heat resistance of microorganisms in alkaline media, and challenged him to repeat his experiments using potash—whether solid or in aqueous solution—that had been previously heated to 110° C. Under these conditions, Pasteur asserted, the urine would remain sterile and Bastian’s “spontaneous generation” would cease to exist.

The terms of Pasteur’s challenge imply his belief that Bastian had unwittingly introduced the germs of microbial life into his urine flasks by using germcharged potash or germ-charged water. Over the next several months Bastian refused to abandon his claim, insisting on the absurdity of the notion that germs could resist so caustic a substance as potash, demanding a direct demonstration of the heat resistance of germs, and complaining that his experimental procedures (including the exact neutralization of urine by potash) had not been faithfully reproduced by Pasteur and his collaborators, Jules Joubert and Charles Chamberland. As they fended off these objections, Pasteur and his collaborators sought to establish more precisely the external origin and degree of heat resistance of the germs supposedly introduced into Bastian’s flasks. Pasteur and Joubert launched a study of the distribution of germs in water, reinforcing and extending the earlier results of the English physiologist Burdon-Sanderson concerning the enormous quantity of bacteria in ordinary streams and the presence of germs even in distilled water unless it was stored in vessels rendered germ-free by flaming. They also noted the absence of germs in water from deep sources, where surface germs could not penetrate, and insisted on the extreme minuteness of the bacterial germs, which passed through all ordinary filters and required the invention of a new method for their collection (presumably a prototype of Chamberland’s porcelain bacterial filter).

In July 1877, having accepted Pasteur’s challenge to submit their dispute to a commission of the Académie des Sciences, Bastian went to Paris to repeat his experiment in the presence of this commission. Like Pouchet, however, Bastian eventually withdrew after a long and confusing dispute with the commissioners.¹⁰² Once again facing a commission on spontaneous generation without an opponent, Pasteur reaffirmed his claim that neutral urine could be kept sterile if all proper precautions were observed. By this time he had clearly identified three possible sources of germ contamination in Bastian’s experiments: to the potash solution originally suspected he added the experimental apparatus (even when carefully washed, since all water contains germs) and the urine, which can from the outset harbor germs capable of surviving boiling at 100°C. He did not yet fully appreciate the latter possibility, however, believing that the acidity of the normal urine with which Bastian began would prevent the appearance of these heat-resistant germs, and he chose instead to indict contaminated apparatus as the source of germs in Bastian’s experiments.

Only after Cohn, Koch, Tyndall, and others had established the existence of highly resistant bacterial endospores; only when it became clear that certain microorganisms could survive a temperature of 100°C, even in acid media; and only as microbial life continued to appear in certain liquids (notably urine and infusions of hay or cheese) despite every precaution to eliminate germs from the experimental apparatus—only then did Pasteur begin fully to perceive the possibility that the liquids used by Pouchet, Bastian, and other advocates of spontaneous generation may sometimes have harbored microbial life from the beginning rather than having subsequently acquired it through careless experimental technique.

By this time other aspects of Pasteur’s doctrine had come under open and serious challenge, especially in England.¹⁰³ Some challenged his evidence that the “organized corpuscles” in the air were living organisms, for that evidence was largely indirect and failed to establish a direct link between any particular living microorganism and its presumed antecedent germ or corpuscle. Others asked how germs living in the air– and thus presumably aerobic—could be responsible for processes that Pasteur ascribed to the activity of anaerobic microorganisms. To meet this argument, Pasteur suggested that germs possessed only latent life while in the air and therefore should not be called aerobic organisms in the ordinary sense of the word.¹⁰⁴

More or less convergent with these challenges were two doubts shared even by those who fully accepted his claim that the air contained living ferments. One doubt concerned whether the atmosphere in fact carried as much microbial life as Pasteur supposed. Pasteur himself had contributed toward this question by showing that microbial life was variably disseminated in the atmosphere and was certainly not so widespread as to exist in every sample of air. He had also drawn attention to the relatively high concentration of microbial life on grape clusters and in water as compared with the atmosphere, but some of his contemporaries advocated an even greater shift of emphasis to liquids and solid surfaces. The second doubt concerned the precise meaning of Pasteur’s often casual use of “germ.” In 1877 Burdon-Sanderson argued that Pasteur’s “organized corpuscles” were in fact finished, adult microorganisms and not their “germs” or precursors.¹⁰⁵

In both cases subsequent research has tended to confirm the doubts. Indeed, Pasteur himself emphasized in 1878 that surgeons had far more to fear from germs on their instruments or hands than from germs in the air,¹⁰⁶ and he seems not to have disputed the growing belief that many of his “germs” were adult microorganisms. Insofar as the word “germs” is used for adult microorganisms today, it is merely a perpetuation of Pasteur’s vague designation.

On the other hand, none of these doubts and criticisms really undermined Pasteur’s central positions on spontaneous generation and on “the infinite role of infinitely small” organisms. If some of his earlier views now required modification, and if Cohn, Tyndall, and others ultimately contributed as much as he to the still dominant sentiment against the doctrine of spontaneous generation, he had nonetheless laid the groundwork. Nor did Pasteur fail to derive practical benefit from the new attention to bacterial spores and to liquids and solids as the main vehicles of germ contamination. In Pasteur’s laboratory, and almost certainly under his watchful eye, Chamberland pursued some of the issues arising from the dispute with Bastian. In his doctoral dissertation (1879) Chamberland established the basic rules of modern bacteriological technique by showing that temperatures of at least 115^oC. were required to ensure the destruction of heat-resistant microorganisms in liquids, while temperatures of at least 180^oC. were required to achieve the same result on dry surfaces. Especially in the wake of Chamberland’s work, the autoclave and the flaming of glassware became standard in microbiological equipment and technique.¹⁰⁷

Pasteur and Medicine: The Background. Almost from the beginning of his work on fermentation and spontaneous generation, Pasteur made frequent reference to its potential medical implications. Sharing the common belief that fermentation and disease were analogous processes, he naturally supposed that the germ theory could apply to disease as well as to fermentation—as Theodor Schwann, among others, had supposed before his study of fermentation and spontaneous generation, the status of the germ theory of disease paralleled almost precisely the status of the germ theory of fermentation. In both cases the germ theory held less favor than alternative theories, but serious claims had been made for it on the basis of solid and highly suggestive evidence. Advocates of the germ theory of fermentation appealed chiefly to evidence that yeast was a living organism; the germ theory of disease drew its most impressive support from accumulating evidence of the important role played by living parasites in a number of plant and animal diseases, including such human maladies as trichinosis, scabies, and the fungal skin diseases, notably scalp favus.

At the same time, however, critics of the germ theory could cite apparently contradictory evidence, could insist that any microorganisms associated with disease or fermentation were merely epiphenomenal products of these processes rather than their cause, and could argue that the alleged examples of microbial processes were atypical or unimportant. With regard to disease, even those who accepted the pathogenic role of microscopic parasites in certain diseases often doubted or denied their role in the major killer diseases of man or other vertebrates. The notion that tiny living agents could kill vastly larger organisms struck many as absurd. Moreover, the complexity of disease, and the peculiarity of its expression in each patient, impressed most physicians with the seeming irregularity, spontaneity, and mystery of the process. From this perspective the germ theory of disease seemed too simplistic, inflexible, and remote, particularly because it emphasized the role of agents possessing a life and origin independent of the organisms in which disease became manifest.

In contrast with the emphasis of the germ theory on the “exteriority” of disease, the dominant concepts of the process stressed the internal state and quality of the affected organism. When external agents found a place in these schemes—and the existence of epidemics virtually required their inclusion—they were generally denied a life of their own and accorded a distinctly secondary role. In traditional medical doctrine these external agents—whether meteorological conditions, “cosmic-telluric” forces, subtle fluids, noxious effluvia, chemical poisons, or inanimate particles—acted chiefly as contributors to, or as transmitters of, pathological states the proximate genesis of which was internal and spontaneous. In Pasteur’s view the future of medicine depended on a literally life-and-death struggle against this traditional doctrine of the interiority and spontaneity of disease, a doctrine which found capsule expression in the slogan “Disease is in us, of us, by us.”¹⁰⁸

Through his efforts on behalf of the germ theory of fermentation and against spontaneous generation, Pasteur became a highly influential, if largely indirect, participant in this struggle during the two decades after 1857. His studies on the silkworm diseases may seem to represent his most direct and important contribution to the germ theory of disease, but persuasive evidence of microbial participation in certain insect diseases had long existed without transforming medical theory. Vastly more influential in this regard were two medical contributions immediately inspired and encouraged by Pasteur’s work on fermentation. The more familiar and dramatic of these was antiseptic surgery, introduced in the 1860’s by Lister, who openly saluted Pasteur for having provided in the germ theory of fermentation “the sole principle” upon which the antiseptic system had been built.¹⁰⁹ Although only gradually and rather reluctantly accepted, especially in England, Lister’s method eventually created a revolution in surgery and enormously advanced the cause of the germ theory of disease.

Almost simultaneously the French pathologist Casimir Joseph Davaine sought to establish a microbial etiology for anthrax or splenic fever, taking as his point of departure a paper by Pasteur on the fermentation of butyric acid. Struck by the similarity between Pasteur’s butyric ferment and some rods he had observed more than a decade before in anthrax blood, Davaine in 1863 launched his attempt to demonstrate experimentally that anthrax was caused by these rodlike organisms or “bacteridia.” ultimately the path from Pasteur’s work on fermentation to Davaine’s on anthrax carried traffic both ways, for anthrax became the subject of Pasteur’s first excursion into medical research per se. Twice in 1865 Pasteur took part in discussions on anthrax at the Académie des Sciences. On both occasions he gave qualified support to Davaine’s basic position, but the tone of his remarks betrayed his belief that anthrax remained obscure in many respects.¹¹⁰ As early as 1867 he specifically identified anthrax as the disease he hoped soon to study.¹¹¹ Not until 1877, however, did he publish the first of his papers on anthrax.

For a man of his bold readiness to tackle the major problems of the day, and for a man whose research had so long approached the medical domain, Pasteur seems to have hesitated a surprisingly long time before entering the struggle against traditional medical doctrine. His hesitation is all the more surprising because it persisted despite his expressed desire to undertake specifically medical research and his possessing ample opportunity, adequate resources, and–in a sense—an imperial mandate to do so. This mandate–along with the resources and facilities to carry it out—followed a remarkable appeal that Pasteur addressed simultaneously (on 5 September 1867) to Louis Napoleon and to the minister of public instruction.

Having just removed Pasteur from his administrative posts at the École Normale, the Ministry of Public Instruction had offered him a professorship in chemistry at the Sorbonne and a position as maitre de conférences in organic chemistry at the École Normale, with the right to retain his old apartment and laboratory there. Pasteur submitted a counter proposal. He agreed fully with his appointment at the Sorbonne but objected to the proposed position at the École Normale on several grounds, including his concern that two teaching posts might impede his research. Instead, he proposed the construction at the École Normale of a new, spacious, and well-endowed laboratory of physiological chemistry in which he would not teach but would continue his research. He supported his proposal by referring to “the necessity of maintaining the scientific superiority of France against the efforts of rival nations” and by projecting studies of immense practical importance on infectious diseases in general and on anthrax in particular.¹¹²

The emperor immediately expressed his support for Pasteur’s project in a letter to the minister of public instruction. Construction began in August 1868, the cost of 60,000 francs being shared equally by the Ministry of Public Instruction and the Ministry of the House of the Emperor. The new laboratory, thirty meters long, was to be linked by a gallery with the pavilion Pasteur had occupied since 1859. Largely because of the Franco-Prussian War, however, the laboratory remained incomplete as late as 1871. In September of that year, following the departure from Paris of the Prussian troops and the Communards, Pasteur returned from the provinces and immediately asked to be relieved of his remaining teaching duties at the Sorbonne because of his health. Claiming thirty years in university service (including his days as a tutor at Besançon), he requested a retirement pension as well as a separate national recompense in recognition of his contributions.¹¹³

By 1874, when Pasteur achieved the last of these goals, he had still taken no direct steps toward the study of anthrax projected in 1867. For the first four of the intervening years, his attention had been diverted by his desire to complete the silkworm studies under way since 1865 and by the Franco-Prussian War. By late 1871, however, he had solved the silkworm problem to his satisfaction and had at his disposal the new and presumably disease-oriented laboratory, as well as an annual research allowance of 6,000 francs. And yet, instead of turning to the direct study of disease, he continued through 1876 to devote his energies and the resources of his laboratory to his studies on been and to the persistent controversies over spontaneous generation and his germ theory of fermentation.

To a degree Pasteur considered the solution of these problems–and especially the destruction of the doctrine of spontaneous generation—a prerequisite to the direct and effective study of disease.¹¹⁴ But in the paper of 1877 that marked his full-fledged entry into the medical arena, Pasteur offered another explanation for his prior absence. Although long “tormented” with the desire of tackling the great medical problems of the day, he wrote, he had hesitated until now for two reasons:(1) he had needed a “courageous and devoted collaborator,” a requirement at last fulfilled in Jules Joubert, and (2) being “a stranger to medical and veterinary knowledge,” he had needed to overcome his fear of his own “insufficiency.”¹¹⁵

That Pasteur required assistance to undertake the experimental study of disease can scarcely be denied—not only because of his partial paralysis but also because of his attitude toward vivisection. As one who found vivisection personally repugnant,¹¹⁶ and yet considered it essential to his task, he needed collaborators who were willing and able to undertake the animal experiments he designed. But in view of the seeming ease with which he attracted such assistants—not only Joubert but also Duclaux, Chamberland, Emile Roux, Louis Thuillier, and Adrien Loir—one wonders whether he could not have found them long before 1877 had he really tried. On the other hand, Pasteur’s fear of “insufficiently”—while scarely in keeping with his usual self-assurance and his bold excursions into other fields in which he could claim no professional competence—does find some echo in his general ambivalence toward holders of the M.D. degree. Although he tended to disdain doctors for their traditionalism, their pretensions to scientific knowledge, and their preference for ritual and oratory over experiment, he envied their social status, their clinical experience, and their immediate, dramatic utility.

Much of this ambivalence emerged during meetings of the Académie de Médicine, where Pasteur became a frequent and controversial participant after his election to membership in 1873. Besides repeatedly defending his views on fermentation, putrefaction, and spontaneous generation, he occasionally ventured into discussions of more strictly medical topics even before 1877—most notably on urinary disorders and the use of cotton wool dressings in surgery. As might be expected, he linked ammoniacal urine with the “true ferment of urine” which he had discovered in the early 1860’s and which had since been studied in great detail by van Tieghem. For the treatment of such disorders he proposed the injection into the bladder of antiseptics, particularly dilute boric acid, the destructive action of which on the ammoniacal ferment he examined and the therapeutic efficacy of which he later affirmed on the basis of clinical reports from those willing to adopt his suggestion.¹¹⁷

With regard to cotton wool dressings, Pasteur argued that their efficacy depended not on the exclusion of air, as many surgeons supposed, but on the capacity of cotton wool to trap germs without impeding the circulation over the wound of presumably beneficial pure oxygen.¹¹⁸ If physicians and surgeons were annoyed by these unsolicited incursions into their domain by a “mere chemist,” they were incensed by his implicit charge that they often produced disease by carrying pathogenic microorganisms into their patients on contaminated hands or instruments. As early as 1874, in a passage reflecting his deep commitment to the germ theory of disease before he had entered strictly medical research, Pasteur wrote: “If I had the honor of being a surgeon, I would never introduce any instrument into the human body without having passed it through boiling water, or better yet through a flame, immediately before the operation.”¹¹⁹

The Etiology of Anthrax: The Background. By the time Pasteur finally did undertake his study of anthrax, its etiology had been largely resolved. Perhaps because it was a well-defined, economically important, and often fatal epidemic disease of large animals—particularly of cattle and sheep, although it could occur in humans in the form of “the malignant pustule”—anthrax had long been the subject of intense study and controversy. Davaine’s work of the 1860’s therefore aroused great interest, and anthrax quickly became a major focus for the debate between advocates and opponents of the germ theory of disease. Advocates of the germ theory emphasized Davaine’s claim that bacteridia always appeared in the blood of animals afflicted with anthrax but never in that of animals free of its symptoms, while opponents of the theory denied this invariable association and insisted that Davaine had failed in any case to prove the causative role of the bacteridia. If he had shown that anthrax blood could transmit the disease from one animal to another, he had not fully demonstrated that the bacteridia were the agents of this transmission. Moreover, Davine’s conception of anthrax scarcely helped to explain its behavior under natural conditions—its appearance or frequency in any given season or why it should selectively attack certain herds or fields while spring others. His attempt to implicate flies as vectors of the infection failed to account persuasively for these and other features of the disease.¹²⁰

Into this breach stepped Robert Koch, whose classic study of 1876 unraveled the complete life cycle of Davaine’s bacteridia (Koch’s Bacillus anthracis) and established the existence of an endospore phase. These anthrax spores, which preserved the virulence of the rods, could form in the blood and tissues of an animal after death and, once formed, resisted subsequent putrefaction or drying. Koch immediately recognized that these resistant spores held the key to understanding the natural behavior of anthrax, for they could retain their pathogenicity from one season to the next and could produce a recurrence of the disease in specific localities under appropriate conditions of temperature and moisture. Suggesting that natural infection probably took place through the food, he proposed preventive measures against the disease. In addition he developed new techniques for cultivating the anthrax bacillus and showed that successive cultures remained virulent despite repeated dilution.

Pasteur on the Etiology of Anthrax and Septicemia . Despite these achievements, which attracted widespread attention and acclaim, Pasteur believed that some doubts remained. As evidence he cited Paul Bert’s claim of January 1877 that anthrax blood could produce death even after its bacteridia had been killed by compressed oxygen. Since death occurred “without any trace” of bacteridia. Bert concluded that the latter anthrax.” Instead, he ascribed the disease to a “virus,” by which he meant a soluble chemical poison or some other inanimate agent. In his first memoir on anthrax (April 1877), Pasteur challenged Bert’s hypothesis by extending Koch’s successive dilution experiments. By greatly increasing the number of cultures (Koch had stopped at eight) and by using a much larger volume of cultural liquid each time, Pasteur diluted an initial drop of anthrax blood to the point of virtual disappearance. Nonetheless, each successive culture retained the original virulence. In his view this result persuasively established the dependence of anthrax on a living microorganism, for no other agent could have retained its power through so drastic a dilution. Only an agent which reproduced itself in each successive culture—almost certainly a living organism-could be responsible for the continued virulence of the original drop of blood. If Bert’s hypothetical chemical poison did exist, it must be capable of self-reproduction or must be continuously secreted by the multiplying bacteridia. But these possibilities, remote in any case, became even more so in view of the fact that the filtered liquid from each culture (which ought to contain any soluble poison) produced no effect when injected.

In his next paper on anthrax (July 1877), Pasteur offered his own interpretation of Bert’s experiment and applied it as well to the most damaging earlier evidence against Davaine’s work. In essence, he argued that the architects of this earlier evidence (notably Leplat and Jaillard), and probably Bert as well, had confused anthrax with a form of septicemia. As early as 1865, when Davaine made a similar charge, Pasteur had lent credence to it by reporting that Leplat and Jaillard’s supposed anthrax blood contained putrefactive microorganisms foreign to anthrax.¹²¹ What he sought now to do was to develop this argument and, more generally, to clarify the relationship between anthrax and septicemia. In this relationship, he insisted, the crucial factor is the time that elapses between death and the extraction of blood. At first, for perhaps eighteen hours, the blood of an animal dead of anthrax contains only the anthrax bacteridia. Eventually, however, this blood undergoes putrefaction and the bacteridia progressively disappear. Despite this disappearance, or despite the destruction of the bacteridia by compressed oxygen, the blood can remain virulent and can produce death in another animal.

One reason for the continued virulence, Pasteur suggested, was that such blood might continue to harbor anthrax bacteridia in the endospore phase, for the anthrax spores not only resist putrefaction (as Koch had already shown) but also survive the action of compressed oxygen. In such cases, however, the spores ought to germinate when injected into another animal, reproducing ordinary anthrax with its familiar rods. But Leplat and Jaillard, and apparently Bert as well, had insisted that their injections of anthrax blood had produced death in the absence of any microorganisms whatever. In these cases, Pasteur argued, the blood must have ceased to carry anthrax and must have become putrid or septic instead. More important, he claimed that the most familiar effects of putrid or septic injections also depended upon a microorganism —the hitherto unknown vibrion septique–and not an inanimate septic “virus,” as was commonly believed. To explain how the vibrion septique had previously escaped detection, Pasteur focused on the preoccupation of earlier observes with the blood a concern that had distracted them from a systematic search for pathogenic microorganisms in other parts of the body. In an animal dying of septicemia, microorganisms could be found in abundance in the muscles and in the abdominal serosities near the intestinal canal, but not in the blood until just before death. And when these organisms finally did enter the bloodstream, they became peculiarly long and translucent and easily escaped detection.

But even if such organisms did exist, and even if they had invaded the blood used by Bert, how could they have retained their virulence after being subjected to compressed oxygen? Pasteur’s answer hinged on the assertion that the new septic vibrio, like the anthrax bacteridium, had a resistant spore phase. In fact, he insisted, this spore phase appears within hours of the application of compressed oxygen to septic blood. Preserved in this immobile, resistant phase from further attack by oxygen, the septic vibrio can return to its motile, filamentary phase upon injection into another animal, producing death with the usual symptoms of septicemia. With only slightly less confidence, Pasteur suggested that the septic vibrio was one of the putrefactive vibrios found in the intestinal canal. If so, septicemia might properly be called “putrefaction on the living.” And since various putrefactive vibrios exist, one could expect a corresponding range of septic infections from the inoculation of putrid materials.

On the way to this new interpretation of Bert’s experiment—which Bert soon adopted—Pasteur offered some novel views on the physiological properties and modus operandi of the anthrax bacteridia. Having observed that filtered anthrax serum produced agglutination of the blood, he suggested that this familiar symptom of the disease might be due to a soluble ferment produced by the bacteridia. But this suggestion produced no shift in his basic conviction that the bacteridia themselves, and not any soluble ferment, were responsible for death from anthrax. In search of a mechanism by which the bacteridia might kill, he began by insisting on their aerobic character. Once in the blood, he supposed, these aerobic bacteridia would compete with the red blood cells, “those aerobic beings par excellence,” for oxygen. If the bacteridia won this struggle for existence, the animal would die of asphyxia, as suggested by the black color of the blood and viscera. In support of this notion, Pasteur reported that other aerobic microorganisms could impede the development of the bacteridia in cultural liquids or in animal bodies. Most remarkably, even animals highly susceptible to anthrax could survive an injection of bacteridia so long as the latter were accompanied by competing aerobic microorganisms. By his suggestion that these facts “authorize the greatest hopes from the therapeutic point of view,” Pasteur has won credit as a prophet of bacteriotherapy, in the development of which he played no direct or substantial role.¹²²

In March 1878 Pasteur described a remarkable new experiment on which he placed great importance for both the etiology and the treatment of anthrax. He showed that it was possible to transmit anthrax to hens, which are ordinarily refractory, merely by lowering their body temperature a few degrees. Aware that anthrax bacteridia could not develop in otherwise appropriate media at a temperature above 44°C., Pasteur had wondered whether the natural immunity of hens to anthrax might be due to the naturally elevated temperature of their blood. By plunging the legs of a chicken in an ice bath, he lowered its blood temperature several degrees; previously injected bacteridia were then able to develop and to induce death from anthrax. Conversely, he was able to prevent anthrax in rabbits, which are ordinarily susceptible, by raising their blood temperature several degrees. On this basis he hoped that it might prove possible to cure humans of “malignant pustule” by placing them in a bath warm enough to maintain a blood temperature of 41–42°C. By July 1878 he had cured a chilled hen of advanced anthrax by warming it. When some members of the Académie de Médicine raised objections against these experiments, Pasteur effectively demolished them in dramatic confrontations before the full Academy and by demanding a judiciary commission, which verified the exactitude of his results. In the light of subsequent research, Pasteur’s interpretation of these results, as well as the therapeutic hopes he based on them, seem somewhat naive, for such drastic changes in body temperature produce effects far more general and profound than those bearing directly on the anthrax bacteridia. Nonetheless, his results offered striking experimental evidence that receptivity to disease depends on factors beyond the mere presence of pathogenic agents.

Pasteur on the Etiology of Natural Anthrax. Beginning with reports to the minister of agriculture in September and October 1879, and more fully in a memoir of July 1880. Pasteur extended and refined Koch’s views on the etiology of natural anthrax. Through feeding experiments on large domestic animals (which Koch had not used), he confirmed Koch’s suggestion that the natural mode of transmission was the food. More specifically, he showed that sheep could contract anthrax by ingesting bacteridia spores, especially when the spores were mixed with a prickly diet of thistle leaves or short barbs of oats and barley. The resulting lesions strongly suggested that the disease began in the mouth and back of the throat. To explain how sheep and cattle came upon anthrax spores under natural conditions, Pasteur recalled that these spores withstood putrefaction and could therefore persist for months or even years in soil where diseased animals had been buried. Indeed, these spores could be found on the soil above such graves—where grazing animals might ingest them—while no spores could be found on the soil just a few meters away. In this way the existence of “infected fields” could be readily understood; they were fields in which animals dead of anthrax had been buried.

Pasteur’s most original contribution to the problem concerned the mechanism by which the immotile anthrax spores were brought from animal graves to the surface of the earth. The agent of this transfer, he insisted, was the common earthworm. After several days in soil containing anthrax spores, earthworms carried the spores in their intestinal canals. When they rose to the surface, they ejected these spores along with their earth castings. Once on the surface, the anthrax spores could attach to the plants on which sheep and cattle grazed or—as Pasteur recognized in January 1881¹²³—could be inhaled. These conclusions authorized a fairly obvious and simple prophylactic measure: animals dead of anthrax must never be buried in fields intended for grazing or the growing of fodder, at least not unless the soil in such fields was inimical to earthworms. If this measure were followed, Pasteur rather extravagantly predicted, anthrax could be a thing of the past, for the disease is never spontaneous and can be found only where its germs have been disseminated “by the innocent complicity of earthworms.”¹²⁴

The Extension of the Germ Theory to Other Diseases. Although Pasteur’s work on the etiology of anthrax and septicemia was largely a confirmation and extension of Koch’s work, it helped to raise anthrax to its special status as the first major killer disease of large animals widely admitted to be parasitic. Besides lending credence and interest to a series of earlier but inconclusive attempts to implicate microorganisms in major vertebrate and human diseases, this achievement ushered in what came to be known as the golden age of bacteriology. In less than two decades the microbial theory of disease was extended to tuberculosis, cholera, diphtheria, typhoid, gonorrhea, pneumonia, tetanus, and plague. Surprisingly, Pasteur and the French school contributed only minimally. The vast majority of these pathogenic microorganisms were isolated and studied by Koch and the German school, thanks in part to Koch’s mastery of microscopic morphology, classification, and technique and more particularly to his method of pure solid cultures, which Pasteur praised without adopting. For the most part Pasteur and the French school focused instead on the problems of immunity from and prophylaxis against microbial diseases—in a word, on vaccination.¹²⁵ But only after 1880 did these differences become dramatically clear, to be quickly reinforced by national and personal rivalries. Between 1878 and 1880 Pasteur and Koch seemed to be aiming toward similar goals: the elucidation of septicemia in its various forms and the extension of the germ theory to diseases other than anthrax.

Pasteur’s contributions toward these goals include a lecture of April 1878, “La theorie des games et ses applications a la medicine et la chirurgie,” and a memoir of May 1880 on the extension of the germ theory to the etiology of certain common diseases. In the 1878 lecture, delivered before the Académie de Medecine, Pasteur described the results of studies undertaken on the vibrion septique since discovering it the year before. To a large degree these results merely gave more explicit, elaborate, and confident form to his original conception of the septic vibrio. After several unsuccessful attempts to cultivate this organism by ordinary means, Pasteur and his collaborators had decided that it might be an obligate anaerobe, incapable of living in the presence of the oxygen dissolved in ordinary cultural liquids. They therefore switched to cultures in a vacuum or an atmosphere of carbon dioxide, with immediate success. But this obligate anaerobism applied only to the motile, filamentary phase of the vibrio. In its spore phase, the vibrion septique could obviously live in oxygen; it even survived could the compressed oxygen used by Bert. The perisstant virulence of the septice blood in Bert’s experiment—as well as the existence of natural septicemia in any form—depended absolutely on this spore phase. Only in the form of resistant spores could the otherwise anaerobic vibrio exist in ordinary air, ready to germinate and to produce septicemia if the spores penetrated a portion of an animal where oxygen was absent or nearly so. Until they reached such a site, the spores could not germinate and thus remained harmless.

In other words, Pasteur argued, the vibrion septique may be harmless or pathogenic according to environmental circumstances, just as its form, reproductive capacity, and virulence vary in different artificial media. Similarly, one of the most common bacteria remsembles the anthrax bacillus in its physicological properties—including obligate aerobism—and yet is harmless because it cannot live at the temperature of the animal body. yet another vibrio—the hitherto unrecognized “microbe of pus”—resembles yeast in its capacity to live either aerobically or anaerobically. And, like any solid body, the microbe of pus produces an abscess, or pocket of pus, upon injection into a guinea pig or rabbit. But the inordinate size of the resulting abscess clearly depends on the vital activity of the new microbe; if killed by heat before injection, it produces a much smaller abscess. Although far less dangerous than the anthrax bacillus or the vibrion septique, the microbe of pus can sometimes produce metastatic abscesses, purulent infection, and death. It can also modify the action and virulence of those more dangerous microorganisms when associated with them. More generally, the nature and relative proportions of specific microbes determine a richly varied set of pathological states.

If this is the central of Pasteur’s lecutre of April 1878, the message must be extracted from a diffuse and atypically obscure presentation of his views. In the same lecture, and more or less haphazardly, he also described methods for separating aerobic from anaerobic microorganisms; mentioned the difficulties his results posed for microbial classification; offered hygienic advice to surgeons; insisted that the acquired knowledge of anthrax and septicemia upset the doctrine of spontaneity; and argued that the vibrion septique was the true cause (rather than a product) of septicemia. probably without the intervention of any soluble ferment. In his advice to surgeons, probably the most famous section of the lecture, pasteur re peated and embellished the counsel he had given in 1874, before his entry into the medical arena. After the same opening phrase (“if I had the honor to be a surgeon”) he stated: “Impressed as I am with the dangers to which the patient is exposed by the germs particularly in hospitals, not only would I use none but perfectly clean instruments, but after having cleansed my hands with the greatest care and subjected them to a rapid flaming…. I would use only lint, bandages and sponges previously exposed to air of a temperature of 130 to 150° C; I would never use any water which had not been subjected to a temperature of 110 to 120° C; Finally, Pasteur quoted with price from a lecture given at the Acedmie des Sciences several weeks earlier by the distinguished surgeon Sédillot, who introduced the word “microbe” for microorganism and enthuisatically supported the germ theory and the new “Listerian” surgery arising from it.

In his paper of May 1880, “De l’extension de la theorie des germes a l’étiologie de quelques maladies communes,”Pasteur implicated micorbes in furuncles (boils), osteomyeitis, and puerperal fever. He reached his views on boils and on osteomyelitis after studying a single case of each. The case of boils belonged to one of Pasteur’s own assistants (Duclaux). when picked and submitted to culture, these boils gave a unique aerobic microbe of the form later called staphylococcus, to which Pasteur ascribed the local inflammation and consequent pus. When he found this same microbe in pus taken from the infected bone of a girl, he boldly marrow.” In his discussion of puerperal fever, Pasteur described seven cases of the disease, in each of which he found highly presumptive evidence of microbial participation, and then developed the views he had already expressed during a debate on puerperal fever at the Académie de Medecine in March 1879¹²⁶ During that debate Pasteur asserted that a microbe shaped like strings of beads caused most childbed infections, and he joined Semmelweiss in charging doctors themselves with the transmission of these infections. With his usual tone of disdain toward those who tried to classify microbes, he noted that some German authors had given the Latin name “micrococcus” to organisms having the form of the new puerperal microbe—including the ferment of ammonia al urine and the microbe of flacherie—and had enen tried to implicate micrococci in puerperal fever. Despite these attempts the etiology of puerperal fever remained obscure, chiefly because various microbes associated with pus could intevene to modify the symptoms and course of the disease. Finally, for the treatment of puerperal infections, Pasteur advocated the use of sterile water and bandages and, more specifically the application to the infected genital tissues of 4 percent solution of boric acid, which combined the advantages of known destructiveness toward at least one micrococcus (the ferment of ammoniacal urine) and inoffensiveness to mucous membranes.

Immunity, Virus Diseases, and the Discovery of Vaccines: The Background. From the outset of his work on anthrax, and even as his study of spetic infections converged with the German effort to identify new pathogenic microbes, Pasteur pondered what were then known in France as the “virus diseases” Typified by smallpox and presumed to be nonmicro bial their most striking feature was that they did not recur (or recurred in milder form) in the same individual. The strength of the “viru” (or poison) considered responsible for each of these diseases was usually assumed to be fixed and uniform for any given prices nut variable from one species to another. In particular the cowpox virus, which maintained a constant virulence through hundreds of transfers from man to man, clearly declined in strength when passed from cow to man. Thus “humanized,” the cowpox virus became the “vaccine” introduced by Edward Jenner at the end of the eighteenth century to protect man from attacks of small pox. Most authorities adopted Jenner’s belife that his vaccine was simply a milder form of the smallpox virus, modified by passage through the cow. But others claimed that smallpox and cowpox were independent diseases, due to distinct viruses of inherently different strengths. Variations in severity betwen different smallpox epidemics and in the course of the same epidemic, as well as variations in the duration of the immunity produced, further obscured the nature of the virus disease. Moreover, attempts to find “vaccines” or modified viruses against other diseases had produced nothing. and Jenner’s vaccine remained unique.

As early as June 1877, Pasteur announced that he had begun to study the virus diseases, and particularly the cowpox virus that served as Jenner’s vaccine¹²⁷ He clearly hoped to isolate a cowpox microbe (a vain hope), and he may already have perceived some connection between the virus diseases and the microbial disease of anthrax and septicemia. In fact, Davaine and others had already shown that anthrax and septicemia shared one property of the virus diseases: their virulence could be modified by passage through living animals. But the meaning of this isolated fact was obscure, and the possibility that such variations might be related to variations in the microbes of anthrax and septicemia ran afoul of the doctrine of microbial specificity. Although pasteur had done much to establish this doctrine, and continued to deny the transmutability of microbial species, his position was somewhat more flexible than that of Cohn or Koch. During his study of septicemia, he noticed that different cultures of the vibrion septique varied in virulence when injected into animals. At first, in keeping with the doctrine of microbial specificity, he supposed that these variable virulences depended on different species or varieties of septic vibrio. In April 1878, however, in his lecture on the germ theory to the Acadmeie de Medicine, he suggested that these variations should be ascribed to the effects of different cultural media on the properties of a single vibrion septique To suspect a connection between microbial diseases and the virus disease, an d to recognize that the virulence of the vibrion septique could be artificially modified, were to take some preliminary steps toward the concept of attenuated viruses and the technique of vaccination. But these early, almost instinctive steps gained real force and direction only through Pasteur’s study of fowl cholera.

Fowl Cholera and the Discovery of Vaccines. In December 1878 Toussaint, a professor at the Alfort Veterinary School, sent Pasteur some blood from a cock dead of fowl cholera¹²⁸ The symptoms of this disease, which has no relation to human cholera, include weakness, loss of coordination, droopy wings, erect feathers, and somnolence usually ending in death. Its progress through an infected poultry yard can be extremely swift, with most of the hens dead or dying in a few days. Like a few others before him, Toussaint linked the disease with a microbe, which he found in the blood of all hens having the disease. Beginning with the blood sent him by Toussaint, Pasteur immediately sought to isolate the microbe in a state of perfect purity¹²⁹ and to demonstrated by the method of successive cultures that it was the true and sole cause of fowl cholera. He soon found that this nonmotile microbe—in the from of a figure eight but so tiny as to resemble isolated dots—developed much more readily in neutral chicken broth than in the neutral urine used by Toussaint. By March 1879 he had found that a culture almost uniformly fatal for chickens was relatively benign for guinea pigs, and he drew an analyogy between the guinea pig and yeast extract, both being cultural media ill-suited to the development of the fowl cholera microbe.¹³⁰

In February 1880 Pasteur announced that although the fowl cholera microbe retained its virulence through successive cultures in chicken brothe, he had found a way of decreasing its virulence “by certain changes in the mode of culture.” In this milder form the microbe usually produced disease, but not death, in chickens. More important, the chickens that recovered from this less virulent form of the microbe became relatively immune to the highly virulent from. Unlike ordinary chickens they did not die from an injection of the microbe in its usual form. In other words, Pasteur concluded, “The disease is its own preventive. It has the character of the virus diseases, which do not recur. “what gave this result special importance and novelty was the demonstrably microbial nature of fowl cholera. Preventive inoculations were not new, but they had never been used against a disease known to be caused by a microorganism that might be cultivated outside of living organisms. Never had it been known that the property of nonrecurrence, associated with the so-called virus disease, could belong to a microbial disease. Fowl cholera thus formed the first clear link between microbial diseases and diseases “in the virus of which life has never been recognized.” Although many diffiuclities remained before the attenuated microbe of fowl cholera could be properly compared with Jenner’s vaccine—in particular, its constancy through a series of inoculations had yet to be assured—it offered hope that every “virus” might be artificially cultivated and that “Vaccines” might be obtained against the infectious diseases “which afflict humanity, and which are the greatest scourage of agriculture in the rearing of domestic animals.”

In announcing these dramatic results, Pasteur declined to reveal the method by which he had obtained the attenuated form of the fowl cholera microbe, saying that he wished to assure independence in his studies. Despite complaints from members of the Académie de Medecine in particular, he persisted in this course for nine months, during which period he reported the results of his subsequent studies. In April 1880 he admitted that inoculation with the attenuated form of the fowl cholera microbe produced very different results in different hens, but he insisted that the procedure always conferred some benefit. Even when two or more inoculations were required for complete protection against the disease, each acted in some measure to impede its course. He emphasized that “vaccinated” chickens, as well as species naturally resistant to the disease, must represent cultural media somehow ill-suited for the development of the microbe and suggested that this immunity probably resulted from the absence of some substance essential to the life of the microbe.

This suggestion drew support from the fact that cultivations of whatever sort (whether ordinary plants, parasites, or micorbes) modify a given medium (or “soil”) in such a way as to make subsequent cultivations of the same species difficult or impossible. Thus, after four days as a medium for the fowl cholera microbe, chicken broth will not support a new inoculation of the microbe. After the second day it will do so, but less readily than at first, which suggests that from the medium by the microbe. The same effects might be explained by supposing that the developing microbe produces some substance which is toxic to itself, but Pasteur rejected this hypothesis on the ground that cultural extracts developed easily in new chicken broth, although such extracts should contain any self-toxic substance secreted by the fowl cholera microbe.

In May 1880 Pasteur suggested that the fowl cholera microbe produces a soluble narcotic responsible for the characteristic somnolence of the disease. This suggestion echoes his earlier proposal that the anthrax bacillus produces a soluble substances responsible for the agglutination of the blood in that disease. Now, as then, he made the soluble substance responsible for only one symptom of the disease and ascribed death chiefly to asphyxia, citing the violet-tinged combs of diseased chickens and the aerobic character of the fowl cholera micobe, which implied a struggle for oxygen with the red blood cells. As evidence that somnolence and death had independent causes, he reported that vaccination prevented death but not extract-induced somnolence.

From late May to early October 1880, Pasteur participated in heated debates at the Académie de Medecine over the significance of his work on fowl cholera vis-a-vis smallpox and Jenner’s vaccine. Having shown that the fowl cholera “Vaccine” was only modified fowl cholera “virus” (or microbe), he felt confident that Jenner’s vaccines was only modified smallpox virsu. His opponents denied the relevance to this question of experiments on fowl cholera, claimed that physicians had long held the view that Pasteur was now needlessly repeating, and criticized him for keeping secret his method of attenuating the fowl cholera microbe. In return pasteur insisted on the importance of experimental evidence, accused his opponents of failing to grasp the real issue in dispute (the relation between smallpox and vaccine, not between cowpox and vaccine), defended his “reserve” On the method of attenuation, and ridiculed one opponent’s surgical procedures so viciously that the latter had to be restrained from physically assaulting Pasteur, whom he soon challenged to a duel¹³¹.

Finally, in October 1880, Pasteur described his method of attenuating the fowl cholera microbe. The first step was to procure the microbe in its most virulent form by taking it from a chicken dead of the chronic form of the disease. In successive cultures made at brief intervals, this virulence remained constant; but attenuation set in when the intervals reached two or three months. In general, the longer the intervals, the weaker the virulence became, although the results defied mathematical regularity. Throughout these changes in virulence, the microbe remained essentially constant in form. Furthermore, a virus (or microbe) of any given virulence retained this degree of virulence so long as successive cultures were made at brief intervals. To explain attenuation, Pasteur invoked the effect on the microbe of prolonged exposure to atmospheric oxygen. As proof he reported that no attention occurred in closed tubes, however, long the intervals between cultures might be. He suggested that oxygen might have a similar effect on other viruses or microbes and might even be responsible for the natural limits characteristic of great epidemics. Neither here nor anywhere else did Pasteur specify why oxygen should weaken microbes, especially those aerobic microbes (including the anthrax bacillus and the fowl cholera microbe) which ordinarily depended on it for life.

At one point in this memoir, Pasteur alluded again to his prior silence on the method of attenuation. The “true reason” for that silence, he said, ought now to be clear: “Time was an element in my researches.” What he did not reveal even now was the remarkable manner in which the crucial role of time had become known. In this case, as in his discovery of hemihedrism in the paratartrates, Pasteur seemed to enjoy extremely good luck.¹³² During his early experiments on fowl cholera, he followed his usual practice of making fresh cultures of the microbe every day or so. From late July to October 1879, however, the cultures were allowed to lie idle while he vacationed at Arbois.¹³³ During this period nearly all the cultures had become sterile and resisted attempts to restore their fecundity by inoculation into chickens. The seemingly useless cultures were about to be discarded when Pasteur proposed that the chickens in which they had produced no apparent effect be subjected to a fresh inoculation from a fecund, virulent culture. The chickens survived. “With [this] one blow,” wrote Duclaux, “fowl cholera passed to the list of virus diseases and vaccination was discovered!”¹³⁴ Against those who might call this discovery mere luck, Duclaux insisted that some “secret instinct,” some “spirit of divination” had led his master to it, while Pasteur himself might have repeated his famous phrase, “Chance favors only the prepared mind.”¹³⁵

In any case Pasteur immediately recognized that he had found a technique capable of extension to other diseases, and he moved toward this goal even as he kept secret his method of attenuating the fowl cholera microbe. Anthrax, the disease he knew best, served naturally as his first choice in the effort to find other vaccines. One may wonder how far this effort would have gone or how successful it would have been without a major expansion in Pasteur’s facilities and resources. In May 1880, shortly after the discovery of the fowl cholera vaccine, the city of Paris gave him access to some unoccupied land near his laboratory. On this site, which belonged to the old Collège Rollin, he made extensive provisions for the care and shelter of the many animals used in his experiments. Simultaneously the annual budget for his laboratory—fixed at 6,000 francs since 1871—was supplemented by an annual credit of 50,000 francs from the Ministry of Agriculture.¹³⁶ As he surveyed his new domain and as his team of assistants grew larger, Pasteur found new scope for those qualities that led Duclaux to compare him to “a chief of industry who watches everything, lets no detail escape him, wishes to know everything, to have a hand in everything, and who, at the same time, puts himself in personal relation with all his clientele…”¹³⁷

Pasteur and the Discovery of Antrax Vaccine . In his attempt to place anthrax among the virus or nonrecurring diseases and to find a vaccine against it, Pasteur faced competitors, notably Auguste Chauveau and Toussaint. As early as September 1879, Chauveau undertook to explain the relative immunity of Algerian sheep from anthrax and to reinforce that immunity by preventive inoculations. In July 1880 Toussaint announced that he had obtained an effective vaccine against anthrax. In opposition to Pasteur, Chauveau and Toussaint shared an essentially chemical theory of immunity, ascribing it to a soluble substance released by and noxious to the developing anthrax bacilli. Toussaint’s proposed vaccine reflects this view: he used filtered and defibrinated anthrax blood heated for ten minutes at 55° C. He supposed that these procedures freed a soluble vaccine from its microbial companions and claimed that sheep injected with this serum survived inoculations of virulent anthrax.

Toussaint’s announcement clearly shook Pasteur, whose biological theory of immunity and vaccination it directly threatened. Immediately upon hearing of the announcement, while on vacation at Arbois, he wrote Chamberland and Roux, his collaborators throughout his studies on anthrax, and asked them to join him for experiments designed to examine Toussaint’s claims¹³⁸. They soon found that Toussaint’s proposed vaccine did indeed provide protection in most cases; but they rejected his interpretation of how this process took place, criticized his experimental technique on several grounds, and disputed the general safety and practicability of his method of vaccination. While doing so, they defended Pasteur’s alternative conception of immunity and developed a different anthrax vaccine, based on fundamentally the same principles and techniques employed in the discovery of the fowl cholera vaccine.

As a matter of fact, Pasteur briefly considered the possibility that fowl cholera vaccine might also serve as an anthrax vaccine. In August 1880, on the basis of preliminary experiments, he claimed that chickens inoculated with the fowl cholera vaccine became simultaneously immune from anthrax. Unlike ordinary chickens, they did not contract anthrax when injected with its bacilli and subsequently chilled. Pasteur noted that this result, if established, would constitute the creation of immunity from anthrax by means of an entirely different parasitic disease. If applicable to other virulent diseases, it gave hope of immense therapeutic consequences, even in human diseases. Since he made no further mention of this result, one can only surmise that subsequent experiments failed to corroborate these preliminary claims.

Slightly earlier, in July 1880, Pasteur had made brief and passing reference to another possible mode of vaccination against anthrax: the gradual and moderate feeding of anthrax spores. He claimed that this idea had first occurred to him in the late summer of 1878, during his experiments on the etiology of natural anthrax. Having noticed that some sheep fell sick but did not die from the ingestion of anthrax spores, he injected eight of them with virulent anthrax blood. Of these eight sheep all but one survived the virulent injection, leading Pasteur to conclude that their recovery from diet-induced anthrax had rendered them immune to subsequent attacks of the disease. In reporting these results, nearly two years after they had been achieved, Pasteur recalled that Toussaint, who had just announced the discovery of a new anthrax vaccine, had witnessed these experiments, initially with skepticism but ultimately with conviction as to their accuracy¹³⁹.

Pasteur drew additional attention to these experiments and extended their basic result to cows in a letter of 27 September 1880. The occasion was a report to the minister of agriculture on a proposed empirical treatment for anthrax in cows. He reported that no valid judgement could be made of the proposed treatment because cows inoculated with anthrax sometimes succumbed despite the treatment, while others recovered in the absence of any treatment whatever. A far more interesting and significant conclusion—based on experiments conducted in August 1879 and in midSeptember 1880—was that recovery from an initial attack of anthrax preserved cows subsequently injected with virulent anthrax blood. Thus in cows, as in sheep, anthrax does not recur and inoculations that do not kill act as preventives. In the same report Pasteur defended his biological theory of immunity against Chaveau’s chemical theory. Contrary to Chaveau, he insisted that no toxic substance need be invoked to explain the relative immunity from anthrax of Algerian sheep and the reinforcement of the immunity by preventive inoculations. Instead, Algerian sheep ought to be compared with chickens, which are naturally and inherently resistant to anthrax without the intervention of any substance toxic to the anthrax bacillus. The proof of this contention lay in the fact that the mere act of chilling (which could hardly destroy any such substance) permitted the development of the anthrax bacillus in otherwise refractory hens. Moreover, the reinforcement of immunity by preventive inoculations could be likened to the progressive sterility of successive cultures of the bacilli in a given medium.

Pasteur undoubtedly realized that defending his theory of immunity or claiming priority for the discovery of nonrecurrence in anthrax was quite different from producing a safe and effective vaccine. After his “accidental” discovery of the fowl cholera vaccine, the path to such a vaccine must have seemed fairly direct: by increasing the interval between successive cultures of the anthrax microbe, and thus prolonging its exposure to atmospheric oxygen, he could hope to attenuate it. However, the extension of this method to the anthrax microbe was neither so obvious as he might have feared nor so rapid and straightforward as he might have hoped. Not until February 1881 did Pasteur announce the production of the new anthrax vaccine; the resistant spore phase of the anthrax bacillus (a phase which the fowl cholera microbe does not possess) had formed the chief obstacle because it undergoes no alteration upon exposure to atmospheric oxygen.

To attenuate the anthrax microbe, therefore, it was necessary to prevent the production of spores without simultaneously killing the microbe. This feat could be accomplished only by a quite delicate application of heat during cultivation. More specifically, in a medium of neutral chicken broth, the bacillus could live and grow without forming spores at a temperature between 42° and 44° C., while a temperature of 45° C. killed it. Once obtained, however, this asporogenous culture underwent rapid attenuation. After only eight days at 42–44° C., the culture proved harmless to guinea pigs, rabbits, and sheep, three species otherwise highly susceptible to anthrax. Most important, the microbe could be cultivated and conserved in this harmless state, as well as in each degree of attenuation achieved during the previous eight days; and each of these attenuated strains acted as a preventive or vaccine for the less attenuated strain that immediately preceded it. Pasteur claimed that he had already had great success in protecting sheep from anthrax with these vaccines and announced that the method would be given a large-scale trial when the sheep-penning season arrived in the Beauce district.

Also in the memoir of February 1881, Pasteur described the results of experiments in which animals of various ages and species had been injected with variously attenuated strains of the anthrax microbe. Despite the almost random character these experiments must sometimes have presented, they led to a general conclusion of great theoretical and practical importance—that attenuated viruses (or microbes) could return to their original virulence after successive cultures in appropriate animals. Thus a one-day-old guinea pig might succumb to an anthrax microbe that had been attenuated to the point of harmlessness for an adult of the species. If passed from this one-day-old guinea pig to progressively older ones, the microbe gained steadily in virulence until it reached its original capacity to kill adult guinea pigs and even sheep. Unless subjected anew to the attenuation procedure, the microbe would retain this original virulence. In similar fashion a fowl cholera microbe attenuated to harmlessness for chickens might remain virulen for canaries or other small birds and might regain its original virulence. In harmlessness for chickens might remain virulent for canaries or other small birds and might regain its original virulence by passage through them. This progressive return to original virulence not only offered a means of preparing vaccines of all intermediate degrees but also suggested a possible explanation for new eruptions of old epidemic diseases and for the occasional appearance of entirely new epidemic diseases. By progressive passage through other species, a microorganism might regain a virulence once lost through natural attenuation or might become virulent to a species for which it had hitherto been harmless. With remarkable prescience Pasteur thus broached the question of the evolutionary relationship between parasites and their hosts. In essence, he had perceived that different animal species, including man, can serve as reservoirs of inflection for each other; and he recognized that there was virtually no hope of a complete and final victory over epidemic diseases by preventive measures of any sort, including his own.

When this memoir appeared, Toussaint had not yet published the results obtained with his proposed anthrax vaccine. But Pasteur already felt confident that Toussaint’s “uncertain” method would compare poorly with his own, which rested on the existence of vaccines producible at will and without resort to anthrax blood. A month later, in March 1881, he subjected Toussaint’s proposed vaccine to a probing critique. In the first place, he argued, whatever success Toussaint had achieved resulted not from the death of the anthrax microbe (and consequent isolation of a presumed soluble vaccine) but from its unintentional attenuation by heat. Unfortunately, this protective modification of the anthrax bacillus was only one of three possible effects of Toussaint’s unreliable method of heating anthrax blood to 55° C. In certain cases the microbe might survive without modification and thus retain its original virulence upon injection. In still other cases it might indeed be killed, as Toussaint supposed; but its injection would then fail to protect the animal from a subsequent attack of anthrax. Nor did the use of filtration improve the reliability of the method. Filtered anthrax blood might retain all its original virulence; more commonly, it would fail to act at all and would thus confer no protection against a subsequent attack. In short, no anthrax vaccine could be produced by successive filtrations or dilutions of an original quantity of anthrax blood. Moreever, even when Toussiant’s method did attenuate the anthrax microbe, and even if it could be made to do so consistently and reliably, it still presented serious practical difficulties. Unlike Pasteur’s fowl cholera vaccine or his new anthrax vaccine, Toussaint’s heatmodified anthrax microbe could not be reproduced in culture so as to preserve its modified virulence. His method therefore required a large and continually renewed supply of anthrax blood.

In a separate paper of the same day (21 March 1881), Pasteur reported that he and his collaborators had produced an anthrax vaccine so attenuated that it failed to kill even newborn guinea pigs. This vaccine, the product of forty-three days of attenuation at 42–43° C., could therefore regain its original virulence only through some new species even more susceptible to anthrax. Nonetheless, the new vaccine displayed no appreciable morphological differences from the most virulent form of the bacillus and grew with equal facility in artificial media. Most important, this fully attenuated microbe (and all others of intermediate virulence) shared with the original, fully virulent culture the capacity to form spores that preserved the virulence of the anthrax rods. This meant that anthrax vaccines of whatever degree of virulence could be fixed in that state by passage into the spore phase and could then be stored or transported over long distances without fear of alternation.

The Experiments at Pouilly-le-Fort. Unlike fowl cholera—which was quite rare and local in its effects —anthrax posed a severe economic threat to French agriculture and animal husbandry. According to Pasteur, estimates of the annual loss from anthrax ranged from 20 to 30 million francs¹⁴⁰. His announcement of an effective anthrax vaccine therefore excited great interest, and the Agricultural Society of Melun quickly proposed a public field test of the new method. Much of the initiative came from H. Rossignol, a veterinarian who had earlier satirized the growing deification of the germ theory and of Pasteur as its “pontiff” and “prophet,” and who new produced a list of] about 100 subscribers willing to underwrite the costs of a field trial of Pasteur’s anthrax vaccine¹⁴¹. At the end of April 1881, Pasteur and the Agricultural Society of Melun agreed upon a course of experiments, to be arranged and supervised by Rossignol, who gave the program wide publicity by sending copies throughout the world. The program captured international attention as much by its uncompromising and boldly prophetic character as by its inherent importance-so much so that the Time of London sent its paris correspondent to Rossignol’s farm at Pluilly-le-Fort to provide a serial eyewitness account.¹⁴²

As initially agreed upon, the program called for the injection of virulent anthrax culture into fifty sheep of any age, variety, or sex, of which half were to be unvaccinated while the other half were to be previously vaccinated by separate inoculations of two unequally attenuated by separate inoculations of two unequally twenty-five unvaccinated sheep would die from the virulent injection, while all twenty-five vaccinated tinguishable from ten additional sheep kept apart as an index of normalcy. At the request of the Agricultural Society of Melun, Pasteur later agreed to substitute two goats for two of the fifty sheep to extend the trial to ten cows, of which six were to be vaccinated and four unvaccinated. Although somewhat less confident of the results on cows, he predicted that the six vaccinated cows would remain healthy when injected with the virulent culture, while the four unvaccinated cows would die or at least become very ill.

The experiments began on 5 May 1881 with the injection of an attenuated anthrax culture into twentyfour sheep, one goat, and six cows. On 17 May each of these animals was inoculated with a second attenuated culture, somewhat more virulent than the first. On 31 May Pasteur and his assistants-Chamberland, Roux, and Thuillier—injected a fully virulent anthrax culture into each of these thirty-one vaccinated animals and into twenty-nine unvaccinated animals —twenty-four sheep, one goat, and four cows. They inoculated the vaccinated and four cows. They alternately, “to render the experiments more comparative” and set 2 June as the date on which the crowd should reassemble to observe the results. In the meantime some of the vaccinated animals became feverish and Pasteur’s faith wavered briefly; indeed, it has been asserted that he temporarily feared the possibility of public ridicule and, in a overwrought state accused Roux of carelessness and thought of sending him to face the crowd alone¹⁴³. But a telegram from Rossignol informed him on the morning of 2 June that the would find a “stunning success” when he arrived at Pouilly-le-Fort that afternoon¹⁴⁴. When he and his collaborators made their triumphant arrival at two o’clock, all to the vaccinated sheep were alive and apparently healthy; all but three of the unvaccinated sheep were dead, and they were failing repidly. Two dropped before the spectators’ eyes and the third died at the end of the day. The six vaccinated cows were also perfectly healthy, while the four unvaccinated ones were swollen and feverish. Upon seeing Pasteur, the crowd burst into applause and congratulastion. It was perhaps the single most dramatic moment in a singularly dramatic scientific career.

In his published account of these experiments (13 June 1881), Pasteur reported that one of the vaccinated sheep (a ewe) had died on 3 June. But an autopsy revealed that this ewe had been pregnant and that her fetus had been dead for two weeks. Rossignol and a fellow veterinarian, who had jointly conducted the autopsy there fore linked the ewe’s death with that of her fetus, a diagnosis that aroused acrimonious but inconclusive debate. In the same report Pasteur insisted that the vaccine should be prepared and controlled in his laboratory, at least for the time being lest a poor application of the method compromise its future. Finally, the emphasized that the new vaccine, as an artificial product of the laboratory, market a great advance over Jenner’s smallpox vaccine, which 22 June 1881 he developed this distinction further, noting that the smallpox microbe remained unknown if indeed it existed at all and that the preservative powers of the Jennerian vaccine gradually deteriorated, presumably because it could not be conserved in the form of spores.¹⁴⁵

Anthrax Vaccination After 1881. Controversy and Triumph. In the wake of the dramatic success at Pouilly-le-Fourt, Pasteur and his laboratory received a flood of requests for supplies of the new anthrax vaccine. On Christmas Day 1881 in a private note to the president of the Council of Ministers, Pasteur proposed the creation of a state factory for the manufacture of anthrax vaccine, of which the should be the director assisted by Chamberland and Roux. By its support for this project, the French state would gain prestige and gratitude as the disease disappeared. In return Pasteur asked only that he and his family “be freed of material preoccupations.”⁴⁴⁶ Ultimately the government rejected Pasteur’s proposal, and his laboratory remained the center for the manufacture of anthrax vaccine; one annex of the laboratory, under Chamberland’s supervision, was given over entirely to the production of this and other vaccines discovered subsequently.

As efforts were made to meet the growing demand for the anthrax vaccine, Pasteur noted that his achievement raised at least one important new problem—the duration of immunity conferred by the vaccine. By June 1881 his experiments suggested that protection against injections of highly virulent anthrax culture lasted at least six months leading him to suppose that it would last a year under normal conditions of field exposure. If it proved necessary, annual revaccination should pose no serious obstacles, for the procedure took little time and the vaccine cost very little to produce.¹⁴⁷ In late January 1882 Pasteur injected a new virulent anthrax culture into the sheep vaccinated nearly eight months before at Pouilly-le-Fort. All survived. In his view this result solved the question from a practical point of view, since the normal anthrax season ran only from April to October. Animals vaccinated in April of each year would therefore acquire complete protection from the disease.¹⁴⁸ By March 1883 Pasteur realized that the duration of immunity followed no general law, varying from animal to animal, so that annual revaccination was indeed indicated.¹⁴⁹

In the meantime Pasteur basked in the fame and general success of his method of anthrax vaccination, while seeking to explain to minimize those failures or “accidents” which occurred as the procedure became increasingly common and increasingly distant from his direct control. In August 1881 he went in triumph to London, where he addressed the International Congress of Medicine on vaccination. While summarizing his earlier achievements, Pasteur reported that a commission of doctors and veterinarians had asked him to repeat the Pouilly-le-Fort experiments using infected anthrax blood in place of a virulent anthrax culture as a test of the preservative powers of the attenuated vaccine. These experiments, conducted at Chartres, produced equally decisive and favorable results. Pasteur characterized vaccination as a great advance in “microbiology” (the word he preferred to the more restrictive and “Germanic” word “bacteriology”)¹⁵⁰ and emphasized that his extension of the word “vaccination” to include preventive inoculations of any sort of attenuated culture was meant as homage to Jenner. What he had seen and heard during the Congress (including Koch’s technique of solid culture) struck him as evidence not merely of the advance but of the triumph of the germ theory of disease.¹⁵¹

Late in January 1882, during his return to Pouilly-le-Fort for experiments on the duration of immunity, Pasteur received three medals commemorating his original experiments there. At the festive meeting of the Agricultural Society of Melun, where this honor was bestowed, Pasteur reported that more than 32,000 sheep had already been vaccinated, with a mortality rate about one-tenth that of unvaccinated sheep under ordinary conditions of field exposure. In fact, about 400 sheep had been saved, and the number would have been even greater had the vaccinations been made earlier in the season. As for those deaths which did occur immediately after vaccination, only a portion should be ascribed to accidents in the procedure itself; the others should be charged to the disease having already invaded the animal before its vaccination.

By June 1882, however, as reports of accidents increased, Pasteur admitted that the vaccines supplied by his laboratory from November 1881 to March 1882 had been less than adequate, despite their being direct cultural descendants of earlier, completely successful vaccines. Experience revealed that the vaccines gradually deteriorated (like Jenner’s vaccine), leading to two sorts of unfortunate accidents: (1) the first of the two preventive inoculations might be made with a culture too weak compared with the second, so that the latter produced death upon injection; and (2) both vaccines might be too weak to act as a preventive against the natural disease. When these problems and their causes became clear, effective new vaccines were developed and sent free of charge to all who requested them. Pasteur also insisted again that accidents could occur through no fault of the vaccine itself: not even Jenner’s vaccine could prevent smallpox once the disease had become established. Moreover, because of interspecific or interracial differences in susceptibility to anthrax, a vaccine perfectly appropriate for, say, one race of sheep might be entirely unsuited to another. Therefore vaccination should be extended to a new race of sheep or cattle only after preliminary tests had determined the appropriate degree of attenuation. In any case, occasional accidents should not be allowed to obscure the demonstrable overall value of anthrax vaccination. To encourage its general adoption, Pasteur proposed that farmers be reimburse for any losses suffered from accidents in the procedure, with the revenues for this guarantee to be raised by a surcharge of ten centimes on each vaccination.¹⁵²

At the end of this paper of June 1882, in response to a remark from the floor, Pasteur charged the veterinary school at Turin with a careless experimental error that had undermined confidence in his method of vaccination. A commission from that school had found that his vaccines failed to prevent death from the injection of virulent anthrax blood. In a bold assertion from after Pasteur ascribed their failure to the inadvertent use of anthrax blood contaminated with septicemia. For nearly a year thereafter, Pasteur and the Turin school exchanged charges and invective in open forum. When the Turin school denied his assertion and accused him of arrogance for his diagnosis-at-a-distance, Pasteur offered to come to Turin to demonstrate that anthrax blood becomes partially septic within a day. The Turin school replied that no such simple and restricted demonstration could decide the real issues in dispute and compared Pasteur to a “duelist who challenges all those who dare to contradict him….but who has the habit of choosing the weapons and of obliging his adversaries to fight with their hands tied.¹⁵³

In his rejoinder Pasteur continued to limit the debate to the narrow confines within which he had placed it. He reported that Roux had confirmed the point he wished to demonstrate before the Turin school by showing that the blood of an anthrax victim dead for twenty-six hours contained both the anthrax bacilus and the vibrion septique which could be separated by appropriate methods of culture (the bacillus grew in air; the vibrio in vacuo). Besides implying that his adversaries feared a direct confrontation with him, Pasteur impugned their motives by citing a passage in which they had distorted his views by quoting him out of context. According to Pasteur Vallery-Radot, the Turin school never admitted defeat; nevertheless anthrax vaccination soon became as widespread in Italy as elsewhere.¹⁵⁴

More disturbing criticism of Pasteure’s work came from Germany, where Koch and his school contributed their impressive authority to the cause. Scarcely concealed beneath the scientific and methodological issues dividing Pasteur and Koch were powerful personal and national antagonisms. As one whose basic training lay in chemistry, and whose attiture toward naturalists and physicians sometimes approached the contemptuous, Pasteur belonged to a tradition different from that of Koch, whose training had been in medicine and whose career owed so much to the botanist Ferdinand Cohn. A more immediate source of their later confrontation lay in Pasteur’s tendency to minimize the originality and decisiveness of Koch’s work on anthrax. Indeed, from 1877 he repeatedly claimed priority for the discovery of resistant bacilli endospores, citing passages in which he had described the formation of resistant “corpuscules brilliants” or “corpuscules-germs” in flacherie.¹⁵⁵ To him Koch’s discovery of a resistant endospore phase for the anthrax microbe amounted to merely a confirmation and extension of this earlier discovery. With a convenient disregard for the difference between his rather brief, ambiguous description of “corpuscules brilliants” in flacherie and Koch’s precise and fullfledged account of the anthrax endospore. Pasteur implied that the special character and full significance of these “corpuscles” had always been clear to him and ought therefore to have been clear to Koch and other naturalists. In fact, as Koch well known the existence and significance of bacilli endospores had received little attention before 1875, when Ferdinand Cohn recognized their crucial place in the life cycle of Bacillus subtilis

However deep and long-standing these tensions between Koch and Pasteur may have been they remained largely suppressed until 1881, when the German Sanitary Office published the first volume of its journal Mittheilungen aus dem Kaiserlichen Gesundheitsamt. In this volume Koch and his students attacked Pasteur’s work on disease on several grounds, of which perhaps the most damming was their charge that his liquid media (as opposed to Koch’s solid media) failed to guarantee pure cultures. In fact, the German school alleged that Pasteur’s supposedly “attenuated” anthrax cultures or “vaccines” were merely contaminated cultures.¹⁵⁶ They also accused him of confusing several other diseases with septicemia and of unacknowledged dependence on Koch and other for the most accurate and valuable portions of his work. Koch disputed Pasteur’s claims that earthworms play a central role in the spread of anthrax and that domestic animals ordinarily contract it through lesions of the mouth and throat caused by prickly diets.

Pasteur was apparently unaware of these charges when he met Koch at the International Congress of Medicine in August 1881 and described the latter’s solid media as a “great progress.” But in September 1882, during the international Congress of Hygiene and Demography at Geneva he mounted a vigorous defense of his work against Koch and his pupils, blaming their “inexperience”: for the “multitude of errors” they had committed.¹⁵⁷ Fortified by the results of his experiments at Pouilly-le-Fort he virtually demanded a response from Koch who sat among the audience. Considering the Congress an inappropriate forum for such a discussion, Koch had little to say, although he promised to respond in print to Pasteur’s address. There months later he kept he kept his promise with Ueber die Milzbrandimpfung. Eine Entgegnung auf den von Pasteur in Genf gehaltenen Vortrag. In an abrupt shift of position, Koch hailed the discovery of attenuation as a major achievement but gave Toussaint, rather than Pasteur, priority for it and justified his own earlier skepticism on the ground that his French rival had failed at first to provide a complete and explicit account of his method of attenuating the anthrax microbe. Moreover, he continued to condemn Pasteur’s method of vaccination from a practical point of view, citing the experiments of the veterinary school of Turin as well as other “accidents” and unresolved issues, including the duration of immunity. He continued also to cast aspersions on the purity of Pasteur’s cultures, on his secrecy, and on his more general knowledge of medicine and pathological bacteriology. Pasteur’s rejoinder took the form of a long open letter to Koch dated Christmas Day 1882. Combining heavy sarcasm with considerable persuasion, he refuted Kock’s critique point by point until it seemed to contain nothing of value but belated and grudging concessions to Pasteur’s point of view.

For several years thereafter, the Pasteur-Koch dispute remained mostly in the shadows, as Pasteur’s method of anthrax vaccination spread throughout Europe with striking success. In April 1883 Pasteur could insist that the new anthrax vaccines—introduced in November 1882—were so safe that not a single animal had fallen victim to a vaccination accident in the meantime, while their efficacy was so great that he could not have been consoled had attenuation been other than a “French discovery.”¹⁵⁸ One month later Pasteur reported that a field trial of his anthrax vaccine had been conducted in two regions of Germany, under the auspices of the Prussian minister of agriculture, and that the results of the first year, released that month in Berlin, had been so favorable that the farmers of those regions had decided to adopt the procedure.¹⁵⁹ In August 1887, after Pasteur announced that the “Berlin school” had been covered, Koch denied that he modified his views on the practical value of vaccination and insisted that no guarantee existed as to the accuracy of Pasteur’s glowing statistics on the procedure. To Pasteur this position represented blind obstinacy in the face of the testimony of veterinarians, whose reports he promised to submit to the forthcoming International Congress of Hygiene and Demogrphy in Vienna. These reports, like all that followed, can only have embarrassed Koch. By 1894 Chamberland could report that 3,400,000 sheep and 438,000 cattle had been vaccinated against anthrax, with respective mortaility rates of 1 and 0.3 percent. Comparing these rates with earlier mortalities among unvaccinated animals, he estimated a saving through vaccination of five million francs for sheep and two million francs for cattle.¹⁶⁰

The Attenuation of the “Saliva Microbe” and of a Microbe Found in “Horse Typhiod.” Pasteur’s work on anthrax vaccines reinforced his belief in the general applicability of the method of attenuation discovered for the fowl cholera microbe. As early as June 1881, soon after the Pouilly-le-Fort experiment, he reported the extension of this method to a third microbe; the “saliva microbe” (later recongnized to be a pneumococcus), first obtained in December 1880 from the saliva of a child dead of rabies. This saliva produced rapid death upon injection into dogs or rabbits, the blood of which become infested by the new microbe, similar morphologically (a figure eight) but not physiologically to the fowl cholera microbe. The origin of the saliva raised the possibility that the new microbe might play some role in rabies; and Pasteur spend several weeks investigating this possibility, while carefully refraining from publishing any definite conclusions. In March 1881, having found the new microbe in the saliva of young victims of other diseases and in healthy adults, he denied any connection between it and rabies. Indeed, by the time he announced his success in attenuating this new microbe, again by prolonged exposure to atmospheric oxygen, he suggested that it might be entirely harmless to man, however lethal its effects when injected into rabbits or dogs.¹⁶¹

In September 1882, at the International Congress of Hygiene and Demography in Geneva, Pasteur gave a much fuller account of his work on the saliva microbe and disclosed the discovery of a fourth example of attenuation by atmospheric oxygeny—that of a microbe obtained from the nasal discharges of a horse dead of “horse typhoid.” Rabbits injected with these discharges died in less than twenty-four hours of a “veritable typhoid fever,” accompanied by the appearance in their blood of a new microbe—once again in the form of a figure eight. Like the microbes of fowl cholera, anthrax, and saliva, the aerobic character of which it shared, this new microbe underwent no change in virulence in closed tubes but became progressively less virulent (or more attenuated) upon exposure to the air. As in his early work on the saliva microbe, Pasteur carefully avoided any conclusion as to the possible role of this microbe in horse typhoid.¹⁶² Despite such caution, his adversaries accused him of trying to forge an etiological link between these microbes and the diseases of the subjects from which they had been taken, especially in the case of the microbe taken from the rabid youth. Koch referred sarcastically to Pasteur’s fondness for microbes in the form of a figure eight and suggested that the animals allegedly killed by these suspicious new microbes had merely died of different forms of septicemia.

In part Koch’s objections reflect a more general difference of emphasis between him and Pasteur (or between the German and French schools). For while they basically agreed on the specificity of microbes, they differed as to the range of variability within a given species and as to the relative importance of morphological and physiological properties in microbial identification. Probably because of his mastery of technique in the naturalist tradition, Koch gave pride of place to morphology—to careful, detailed descriptions and pictorial representations of microbial form. The relative reliability and constancy of form in microbes grown in his solid cultural media tended naturally to reinforce this morphological bias. Pasteur’s lack of training in and relative disdain for the naturalist tradition led him to focus instead on the physiological properties of microbes, and this functional bias drew additional force from observations of morphological variability in the richly varied liquid media he used.

This is not to say that Koch ignored physiological considerations, or that Pasteur ignored morphology,¹⁶³ but merely to assert a difference in emphasis. From this perspective some of their specific disagreements can be more readily understood. Pasteur’s claim that microbes of similar form (notably the figure eight) had radically different functions—produced different diseases—was bound to arouse Koch’s skepticism. But Pasteur’s physiological bias made him rather more sensitive to the variable behavior of a given microbe in different environments, and he early recognized that different animal species constitute different cultural media or “terrains” for the microbe to which they are host. Not surprisingly, therefore, he tended to identify microbes by virtue of their biological action when injected into a given animal species. Thus, his claim that the “saliva microbe” differed from the vibrion septique rested above all on the fact that guinea pigs, which were strikingly susceptible to septicemia, proved entirely refractory to injections of the new microbe.¹⁶⁴

For somewhat similar reasons Pasteur was more disposed than Koch to suppose that a given microbe could undergo intrinsic changes in its properties by successive passages through the same or different animal species. That the virulence of a microbe could be increased by successive passages within a species was known before Pasteur began his work. Indeed, Koch had drawn attention to this fact in the cases of anthrax and traumatic infectious diseases. But Koch emphasized the effect of such passages on microbial purity—he described the technique in 1878 as “the best and surest method of pure cultivation”—and did not suppose that the intrinsic properties of the microbe had thereby been changed.¹⁶⁵ This helps to explain his assumption that Pasteur’s “attenuated” anthrax cultures must have been impure. Pasteur, by contrast, insisted that his attenuated anthrax cultures were pure and that they resulted from real changes in the properties of the microbe itself. These changes could be reversed and the microbe returned to its original virulence by passage through animals of different ages and species.¹⁶⁶

In his address at the Geneva Congress in 1882, Pasteur extended these conclusions to the saliva microbe and to the microbe found in “horse typhoid.” He reported that the virulence of the former microbe in guinea pigs could be increased by successive passages through that species, while the virulence of the latter in rabbits could be increased by successive passages through that species. More important, he now recognized that successive passages through one species could reduce the virulence of a microbe toward another species. Thus the saliva microbe became increasingly less virulent to rabbits by successive passages through guinea pigs, and the microbe found in “horse typhoid” became progressively less virulent to guinea pigs by successive passages through rabbits. In effect this amounted to the discovery of a new method of attenuation, which Pasteur was soon to exploit against swine erysipelas and rabies.

Discovery of the Vaccine Against Swine Erysipelas. Although Pasteur’s attention had been drawn to swine erysipelas (rouget du porc or hog cholera) as early as 1877 by Achille Maucuer, a veterinarian in the township of Bollene, in Vaucluse,¹⁶⁷ he was then too preoccupied with other work to give it any serious attention. In the summer of 1881, he sent Chamberland to Bollene to study the disease, but nothing seems to have come of that effort. Six months later Louis Thuillier, another of Pasteur’s assistants, went to Peux, in Vienne, where in March 1882 he isolated a new microbe (now called Erysipelothrix insidiosa), which he implicated in swine erysipelas. Almost immediately Thuillier returned with cultures of this new microbe to Pasteur’s laboratory at the École Normale, where they began searching for a means of attenuating it. Early in April, however, Thuillier was sent to Germany to supervise a field trial of anthrax vaccination on the model of the Pouilliy-le-Fort experiments, as he had done in Hungary the year before. For the next two months Thuillier remained in Germany as Pasteur pursued the search for a vaccine against swine erysipelas. By mid-October, Pasteur apparently had made considerable progress; and in November he, Thuillier, and Adrien Loir went to Bollene to conduct preliminary small-scale trials. From there, on 3 December 1882, Pasteur sent J.-B. Dumas a letter, to be read at the Academic des Sciences, in which he outlined the basic results to date of their hitherto unpublished studies. He included Thuillier’s new microbe among those having the form of a figure eight and reported that it killed rabbits and sheep as well as hogs but had no effect on chickens. More important, he announced that they had proved the non recurrence of swine erysipelas and had prepared an attenuated form of the microbe, inoculation with which made hogs refractory to the disease. While nothing that additional confirmatory experiments needed to be done, Pasteur expressed confidence that the new vaccine would be ready by the next spring to save hogs from this seasonal blight, which in 1882 had claimed an estimated 20,000 animals in the departments of the Rhone Valley alone and in 1879 an estimated 900,000 hogs in the United States.¹⁶⁸

In November 1883, after further successful testing of the new vaccine, Pasteur gave the Académie des Sciences a more extended account of the studies on swine erydsipelas. He began with a warm tribute to Thuillier, who had died of cholera in September, at the age of twenty-seven. His death affected Pasteur deeply, in part because it came while Thuillier served on the ill-facted Franch Cholera Commission, sent to Egypt at Pasteur’s urging and under his guidance to study the very disease that killed him. As if to intensify the tragedy, the German Cholera Commission, in Egypt at the same time under Koch’s leadership, made considerable progress and eventually isolated a commashaped bacillus to which Koch definitely and triumphantly ascribed cholera in the early months of 1884.

Pasteur took consolation in the heroic quality of Thuillier’s death and in the outcome of their joint study of swine erysipelas, the results of which he presented in both their names. He reported that the immunity conferred by the new vaccine lasted at least a year, but that its general diffusion faced practical difficulties owing to wide variations in the susceptibility of different breeds of hogs to the disease. Studies were already under way, however, to prepare vaccines of a strength appropriate to each breed; and while absolutely definitive results could not yet be claimed, he decided to disclose the method by which the microbe had been attenuated. By way of introduction, Pasteur recalled his earlier discovery that the saliva microbe become attenuated for rabbits by successive passages through guinea pigs.

Having learned that pigeons and rabbits, as well as hogs, suffered severely from infectious disease in the department of Vaucluse, Pasteur and his team wondered whether these species might share with hogs a susceptibility to the microbe of swine erysipelas-and if so, what effects its successive passage through them might have. They quickly established that pigeons and rabbits did indeed die from injections of the microbe; and while successive passages through pigeons increased the virulence of the microbe for hogs, successive passages through rabbits had the opposite effect. In fact, several passages through rabbits so attenuated its virulence in hogs that it become harmless to them. At this point inoculation of the cultures protected hogs from the effects of somewhat less attenuated cultures. By injecting hogs with a series of progressively more virulent cultures, they could be rendered immune to the natural disease. According to Bulloch, this method of vaccination was used on more than 100,000 hogs in France between 1886 and 1892, and on more than 1 million hogs in Hungary from 1889 to 1894.¹⁶⁹

In revealing this new method of attenuation, Pasteur emphasized the variability of viruses or microbes in different media and made an arresting comparison between their variability and that of higher organisms. In fact, he suggested, microbes are no more variable than higher organisms; they seem to be only because they reproduce so rapidly, with an immense number of generations succeeding each other in short order. By contrast, higher organisms require thousands or millions of years to achieve the same number of generations. Thus, even though higher organisms, no less than microbes, display “plasticity” under the influence of the environmental conditions in which successive generations live, they seem static to us. As usual, Pasteur said nothing about the possible implications of such ideas for the transmutability of species or for Darwinian evolutionary theory.

The Search for a Rabies Vaccine, 1881–1884. Because rabies is so rare in man (in France its victims probably never reached more than 100 in any year) and can be quite readily controlled by muzzling and quarantine of dogs, many observers of Pasteur’s career have been somewhat puzzled by his interest in it. Some have traced his concern to a traumatic childhood experience. In October 1831 a rabid wolf bit several Arboisiens and terrorized the entire region. The standard treatment, then as since antiquity, was to cauterize the wounds immediately with a red-hot iron; and the youthful Pasteur reportedly saw a man submit to this excruciating procedure at a blacksmith’s shop near his home. Despite all efforts some of the wolf’s victims died, including at least one whose name and circumstances Pasteur recalled more than half a century later.¹⁷⁰

As a result of this episode, Pasteur may long have shared the popular horror of the disease. Indeed, in several ways rabies was precisely suited to inspire terror and a sense of mystery. Its rarity made it seem that its victims had been perversely singled out, especially since they were often children. Its usual victim and agent was man’s favorite pet. Its long incubation period, ordinarily a month, at least, produced suspense and dread in any victim of an animal bite, especially because medical care was utterly powerless and death absolutely certain once the symptoms became manifest. Above all, the symptoms were believed to embody the ultimate in agony and degradation, stripping the victims of their sanity and reducing them to quivering, convulsive, animal-like shadows of their former selves. Although this conception of rabies depended more on observations of “mad” dogs than on clinical evidence, it so gripped the public imagination that the short, dry cough of human victims was compared to the bark of a dog. Few realized that the disease had a quite peaceful “paralytic” form as well as a “mad” form, or that the supposed fear of water–which gave the disease its other popular name, hydrophobia–stemmed from difficulty in swallowing and not from a fear of water per se.

Thus, however unimportant rabies may have been in terms of vital statistics, Pasteur must have realized that its conqueror would be hailed as a popular savior. And indeed he was. For if the anthrax experiments at Pouilly-le-Fort had created public confidence in the germ theory of disease, his treatment for rabies set off an international chorus of cheers the tangible echo of which was the Institut Pasteur. Not even Pasteur could have hoped for such a result from the outset, however; and before he had fully achieved it, he offered an additional explanation for his interest in rabies–an explanation at once more prosaic and plausible than the others. Speaking at Copenhagen in 1884, he emphasized that the extension of vaccination to human diseases presented special difficulties, notably because “experimentation, [if] allowable on animals, is criminal on man.” For this reason vaccination could be extended to man only on the basis of a deep knowledge of animal diseases, “in particular those which affect animals in common with man.” As the oldest, most familiar, and most striking example of such a disease, rabies was a natural choice to satisfy Pasteur’s “desire to penetrate further” into the problem.¹⁷¹

Initially, from December 1880 through March 1881, Pasteur’s work on rabies was bound up with that on the “saliva microbe.” Once convinced that this microbe had no connection with rabies, and finding himself unable to implicate any other microbe in the disease, Pasteur approached rabies rather differently from the way in which he had so successfully attacked fowl cholera and anthrax. The central feature of his work on these disease, as he often insisted, was the cultivation and attenuation of the implicated microbe in sterile cultural media, outside the animal economy. With a flexibility born partly of necessity, Pasteur now made the living organism the sole cultural medium for the rabies virus. In this, as in so much of his work, a thread of continuity runs through the seemingly dramatic shift in approach. For he had long conceived of living organisms as cultural media, and he already knew that the microbes of fowl cholera and anthrax could vary in virulence in different living media. Moreover, believing that Jenner’s still mysterious vaccine was merely attenuated smallpox virus, he had additional reason to hope that any “virus,” including that of rabies, might be altered in virulence by passage through appropriate animals, even though it resisted attempts to cultivate it in vitro. In fact, as we now know, Pasteur could have accomplished what he did toward the conquest of rabies only by this rather indirect approach. Of the “virus” diseases that he studied, only rabies is a virus disease in the modern sense; its agent is a filterable virus, invisible under the ordinary microscope, the in vitro cultivation of which has not yet been achieved. In this connection it is interesting that Robert Koch studied rabid brains during the 1880’s.¹⁷² That this work was apparently fruitless may well have been partly due to Koch’s tendency to emphasize the visible and tangible aspects of disease agents over their physiological behavior in different media.

Although fortunate and essential, Pasteur’s decision to proceed in the absence of an in vitro rabies culture did not lead far by itself. The lengthy incubation period, as well as the uncertainty of the standard modes of transmission, made new techniques imperative. Neither the injection of rabid saliva nor the bite of a rabid animal produced rabies consistently, and neither method reduced the incubation period. Similar objections applied to the subcutaneous inoculation of rabid nerve tissue, a method that seemed well chosen in view of the patently neuropathic symptoms of the disease. In May 1881, in his first memoir on rabies per se, Pasteur described a new experimental method for transmitting the disease with certainty and with a greatly reduced incubation period. The new method, perhaps suggested by Roux,¹⁷³ involved the extraction of cerebral matter from a rabid dog under sterile procedures and its subsequent inoculation directly onto the surface of the brain of a healthy animal, under the dura mater, after trephining. Under these conditions the inoculated animal invariably contracted rabies after an incubation period of about two weeks.

In December 1882, Pasteur reported that rabies could also be transmitted (usually in paralytic form) by the intravenous injection of its virus, the character of which remained obscure. Whether transmitted by this intravenous method or by the intracranial method announced earlier, the incubation period had now been reduced to six to ten days, although Pasteur declined to reveal how, “leaving aside for the moment all details.” Among the other results of his 200 experiments, perhaps the most important was the discovery that a few dogs were “accidentally” or inherently resistant to injections of the virulent virus. After recovering from the effects of one such injection, these dogs became immune to subsequent injections. This result established that rabies shared the distinguishing feature of the other “virus” diseases–it did not recur in an animal that had survived an attack. That rabies shared this feature had been far from certain, since death so consistently claimed its victims. Only with the removal of this doubt did it become entirely reasonable to hope that the search for a vaccine might eventually succeed.

Fortified by this assurance and armed with their new techniques of transmission, Pasteur and his collaborators pressed toward a rabies vaccine. In February 1884 Pasteur announced that they had reached their goal. By now they had returned to the method of intracranial inoculation, described as easy to learn and almost always successful. Although the virus continued to resist all attempts at artificial cultivation, Pasteur held to his assumption that a microbe of rabies did exist. At the very least, he maintained, a rabid brain could easily be distinguished from a normal one, for the medulla of the former contained numerous fine granules, resembling simple dots and suggesting a microbe of extreme tenuity. Whether or not further research established that these granules were “actually the germ of rabies,” Pasteur and his team had made what seemed to him a vastly more important discovery: the rabies virus (like the microbes of fowl cholera, anthrax, saliva, and “rabbit typhoid”) could be prepared in varying degrees of virulence by successive passages through different animal species. In any given species a series of passages led eventually to a fixed degree of virulence, measured by the number of days of incubation for a given quantity of inoculated virus. This maximum or “fixed” virulence varied in different animals and had already been reached naturally in the dog by virtue of countless transfers by bites through past ages.

As this suggestion implies, Pasteur emphatically rejected the notion that rabies could arise “spontaneously” in the absence of the virus. But the really important consequence of the varying states of virulence was that they allowed “a method of rendering dogs refractory to rabies in numbers as large as desired.” Like his earlier methods of vaccination, this method involved the serial inoculation of progressively virulent cultures, beginning with one attenuated to the point of harmlessness. By this method Pasteur and his team had already produced twenty-three dogs capable of sustaining the most virulent rabies virus. Indirectly the problem of prophylaxis in man had also thus been essentially solved, for he ordinarily contracted rabies only from dogs. Moreover, the lengthy incubation period of the disease offered hope that a victim might be rendered refractory before the symptoms became manifest.

In his fourth memoir on rabies (May 1884), Pasteur elaborated very briefly on the methods by which the rabies virus had been prepared in varying degrees of virulence. To weaken or attenuate the virus, it was passed from dog to monkey and then successively from monkey to monkey. After just a few such passages it had become so attenuated that its hypodermic injection into dogs never resulted in rabies; indeed, even intracranial inoculation usually produced no effect. On the other hand, the virulence of ordinary canine rabies could be increased by successive passages through guinea pigs or rabbits; in the latter it achieved its maximum fixed virulence only after a considerable number of passages. By these means, Pasteur noted, one can prepare and keep on hand a series of viruses of various strengths, the most attenuated of which are nonlethal from the outset but protect the inoculated animal from the effects of somewhat more virulent viruses, which in their turn act as a vaccine against still more virulent strains, until eventually the animal is always rendered refractory to even the most virulent and ordinarily fatal virus. If all dogs were vaccinated in this way, rabies could eventually be eliminated; but until that “distant period” it seemed important to search for a means of preventing the disease during the long incubation that followed the bite of a rabid animal. Indeed, Pasteur believed that the method was already at hand to render bitten patients refractory before the disease became manifest. “But,” he emphasized, “proofs must be collected from different animal species, and almost ad infinitum, before human therapeutics can make bold to try this mode of prophylaxis on man himself.”

Toward this end Pasteur requested the convening of a commission, to be appointed by the minister of public instruction, to which he could submit his present results and future experiments. Two sorts of experiments seemed to him best calculated to carry conviction. First, twenty of his vaccinated dogs should be placed with twenty of his vaccinated dogs should be placed with twenty unvaccinated dogs, and all forty should then be subjected to the bites of rabid dogs. Second, the same experiment should be made, except that the forty dogs should sustain the intracranial inoculation of ordinary canine rabies instead of the bites of rabid dogs. “If the facts announced by me are real,” Pasteur predicted, “not one of my twenty [vaccinated] dogs will contract rabies, while the twenty control animals will.” The proposed commission was duly appointed that very month and issued its initial report early in August 1884. After two months of experiments conducted under its scrutiny, none of Pasteur’s twenty-three vaccinated dogs had contracted rabies–whether from the bites of rabid dogs or from inoculation of the rabies virus. By contrast, two-thirds of the unvaccinated control dogs had already become rabid.

Later in August, in a major address to the International Congress of Medicine at Copenhagen, Pasteur proudly repeated these results and finally described in considerable detail the method of intracranial inoculation and his process of preparing the rabies virus in varying degrees of virulence. He reported that the search for an organism which would act as an attenuating medium for the virus had been long and frustrating. Through a great number of experiments, the animals selected as candidates for this role proved to increase rather than to attenuate the virulence of the virus. Not until December 1883 did they happen upon the proper “attenuating” organism–the monkey. Toward the end of this address, Pasteur again raised the issue of the rabies microbe: “You must be feeling, gentlemen, that there is a great blank in my communication; I do not speak of the microorganism of rabies. We have not got it….Long still will the art of preventing diseases have to grapple with virulent diseases, the microorganic germs of which escape our investigation.”

Despite the encouraging initial results, it gradually became clear that Pasteur’s proposed method was not infallible–no more than fifteen or sixteen dogs in twenty could be rendered refractory to rabies with absolute certainty. Furthermore, the results of the method could be ascertained only after three or four months, a circumstance that would have severely limited its scope in human practice, particularly in emergency cases. For these reasons Pasteur undertook to discover a new method of prophylaxis that would be both more rapid and more certain.

In doing so, Pasteur could look forward to yet another major government-financed expansion of his facilities. Very early in its deliberations, the rabies commission recommended the establishment of a large kennel yard for the housing and observation of Pasteur’s experimental dogs. The site initially chosen, in the Bois de Meudon, was quickly abandoned in the face of vigorous protests from inhabitants of the neighborhood. Similar local protests erupted upon the selection of a second site–in the park of Villeneuve l’Etang, near St.-Cloud, a state domain that had once belonged to Louis Napoleon. Although these protests helped to delay an appropriation of 100,000 francs promised to Pasteur, they ultimately proved ineffectual. By May 1885 the old stables of the chateau of St.-Cloud had been converted into a large paved kennel with accommodations for sixty dogs. A laboratory was also established, and living quarters nearby were renovated for Pasteur’s and private use.¹⁷⁴

Rabies Vaccination, 1884–1886: Its extension to Man. Awaiting the completion of this new complex– which eventually became a branch of the Institut Pasteur and was the site of his death–Pasteur pursued his quest for a perfected method of preventing rabies. In December 1884 he reluctantly declined to treat a bitten child by the means at his disposal, noting that he had not yet established that his method would work on dogs after they had been bitten and confessing that even if he proved successful at that, his hand would “tremble” before applying the treatment to humans, “for what is possible on the dog may not be so on man.”¹⁷⁵ By March 1885, however, he had begun to test his method on dogs already bitten;¹⁷⁶ and on 6 July 1885 he decided to treat nine-year-old Joseph Meister, from Alsace, “not without feelings of utmost anxiety,” even though he had been assured by two sympathetic physicians that the boy was otherwise “doomed to inevitable death” and even though his new method of prophylaxis had never failed in dogs.

In a memoir of 26 October 1885, Pasteur described this new method and the circumstances under which he had made his fateful decision. In essence the new method involved in vitro attenuation rather than the earlier method of passage through monkeys. It depended first on the preparation of a virus both pure and perfectly consistent in its virulence. This had been accomplished by using a virus passed successively through rabbits over a period of three years. Now in its ninetieth passage, this virus invariably produced an incubation period of seven days and had done so for nearly forty consecutive passages. In two earlier memoirs Pasteur had reported that a given rabies virus retained its virulence for weeks in the encephalon and spinal cord of the infected animal, as long as these tissues were preserved from putrefaction by storage at 0–12°C. He now revealed that his technique could be modified in such a way as to attenuate the virus. Adopting a technique introduced by Roux, who prevented putrefaction of rabbit spinal cords by suspending them in a dry atmosphere instead of by cooling,¹⁷⁷ Pasteur excised strips of spinal cord from rabbits dead of the seven-day “fixed” virus and suspended them in flasks in which the atmosphere was kept dry by addition of caustic potash. He found that the virulence of the virus in these strips gradually diminished and eventually disappeared. The time required for this process depended somewhat on the thickness of the strips but more importantly atmospheric temperature. Up to a point, the higher the temperature, the more quickly attenuation was achieved. Ordinarily the virus became attenuated to the point of harmlessness in about two weeks.

Using a spinal strip that had been drying for some two weeks, the first step in the actual treatment was to mash a portion of it in a sterile broth and then to inject the resulting paste into the animal to be protected. On successive days the injections came from progressively fresher marrows and eventually from a highly virulent strip that had been drying for only a day or two. By this method, Pasteur reported, he had rendered fifty dogs of all ages and types refractory to rabies when young Meister appeared unexpectedly at his laboratory, accompanied by his mother and the owner of the dog responsible for the attack. Two days before, on 4 July, Meister had been bitten in fourteen places on his hands, lower legs, and thighs. These wounds, some so deep that he could scarcely walk, had been cauterized with carbolic acid by a local physician twelve hours after the attack. The dog had been killed by its owner, whom Pasteur sent home after having been assured that his skin had not been broken by the dog’s fangs. That the dog was indeed rabid seemed certain from its behavior and from the presence in its stomach of hay, straw, and wood chips.

Pasteur immediately consulted Alfred Vulpian, a member of the rabies commission, and Jacques Joseph Grancher, who worked in his laboratory. Both considered young Meister doomed; and after Pasteur told them of his new results, both urged him to use the new method on the boy. The treatment, begun that evening, lasted ten days, during which Meister received thirteen, abdominal injections derived from progressively more virulent rabbit marrows. By the end of the treatment. Meister was being inoculated with the most virulent rabies virus known—that of a mad dog augmented by a long series of passages through rabbits. Nonetheless, he had remained healthy during the nearly four months since he had been bitten, and his recovery therefore seemed assured. According to Dubos, Meister eventually became a concierge at the Institut Pasteur and lived until 1940, when he chose to commit suicide rather than open Pasteur’s burial crypt to the advancing German army.¹⁷⁸

At the end of his memoir of 26 October 1885, Pasteur announced that a week earlier he had begun to treat a second boy, a fifteen-year-old shepherd named Jean-Baptiste Jupile, who had been viciously bitten while killing a rabid dog that threatened the lives of six younger comrades. He had not arrived at Pasteur’s laboratory for treatment until six days after having been bitten (as compared with two days for Meister). prompting Pasteur to emphasize that the length of time that could safely be allowed to pass between bits and treatment presented the “most anxious question for now.” During the brief and uniformly laudatory discussion that followed Pasteur’s memoir, Vulpain proposed the founding of a special service for the treatment of rabies by Pasteur’s method (a proposal ultimately realized in the Institut Pasteur) and the president of the Académie des Sciences predicted that the date of this meeting would” remain forever memorable in the history of medicine and forever glorious for French science.’ When, a day later, Pasteur read the same memoir to the Académie de Medecine, its president expressed the nearly identical sentiment that the date of the meeting would” remain one of the most memorable, if not the most memorable, in the history of the conquests of science and in the annals of the Academy.”¹⁷⁹

In March 1886, Pasteur reported that young Jupille remained well (like Meister, Jupille ultimately joined the staff of the Institut Pasteur, where he served until his death in 1923)¹⁸⁰ and that 350 patients had now submitted to his rabies treatment. One had died despite the treatment, but Pasteur defended his method by emphasizing that ten-year-old Louise Pelletier had not arrived for treatment until thirty-seven days after being attacked and by showing that the fatal virus had an incubation period characteristic of dog-bite virus and not of the virus used in his prophylactic treatment

In the same memoir Pasteur referred briefly to the problem of reliable statistics, which remained at the center of all subsequent debate over his antirabies treatment. Admitting his surprise at the large number of people who came for treatment, he suggested that the frequency of rabid bites had previously been underestimated out of reluctance to inform victims that they might have contracted a fatal disease. Moreover, he emphasized that he had drawn up a very rigorous catalog of the cases, insisting where possible that the victims bring certificates from veterinarians or doctors testifying to the rabid state of the attacking animal. Although it nonetheless proved necessary to treat cases in which dogs were merely suspected of being rabid, Pasteur declined to treat anyone whose clothes had not been visibly penetrated. Supporting himself particularly on statistics giving an average of the Seine from 1878 to 1883, he insisted that his treatment was “henceforth an established fact” and deserved a special new institution. In the discussion which followed, he argued that one such center in Paris would suffice for all of Europe if those who would eventually apply the treatment abroad came there for training.¹⁸¹

Pasteur and the Rabies Treatment After 1886 . Even a few of Pasteur’s disciples and collaborators opposed his quickness in applying the prophylactic treatment to human cases. Indeed, Roux broke with Pasteur over the issue, refusing to sign the first report on the treatment and leaving the laboratory for several months.¹⁸² Naturally opposition was far more severe outside Pasteur’s circle, particularly among traditional medical men, antivivisectionists, and antivaccinationists, and especially as others died after receiving the treatment. some critics charged that these deaths occurred not despite the treatment but because of it, in effect accusing Pasteur of involuntary manslaughter, and the father of one dead child actually filed suit against him.¹⁸³ Despite overwhelming statistical evidence as to the safety of his treatment, Pasteur was not allowed to forget the occasional failures. By May 1886 he complained, with some justice, that his efforts had made him the target of a “hostile press” and of “malevolent persons” in the Académie de Medecine.¹⁸⁴ Nonetheless, it was impossible to claim absolute safety and efficacy for his treatment, and Pasteur’s attempts to perfect it may have done more to exacerbate doubts than to dispel them.

In Meister’s case the last injection in the series had been prepared from spinal marrow only one day old, but soon afterward Pasteur decided that five-day-old marrow should suffice for the final injection. For certain severe cases, however, he developed a more intensive version of the treatment, which he had begun to apply by September 1886. In these cases he returned to one-day-old marrow for the last injection in each series and increased the number of injections per day so that the patient went through three series of injections in the same period of time (ten days) that Meister and other victims had gone through one series.¹⁸⁵ Besides raising some doubt as to Pasteur’s full confidence in his treatment, these modifications failed to eliminate occasional failures. In a very few cases death occurred under circumstances suggesting that the “intensive” method treatment may have been responsible,¹⁸⁶ and Pasteur abandoned it within a year of its introduction. To some this indecision served as evidence that Pasteur’s method was empirical rather than truly “scientific,’ as did the rather casual leap from animal experiments to human therapeutics and Pasteur’s practice of keeping certain details of the method secret.¹⁸⁷ Against the latter criticism, however Pasteur could appeal to the need for quality control and could produce a list of those to whom every detail of the method had been taught in his laboratory.¹⁸⁸

Ultimately the chief and most persuasive criticism of Pasteur’s treatment concerned the statistical evidence of its efficacy. In its report of 1887, probably the most judicious contemporary evaluation of the treatment, the English Rabies Commission emphasized the unreliability of statistics on rabies. Besides the frequent difficulty or impossibility of establishing that the attacking animal had in fact been rabid, immense uncertainty surrounded the exact influence of the character and location of bites, of interracial and interspecific differences among attacking animals, and of cauterization and other treatments applied before pasteur’s vaccine. The uncertainty of these and other factors helped to explain why previous estimates of the mortality form the bites of rabid dogs varied from 5 percent to 60 percent. Despite its testimony as to the exactitude of Pasteur’s experiments and its conviction that his treatment had saved a considerable number of lives, the English Rabies Commission recommended the less dramatic course of enacting and enforcing more stringent police regulations on dogs. By this approach, already operating with striking success in Australia and Germany, rabies was virtually eliminated from England by the turn of the century.¹⁸⁹

Meanwhile, however, English citizens were among those making the pilgrimage to Paris in hope of being saved from rabies. If Pasteur’s treatment evoked strong opposition from certain quarters, it won lavish praise and gratitude from nearly all who submitted to it; and centers for the treatment quickly spread to other nations. Despite the cavils of unbitten and unthreatened adversaries, a steady stream of fearful victims came to Paris and offered Pasteur living testimony of the value of his achievement. By November 1886, about a year after the first treatment, nearly 2,500 persons had been treated in Paris alone. Of 1,726 French citizens treated, only 12 had died; and Pasteur refused to acknowledge failure in two of these cases, including that of Louise Pelletier. On pasteur’s reckoning, therefore, the mortality rate after his treatment amounted to about 0.6 percent, as compared with the most optimistic estimate of 5 percent in the absence of his treatment.¹⁹⁰

At Pasteur’s death 20,000 persons had undergone his rabies treatment at centers throughout the world, with a mortality rate of less than 0.5 percent.¹⁹¹ By 1905 this number had reached 100,000; and by 1935, 51,057 persons had been treated at the Institut Pasteur alone, with only 151 deaths—a mortality rate of 0.29 percent.¹⁹² Despite these statistics, controversy continued to surround the safety and efficacy of Pasteur’s original method of vaccination and of the modified versions introduces subsequently. By the mid-twentieth century it had become clear that the repeated injection of rabid nerve tissue could sometimes produce paralysis and that such accidents could be strikingly reduced by resort to dead vaccines in place of Pasteur’s living, attenuated vaccine. Even better results were achieved with live vaccine cultivated in duck eggs rather than in nerve tissue.¹⁹³ By 1973, another rabies vaccine had been developed in the hope that a single preventive injection could replace the long and painful series of abdominal injections.¹⁹⁴ If most epidemiologistsd now doubt that Pasteur’s treatment has saved as many lives as once believed. if others deny its value under present social circumstances, and if all agree that muzzling and quarantine of dogs is a preferable approach to the rabies problem, Pasteur’s achievement nonetheless had an impact and importance not fully represented in statistical terms—not only for those whose lives or peace of mind were saved by it but also for the promise and foundation it gave to the immensely successful campaign to extend immunization to other human diseases.¹⁹⁵

Pasteur on Pest Control . On the basis of a few isolated passages in his work, Pasteur has been called a prophet not only of bacteriotherapy but also of chemotherapy. If this was indeed true, he was scarcely a toiler in the vineyard of either discipline. A rather similar judgment attaches to his few scattered remarks on biological methods of pest control, the prophetic character of which may seem more compelling in an era when ecology is in the ascendant and insecticides under suspicion. One pest of particular concern to him was phylloxera, a plant louse which, by its ruinous effects on vineyards in France and elsewhere, interfered for several years with the adoption and spread of his process for preserving wine. “In a time of famine wrote Duclaux, “no one need consider how to keep grapes, and the heating of wines was little practiced except for those which must be shipped under bad conditions as to keeping, for example, in the commissarial of the Navy.”¹⁹⁶ In 1882 Pasteur suggested that if phylloxera were subject to some contagious disease, and if the causative microbe of this disease could and if the causative microbe of this disease could be isolated and cultivated, then the pest might be controlled by introducing the microbe into infested vineyards. This suggestion seems not to have been seriously pursued, however, and the phylloxera plague eventually declined as mysteriously as it had arisen.¹⁹⁷

Under the stimulus of a 625,000-frane prize offered by the afflicted countries, Pasteur sought far more seriously a practical means of reducing the destructively large rabbit population in Australia and New Zealand. Having observed the remarkable susceptibility of rabbits to fowl cholera, he proposed that their food be contaminated with the fowl cholera bacillus, in hopes of establishing an epizootic outbreak of the disease among them. In 1888, following a highly successful preliminary trial of this method on an estate in Rheims, he sent a team of his collaborators to Sydney, Australia, where they were to organize and launch the antirabbit campaign. Ultimately, however, the Australian government refused to authorize a full-scale field trial and Pasteur failed to authorize a He ascribed this outcome chiefly to the irrational fear aroused in Australia by the word “cholera.” even though fowl cholera has nothing in common with human cholera.¹⁹⁸ Subsequent attempts along similar lines, however, have made it clear that Pasteur underestimated the difficulty of establishing a progressive epizootic disease in any animal population. Whether they arise naturally or are produced artificially, epizootics and epidemics are limited in their spread by factors which Pasteur did not fully appreciate and which remain to some degree obscure.¹⁹⁹

Pasteur and Chemical Theories of Immunity . Like some of Pasteur’s contemporary critics, Dubos has characterized his work on vaccination as largely “empirical” rather than “scientific.”²⁰⁰ Compared with the time and energy he invested in the search for effective vaccines, his efforts to establish a theoretical basis for attenuation and immunity were rather casual and undeveloped. Nonetheless, his concepts of immunity are interesting, the more so because they underwent a dramatic shift as a result of his work on rabies. Throughout his work on fowl cholera, anthrax, and swine crysipelas, Pasteur linked immunity with the biological, and particularly the nutritional, requirements of the pathogenic organism. In the case of animals inherently immune to a given disease, he supposed either that their natural body temperature was inimical to the development of the appropriate microbe or that they lacked some substance(s) essential to its life and nutrition. In animals rendered immune by recovery from a prior attack or by preventive inoculations, he supposed that each invasion by a given microbe (even in the attenuated state) removed a portion or all of some essential nutritional element(s). thereby rendering subsequent cultivation difficult or impossible. In January 1880, during a discussion of his work on fowl cholera, Pasteur illustrated his conception by applying it to cases of long-lasting immunity. Such cases could be explained by supposing that elements as rare as cesium or rubidium were essential to the life of the appropriate microbe and present only in trace amounts in the tissues of the invaded animal. Under these circumstances the initial invasion of the microbe could exhaust the supply of the essential element(s), rendering the animal refractory for as long as it took it to recoup a sufficient supply of the rare substance(s).²⁰¹

At some point during his work on rabies, however, Pasteur began to doubt the validity of this biological “exhaustion” theory in the case of immunity against rabies. By his own account, he converted to a chemical “toxin” theory for rabies early in 1884;²⁰² but he gave no public indication of his conversion until his memoir of 26 October 1885, where it paled into insignificance beside the drama of young Meister and Jupille. Moreover, his conversion remained tentative and undeveloped, with the details of the supporting experiments reserved for a later paper. For the time being, Pasteur merely asserted that the vaccinal properties of the desiccated rabbit marrows seemed to result not from a decrease in the intrinsic virulence of the rabies virus but from a progressive quantitative decrease in the amount of living virus contained in the marrows. Then, citing other evidence that microbes could produce substances toxic to themselves (evidence that he had minimized while holding the “exhaustion” theory), Pasteur suggested that the virus might be composed of two distinct substances, “the one living and capable of multiplying in the nervous system, the other not living but nonetheless capable in suitable proportion of arresting the development of the former.”

In January 1887, in the first issue of the Annales de l’Institut Pasteur, Pasteur gave a somewhat fuller account of the considerations that had led him to adopt a chemical theory of immunity for rabies. He noted that in rabbits the same rabies virus could give either a prolonged incubation period or a minimum incubation of seven days, depending on the manner and hence the quantity in which it was injected. This finding upset Pasteur’s earlier assumption that length of incubation depended only on the intrinsic virulence and not on the quantity of the virus. Even more remarkable, large quantities of a given vaccine generally seemed to produce immunity more readily than smaller quantities. If immunity depended only on the action of an attenuated, living virus capable of selfreproduction, then small quantities ought to work just as effectively as large ones. Finally, Pasteur cited cases in which vaccination rendered animals immediately refractory to rabies without their showing any prior symptoms of an attenuated form of the disease.

To Pasteur these results seemed explicable only on the assumption that the rabies virus (or microbe) produced a nonliving vaccinal substance inimical to its own development. If this were so, the result of any given injection would depend on the relative proportions of living virus and vaccinal substance depended to some extent on the amount of living virus from which it was derived. If the quantity of living virus introduced was small, as in intracranial inoculation or animal bites, the quantity of associated vaccinal substance would also necessarily be small. In such cases the supply of vaccinal substance might be inadequate to prevent the multiplication of the virus, and rabies would appear. Such a conception helped to explain why intracranial inoculation invariabley produced rabies and why the bites of rabid dogs never conferred immunity. On the other hand, if the preexisting supply of vaccinal substance were large compared with the amount of living virus, then it might prevent the virus from developing at all—as seemed to be the case in animals rendered refractory to rabies without showing any prior symptoms of an attenuated form of the disease. The progressive loss of virulence in desiccated rabbit marrows could be explained by supposing that the drying process destroyed the living virus more rapidly than it destroyed the nonliving vaccinal substance. On such grounds, Pasteur reported, he had sought marrows in which the rabies virus had been entirely destroyed but in which some vaccinal substance remained. Although his search for such nonliving vaccines had been inconclusive, he continued to hope they would be found, for their discovery would constitute “both a first-rate scientific fact and a priceless improvement on the present method of prophylaxis against rabies.” On 20 August 1888 he announced encouraging results with injections of rabid spinal cord heated at 35° C. for forty-eight hours to kill the virus—results that led him to predict that a chemical vaccine against rabies would soon be found and utilized.²⁰³

In January 1888, Pasteur had thrown his unqualified support behind Roux and Chamberland’s claim that they had found a soluble chemical vaccine against septicemia in guinea pigs. At the same time he described his own preliminary attempts to find a chemical vaccine against anthrax.²⁰⁴ Toward this end he used anthrax blood heated at 45° C. for several days to kill the anthrax microbe—a technique strikingly similar to that which Toussaint had proposed in 1880 and which Pasteur had criticized severely. Thus, at the very end of his scientific life Pasteur proved willing to modify profoundly the biological point of view that underlay his most celebrated achievements in the study of germentation, putrefaction, and disease. He did, however, retain the notion that a living virus or microbe was essential to the production of the chemical vaccine. And he did reveal a continuing sympathy for biological theories of immunity—most notably by drawing early and favorable attention to Élie Metchnikoff’s “phagocytic” theory.²⁰⁵ But in doing so he no longer insisted on the inviolability of his earlier views.

In short, the aging Pasteur demonstrated a remarkable flexibility of mind. Moreover, as Dubos suggests, he seemed to end by groping “towards the new continent where the chemical controls of disease and immunity were hidden.”²⁰⁶ How far he might have progressed toward chemical theories of disease and chemotherapy must remain unknown. But without fully acknowledging it—perhaps without fully recognizing it—he seemed to draw ever closer not only to his erstwhile opponents Liebig, Bernard, and Chaveau but also to his own roots in chemistry. Given just a little more time, he might have closed the circle.

Honored Life, Honored Death. The final decade of Pasteur’s life brought him additional honors, of which the most tangible were the second national recompense of 1883 and the establishment of the Institut Pasteur in 1888. Perhaps the most cherished were his election on 8 December 1881 to the Académie Francaise; an official celebration in July 1883 at Dole, where a commemmorative plaque was placed on the house in which he was born; and, above all, the moving jubilee celebration in the grand amphitheater of the Sorbonne on 27 December 1892, depicted in the painting by Rixens.

So frail that he had to be led in on the arm of Sadi Carnot, president of the Third Republic, Pasteur found the huge amphitheater filled to overflowing with students from the French lycées and universities, with his former pupils and assistants, with delegations from all the major French scientific schools and societies, and with government officials, foreign ambassadors and dignitaries. Of the many speakers who honored his life and work, the surgeon Sir Joseph Lister was perhaps the most notable and certainly the best qualified to testify to the direct influence of Pasteur’s work. Unable to deliver his own brief speech of appreciation, Pasteur delegated this task to his son. In it he counseled the young students to “live in the serene peace of laboratories and libraries” and spoke to the foreign delegates of his “invincible belief that Science and Peace will triumph over Ignorance and War, that nations will unite, not to destroy, but to build, and that the future will belong to those who have done most for suffering humanity.”²⁰⁷

It was Pasteur’s last public appearance but far from his last honor. By the time of his death, his name had been given to the collège in Arbois, to a village in Algeria, to a district in Canada, and to streets and schools throughout France and the world, not to mention the proliferating Pasteur institutes. On 5 October 1895 France honored Pasteur’s passing with a state funeral at Notre Dame, complete with full military honors. Temporarily placed in one of the chapels at Nôtre Dame, his body was moved in January 1896 to the resplendent funeral crypt in the Institut Pasteur where it now reposes, and where his wife was interred in 1910.

NOTES

Pasteur’s scientific papers have been cited only when it seemed that the information provided in the text (notably the dates of memoirs), combined with that given by the editor of Pasteur’s Oeuvres, might be insufficient to guide the reader to the pertinent paper. Similarly, for more strictly biographical material, references have been provided only when that material seemed sufficiently unfamiliar or controversial to warrant documentation.

1. Pasteur, Oeuvres, I, 376.

2. See Dubos, Louis Pasteur, 359–362, 377–387.

3. Pasteur, Correspondance, I, 228.

4. Pasteur to John Tyndall, 8 Mar. 1888, Archives of the Royal Institution of Great Britain.

5.Ibid. Cf. Pasteur, Correspondance, IV, 229–231 and passim.

6. René Vallery-Radot, The Life of Pasteur, 245–246, 374–376. Cf. Pasteur, Correspondance, II, 552,565–570, 573–574, 580–583; III, 350, 364, 373, 384.

7. See Pasteur, Correspondance, IV, 365.

8. See Cuny, Louis Pasteur, 15–18; and Dubos, op. cit., 80–80. For a contemporary attempt to portray Pasteur as greedy and unscrupulous, see Auguste J. Lutaud, M. Pasteur et la rage (Paris, 1887), esp.405–431. Fanatically opposed to Pasteur, Lutaud often distorted and misused the documents he adduced in support of his claims, but those documents are suggestive enough to deserve a more dispassionate reexamination.

9. See Pasteur, Oeuvres, VI, 489; and Pasteur, Correspondance, III, 173 ff.

10. For a valuable but rather uncritical survey of Pasteur’s involvement in controversy, see Pasteur Vallery-Radot, Pasteur inconnu, 62–131.

11. See Roux, “The Medical Work of Pasteur,” 384; Dubos, op. cit., 80, 370; and Louis Chauvois, D. Wrotnowska, and E. Perrin, “L’optique de Pasteur,” in Revue d’optique théorique et instrumentale,45 (1966), 197–213, esp. 197 f.

12. See Pasteur, Correspondance, IV, 336, 341, and 357, n. 1.

13. On Pasteur’s general political views, see Cuny, Louis Pasteur, 19–25; Pasteur Vallery-Radot, op. cit., 175–220; and Pasteur, Correspondance, II, 355, 459, 461–463, 489, 523, 534, 593, 600, 611–630; III, 424, 436–437; IV, 268–270, 300.

14. See Pasteur, Correspondance, I, 228, 230.

15. On the orignis of Pasteur’s study of wine, see especially ibid., II, 128–129; and Pasteur, Oeuvres, III, 481–482. On his relationship with the imperial house, see Correspondance, II, 62, 215–235, 245–246, 268, 286–287, 297, 345–346, 355, 385, 387–388, 407–408, 451, 459, 461–463, 471, 484–485, 489, 586, 627; and his correspondence with Col. Fave, Louis Napoleon’s aide-de-camp, ibid., 98–100, 110–111, 120–121, 125–126, 146–148, 160–161, 236–238. In an unpub. letter on 7 Aug. 1863, announced for sale in The Month at Goodspeed’s (May 1965), 249–250, Pasteur refers to a request from the emperor that he “take care of the aged and their illnesses,” an invitation that Pasteur thought “might be useful to me with public officials whose help I might have to ask.”

16. Pasteur, Correspondance, II, 216–236.

17. See Pasteur Vallery-Radot, ed., Pages illustres de Pasteur,

18. See Pasteur, Correspondance, II, 502–503, 511–514, 517–519.

19.Ibid., 491–492.

20. See “Fabrication de la bière,” in Journal de pharmacie,17 (1873), 330–331.

21. See Pasteur, Correspondance, III, 115–116, 313–314, 335–346, 4230–431; IV, 209 213–214, 358–359. More generally on Pasteur as “patriote,” see Pasteur Vallery-Rodot, Pasteur inconnu, 175–192.

22. Pasteur, Correspondance, II, 612. More generally on his campaign and the election, see ibid., 611–630; and Pasteur Vallery-Radot, Pasteur inconnu, 203–215.

23. See Ledoux, Pasteur et la Franche-Comté, 55ff.

24. Pasteur, Correspondance, IV, 340.

25. On Pasteur’s general philosophical and religious positions, see René Vallery-Radot, op. cit., 242–245, 342–343; Dubos, op. cit., 385–400; Pasteur Vallery-Radot, Pasteur inconnu, 221–238; André George, Pasteur (Paris, 1958); and Pasteur, Oeuvres, II, 328–346; VI, 55–58; VII, 326–339.

26. Pasteur, Correspondance, II, 213–214.

27. Pasteur, Oeuvres, VII, 326–339, quote on 326. For an English trans. of Pasteur’s inaugural address, see Eli Moschcowitz, “Louis Pasteur’s Credo of Science: His Address When He Was Inducted Into the French Academy,” in Bulletin of the History of Medicine,22 (1948), 451–466.

28. Pasteur, Oeuvres, I, 376. For the Sorbonne address of 1864, see ibid., II, 328–346. More generally, see Farley and Geison, “Science, Politics and Spontaneous Generation…” (in press).

29. See Adrien Loir, “L’ombre de Pasteur,” 15 (1938), 508; and Dubos, op. cit., 79–80, 370.

30. See Duclaux, Pasteur, 147–148, 174–175; Roux, “The Medical Work of Pasteur,” 384–387; Loir, op. cit., esp. 14 (1937), 144–146, 659–664; and Dubos, op. cit., 370

31. See Victor Glachant, “Pasteur disciplinaire: Un incident a l’École normale supérieure (novermbre 1864),” in Revue universitaire,47 (1938), 97–104, quote on p. 97.

32.ibid.; Pasteur Vallery-Radot, Pasteur inconnu, 36–58; and Pasteur, Correspondance, II, 136–142, 332–339.

33. See esp. Lutaud, op. cit., 418–430.

34. Ledoux, op. cit., 33.

35. Pasteur, Oeuvres, I, 370. Cf. ibid., 323 ff.

36. Pasteur later wrote that he might never have discovered hemihedrism in the tartrates had not Delafosse given such “particular development and special attention” to hemihedrism in his lectures. See Pasteur, Correspondance, IV, 386. For other expressions of his indebtedness to Delafosse, see Pasteur, Oeuvres, I, 66, 322, 398.

37. See J. R. Partington, A History of Chemistry, IV (London, 1964), 751–752; and Aaron Ihde, The Development of Modern Chemistry (New York, 1964), 322–323.

38. In 1884 Marie wrote to her daughter: “Your father, always very busy, says little to me, sleeps little, gets up at dawn— in a word continues the life that I began with him 35 years ago today.” Pasteur, Correspondance, III, 418.

39. See esp. Pasteur, Oeuvres, I, 203–241.

40.lbid., 275–279, 284–288.

41.lbid., 314–344, esp. 331.

42.lbid., 369–380, 391–394.

43.lbid., 327.

44. See esp. Dorian Huber, “Louis Pasteur and Molecular Dissymmetry: 1844–1857” (M.A. thesis, Johns Hopkins University, 1969).

45. Pasteur, Oeuvres, I, 334–336. But see Huber, op. cit., esp. 40–58.

46. See Pasteur, Oeuvres, I, 345–350, 360–365, 369–386.

47. Pasteur, Correspondance, I, 325–326. Cf. Pasteur Vallery-Radol, ed., Pages illustres de Pasteur, 10–13.

48. This paradox is explored in Farley and Geison, op. cit.

49. See Pasteur, Oeuvres, I, 275; II, 3.

50. Duclaux, Pasteur, 69. Cf. Pasteur, Oeuvres, II 85–86.

51. René Vallery-Radot, op. cit., 84. Cf. Pasteur, Oeuvres, VII, 186.

52. Pasteur, Correspondance, II, 183.

53. Duclaux, op. cit., 73.

54. See Annals and Magazine of Natural History, 3rd ser., 7 (1861), 343, n.

55. See Ferdinand Cohn, “Untersuchungen ¨ber Bacterier, II.,” in Beitr¨ge zur Biologie der Pflanzen,1, no. 3 (1875), 141–207, esp 194–196. More generally on Cohn, see Gerald L. Geison, “Ferdinand Cohn,” in Dictionary of Scientific Biography, III, 336–341.

56. Bulloch, History of Bacteriology, 232.

57. Pasteur, Oeuvres, II, 13–14, n. 3.

58. See John Farley, “The Spontaneous Generation Controversy (1700–1860): The Origin of Parasitic Worms,” in Journal of the History of Biology,5 (1972), 95–125.

59. See Duclaux, op. cit., 107; and Pasteur Oeuvres, II. 190.

60. See Farley and Geison, op. cit.

61. This report is reproduced in Pasteur, Oeuvres, II, 637–647.

62. Duclaux, op. cit., 109–111.

63. Pasteur, Correspondance, II, 198.

64.lbid., 193–195.

65. Pasteur, Oeuvres, IV, 86.

66. Duclaux, op. cit., 163.

67. Pasteur, Oeuvres, IV, 465.

68. See Duclaux, op. cit., 147, 158–159, 165, quote on 147.

69. See esp. Pasteur, Oeuvres, IV, 100–134, 188–199, 500–510.

70. See Duclaux, op. cit., 172–173.

71. See Pasteur, Oeuvres, IV, 544.

72.lbid., 564–571.

73.lbid., 590–595.

74. Dubos, op. cit., 225.

75. Pasteur, Oeuvres, VI, 132.

76.lbid., IV, 729–732.

77.lbid., II, 361–366.

78.lbid., 379, 396.

79.lbid., V, 265, n. 1.

80.lbid., II, 403–404, n, 3. Cf. ibid., 427–429.

81.lbid., 430–435, 44–444.

82.lbid., 387.

83.lbid., 440–442.

84.lbid., 374–380, quote on 375.

85.lbid., VI, 33.

86.lbid., 80–86.

87. Duclaux, op. cit., 128–131.

88.lbid., 206–209.

89. See Robert Kohler, “The Background to Eduard Buchner’s Discovery of Cell-Free Fermentation,” in Journal of the History of Biology,4 (1971), 35–61, on 39–40.

90. See Pasteur, Oeuvres, II, 353, 538, 588–593, esp. 535.

91.lbid., V, 5.

92. Duclaux, op. cit., 188.

93. See Pasteur, Oeuvres, V, 18, n. 1.

94.lbid., 307

95. See Pasteur, Correspondance, III, 71, 78–79, For facsimiles of these letters, as well as several others exchanged between Pasteur and Jacobsen (including two previously unpublished letters from Pasteur), see Lettres échangées entre J. C. Jacobsen et Louis Pasteur au cours des années 1898–1882 (Copenhagen, 1964).

96. Pasteur, Oeuvres, II, 385–386.

97.lbid., 453–455; V, passim; and Duclaux, op. cit., 214–218.

98. Pasteur, Oeuvres, II, 541–545, 559–567.

99.lbid., 150–158, 373, 383, 389 n. 1, 407–408, esp. n. 2; V, 98–101; and Duclaux, op. cit., 192–197.

100. Pasteur, Oeuvres, V, 101; II, 411. Pasteur only once used Darwin’s name in print—while pointing out that the belief in microbial transformism was losing ground by 1876, “in spite of the growing favor of Darwin’s system.” lbid., V, 79.

101.lbid., II, 461.

102. For Bastian’s account of his disagreements with the commission, see Henry Charlton Bastian, “The Commission of the French academy and the Pasteur-Bastian Experiments, “in Nature, 16 (1877), 277–279, Cf. Pasteur, Oeuvres, 11 , 459–473. More generally, see Glenn Vandervliet, Microbiology and the Spontaneous Generation Debate During the 1870’s (Lawrence, Kan., 1971), 55–64; and J.K. Crellin, “The problem of Heat Resistance of Microorganisms in the British Spontaneous Generation Controversy of 1860–1880,” in Medical History, 10 (1966), 50–59.

103. See Vandevilet, op. cit., passim; and J. K. Crellin, “Airborne Particles and Germ Theory; 1860–1880,” in Annals of Science, 22 (1966), 49–60.

104. Pasteur, Oeurvres, 11 , 478–481.

105. J. Burdon-Sanderson, “Bacteria,” in Nature, 17 (1877), 84–87, on 84. More generally, see Crellin, “Airborne Particles and the Germ Theory.”

106. Pasteur, Oeuvres, IV 124.

107. See Duclaux, op. cit., 119; Bulloch, op. cit., 109; and Vandervliet, op. cit., 63–64.

108. See Pasteur, Oeuvres, VI , 167, 188, 590.

109. See Pasteur, Correspondance, 11, 577.

110. Pasteur, Oeuvres, IV, 161–163. Cf. ibid., 469.

111. Pasteur, Correspondance, 11, 350.

112.Ibid., 346–351.

113.Ibid., 551–552, 564–568, 570, 573–574, 580–584.

114. See Pasteur, Oeuvres, IV 166–167, 188; 11, 465.

115.Ibid., IV, 167.

116. See Roux, op. cit., 382. Pasteur’s work made him the target of antivivisectionists and antivaccinationists, especially in England. For his contemptuous attitude toward these movements, see Pasteur, Correspondance, IV, 86, 109, 143, 193, 232, 294, 296–297.

117. Pasteur, Oeuvres, IV, 71–84, 138, 140, 157, 543.

118.Ibid., 89–103.

119.Ibid., 71.

120. See Duclaux, op. cit., 237–241; and Bulloch, op. cit., 179–182, 207, and passim.

121. Pasteur, Oeuvres, IV, 62–163.

122.Ibid., 178; and Dubos, op. cit., 309–310, 380–381.

123. Pasteur, Oeuvres, IV, 271–272

124.Ibid., 262.

125. Bulloch, op. cit., 213, 236–238; and Dubos, op. cit., 261.

126. Pasteur, Oeuvres, IV, 271–272.

127.Ibid., 262.

128.Ibid., VII, 495.

129. Claiming, in private, the Toussaint had failed to do so. See ibid., VII, 49.

130.Ibid., VI, 132–133.

131.Ibid., 471–489, esp. 489. Cf. Pasteur, Correspondance, III, 173–179.

132. But, more generally on luck and chance in Pasteur’s work, see Dobos, op. cit., 100–101, 219, 327, 340, 342.

133. Throughout that period all of Pasteur’s correspondance is addressed from Arbois. See Pasteur, Correspondance, III, 98–115.

134. Duclaux, op. cit., 281.

135. First used by Pasteur in his 1854 inaugural address at Lille. see Pasteur, Oeuvres, VII, 131. He used it again in 1871, in an address at Lyons, and in 1881, while discussing his famous Pouilly-le-Fort experiments on anthrax vaccination. See ibid., 215; VI, 348.

136. See Pasteur, Correspondance, III, 1212, 138–140.

137. Duclaux, op. cit., 178.

138. Pasteur, Correspondance, III, 158–171, esp. 159, 166.

139. Pasteur, Oeuvres VI,, 256, n. 2.

140.Ibid., 371.

141. See Rene Vallery-Radot, op. cit., 313–315.

142. See Pasteur, Oeuvres, VI, 350, 710–711.

143. Charles Nicolle, Biologie de l’invention (Paris, 1932), 62–65. Cf. Roux, op. cit., 379.

144. See Pasteur, Correspondance, III, 196–199.

145. Pasteur, Oeuvres, VI, 358, 360, 363–364.

146. See pasteur, Correspondance, III, 271, n. 2.

147. Pasteur, Oeuvres, VI, 365–366.

148.Ibid., 385.

149.Ibid., 441.

150. See pasteur, Correspondance, IV, 262–263, 286–287.

151. Pasteur, Oeuvres, VI, 370.

152.Ibid., 386–390.

153.Ibid., 454.

154.Ibid., 458, n. 1.

155. See ibid., 115, 165, 174, 424.

156. Perhaps with some justice, since Chamberland reportedly added cultures of Bacillus subtilis to some tubes of anthrax vaccine. See Dubos, op. cit., 341.

157. Pasteur, Oeuvres, VI, 403–411.

158. See ibid., 446–447, 450.

159.Ibid., 459.

160. See Duclaux, op. cit., 293.

161. Pasteur, Oeuvres, VI, 367–368, Cf. 398–399, 570–571.

162.Ibid., esp. 402, n. 1.

163. Cf. Dobos, op. cit., 193–194.

164. Pasteur, Oeuvres, VI, 555.

165. See Bulloch, op. cit., 226.

166. Pasteur, Oeuvres, VI, 332–338, esp. 335–336.

167.Ibid., 525. More generally on Pasteur’s work on this disease, see Frank and Wrotnowska, Correspondance of Pasteur and Thuillier, 53 ff.

168. See Pasteur, Oeuvres, VI, 523, 525.

169. See Bulloch, op. cit., 246–247.

170. Ledoux, op. cit., 16–17. Cf. Dubos, op. cit., 332.

171. See pasteur, Oeuvres, VI, 591.

172. See Frank and Wrotnowska, op. cit., 137.

173. See Dubos, op. cit., 264.

174. See Pasteur, Correspondance, III, 421, 425–428, 441–445; and Rene Vallery-Radot, op. cit., 398, 406, 410–411.

175. Pasteur, Correspondance, III, 445–446.

176.Ibid., IV., 14–15.

177. See Dubos, op. cit., 333–334.

178.Ibid., 336. But if Dubos’s romantic version of Meister’s suicide is true, it seems remarkable that his death should have been reported so briefly and casually in Isis, 37 (1947), 183, where no mention is made of suicide or the German army and where the year of his death is given as 1941 rather than 1940.

179. See Pasteur, Oeuvres, VI, 611–612.

180. See Journal of the American Medical Association, 81 (1923), 1445.

181. Pasteur, Oeuvres, VI, 621.

182. See Dubos, op. cit., 335, 347.

183.Ibid., 347.

184. Pasteur, Oeuvres, VI, 626–627.

185.Ibid., 633–634.

186. See ibid., 875–876.

187. See ibid., 836–844, esp. 841–842.

188. Pasteur, Correspondance, IV, 75–76.

189. See Pasteur, Oeuvres, VI, 870–877; and Black’s Medical Dictionary, 27th ed. (London, 1967), 743. Rabies did return to England, however, between 1918 and 1940, presumably because of violations of the quarantine regulations. See H. J. Parish, A History of Immunization (Edinburgh, 1965), 56–57.

190. Pasteur, Oeuvres, VI, 628–629.

191. Duclaux, op. cit., 299.

192. Bulloch, op. cit., 251.

193. See Parish, op. cit., 58.

194. See New York Times, 21 Aug. 1973, 1:4.

195. Cf. Dubos, op. cit., 350–353.

196. Duclaux, op. cit., 143.

197. See Dubos, op. cit., 310; and Pasteur, Oeuvres, VII, 32–35.

198. See Pasteur, Oeuvres, VII, 86–93; and Pasteur, Correspondance, IV, 227–229, 231–232, 237, 240–251, 257–26k0, 270–273, 278–280, 287–290.

199. Dubos, op. cit., 312. Cf. Bullich, op. cit., 243.

200. Dubos, op. cit., 379–382 and passim.

201. Pasteur, Oeuvres, VI, 290–291.

202.Ibid., 463.

203.Ibid., 550.

204.Ibid., 464–466.

205.Ibid., n. 2.

206. Dubos, op. cit., 357–358.

207. See René Vallery-Radot, op. cit., 447–451. For the text of Pasteur’s address, see Pasteur, Oeuvres, VII, 426–428.

BIBLIOGRAPHY

I. Original Works. Virtually every word that Pasteur published during his lifetime, including all of his books, monographs, and scientific papers, has been reproduced in the monumental and magnificent Oeuvres de Pasteur, Pasteur Vallery-Radot, ed., 7 vols. (Paris, 1922–1939). This work also contains a number of letters, notes, and MSS that were not published during Pasteur’s lifetime and a number of documents by others relating to his work, including several reports by commissions of the Académie des Sciences. Each volume has a brief introduction by Pasteur Vallery-Radot, who adds helpful editorial notes and comments throughout. The volumes are organized topically as follows: I , molecular asymmetry; II , fermentations and spontaneous generation; III , studies on vinegar and wine; IV studies on the silkworm disease; V , studies on beer; IV , infectious diseases, virus vaccines, and rabies prophylaxis; VII , scientific and literary miscellania. Vol. VII also contains a complete index of names cited in all of the volumes, a complete chronological bibliography of Pasteur’s publications, and masterful “analytic and synthetic” subject index. In every way Oeuvres de Pasteur is a triumph of careful and diligent scholarship.

Of the approximately 500 communications published by Pasteur during his lifetime, many cover essentially similar ground, and the great majority are very brief notes or letters. Many others are nonscientific in content. The Royal Society Catalogue of Scientific Papers lists nearly 200 papers. Only the most important and influential of his published works can be listed here. His published books and monographs were Études sur le vin. Ses maladies, causes qui les provoquent. Procedes nouveaux pour le conserver et pour le vieillir (Paris, 1866; 2nd ed., rev. and enl., 1873); Études sur le vinaigre, sa fabrication, ses maladies, moyens de les prévenir; nouvelles observations sur la conservation des vins par la chaleur (Paris, 1868); Études sur la maladie des vers a soie. Moyen pratique assure de la combattre et d’en prevenir le retour, 2 vols. (Paris, 1870); Études sur la biere. Ses maladies, causes qui les provoquent, procede pour la rendre inalterable, avec une theorie nouvelle de la fermentation (Paris, 1876), trans. by Frank Faulkner and D. Constable Robb as Studies on Fermentation; the Diseases of Beer, Their Causes and the Means of Preventing Them(London, 1879); and Examen critique d’un ecrit posthume de Claude Bernard sur la fermentation(Paris, 1879).

Of Pasteur’s papers on molecular asymmetry, the most important are “Recherches sur le dimorphism,” in Annales de chimie et de physique, 3rd ser.,23 (1848), 267–294; “Recherches sur les relations qui peuvent exister entre la forme cristalline, la composition chimique et le sens de la polarisation rotatoire,” ibid., 24 (1848), 442–459; “Recherches sur les proprietes specifiques des deux acides qui composent l’acide racemique,” ibid., 28 (1850), 56–99; “Nouvelles recherches sur les relations qui peuvent exister entre la forme cristalline, la composition chimique et le phenomene de la polarisation rotatoire,” ibid., 31 (1851), 67–102; “Mémoire sur les acides aspartique et malique,” ibid., 34 (1852), 30–64; “Nouvelles recherches sur les relations qui peuvent exister entre la forme cristalline, la composition chimique et le phenomene rotatoire moleculaire,” ibid., 38 (1853), 437–483; “Notice sur l’origine de l’acide racémique,” in Comptes rendus hebdomadaires… de l’Académie des sciences (hereafter Comptes rendus), 36 (1853), 19–26; “Transformation des acides tartriques en acide racémique. Découverte de l’acide tartrique inactif. Nouvelle méthode de séparation de l’acide racemique en acides tartriques droit et gauche,” ibid., 37 (1853), 162–166; “Sur le dimorphisme dans les substances actives. Tetartoedrie,” ibid., 39 (1854), 20–26; “Memoire sur l’alcool amylique,” ibid., 41 (1855), 296–300; “Isomorphisme enter les corps isom#éres, les uns actifis les autres inactifs sur la lumiere polaris#ée,” ibid., 42 (1856), 1259–1264; “Études sur les modes d’accroissement des cristaux et sur les causes des variations de leurs formes secondaires,” in Annales de chimie et de physique, 3rd ser., 49 (1857), 5–31; and “Note relative au Penicillium glaucum et a la dissym#étrie mol#éculaire des produits organiques naturels,” in Comptes rendus, 51 (1860), 298–299

Pasteur’s views on molecular asymmetry and optical activity, as they stood at the end of his active research on the problem, are admirably summarized in “recherches sur la dissymetrie moleculaire des produits organiques naturels,” in L#écons de chimie profess#ées en 1860 (Paris, 1861), 1–48, trans. by George Mann Richardson as “On the Asymmetry of Naturally Occurring Organic Compounds,” in The Foundations of Stereochemistry; Memoris by Pasteur, van’t Hoff, Lebel, and Wislicenus (New York, 1901), 3–33. Pasteur’s continuing interest in the relationship between asymmetry and life can be seen in [“Observations sur les forces dissymetriques”], in Comptes rendus, 78 (1874), 1515–1518; “Sur une distinction entre les produits organiques naturels et les produits organiques artificiels,” ibid., 81 (1875), 128–130; “La dissymetrie moleculaire,” in Reuve scientifique, 3rd ser., 7 (1884), 2–6; and “Reponses aux remarques de MM. Wyrouboff et Jungfleisch sur ’La dissymetrie moleculaire,’” in Bulletin de la Société chimique de Paris, n.s. (1884), 215–220. For a projected volume that would gather his earlier works on molecular asymmetry Pasteur wrote a preface, an introduction, and a historical note (1878); published posthumously by Pasteur Vallery-Radot in Oeuvres de Pasteur, I , 389–412, they serve as an excellent introduction to Pasteur’s mature views on the subject.

Excluding his works on vinegar, wine, and beer (discussed below), the longest and most important of Pasteur’s papers on fermentation and spontaneous generations is “M#émoire sur les corpuscules organises qui existent dans l’atmosphere, examen de la doctrine des generations spontanees,” in Annales des sciences naturelles. Zoologie, 4th ser., 16 (1861), 5–98, significant portions of which are trans. into English in Conant, Harvard Case Histories (see below), 494–504, 509–516. Also important are “Memoire sur la fermentation appelee lactique,” in Memoires de la Société des sciences, de l’agriculture et des arts de Lille, 2nd ser., 5 (1858), 13–26, trans. into English with the omission of three paragraphs in Conant, Harvard Case Histories, 453–460; “Memoire sur la fermentation alcoolique,” in Annales de chimie et de physique, 3rd ser., 58 (1860), 323–426; “De l’origine des ferments. Nouvelles experiences relatives aux generations dites spontanees,” in comptes redus, 50 (1860), 849–854, of which an English trans. appeared in Quarterly Journal of Microscopical Science, 8 (1860), 255–259; “Recherches sur le mode de nutrition des Mucedin#ées,” in Comptes rendus, 51 (1860), 323–426; “De l’origine des fermenappeared in Quarterly Journal of Microscopical Science, 2nd ser., 1 (1861), 213–215; “Animalcules infusoires vivant sans gaz oxygene libre et determinant des fermentations,” in Comptes rendus, 52 (1861), 344–347, of which an English version appeared in Annals and Magazine of natural History, 3rd ser., 7 (1861), 343–344; “Exp#ériences et vues nouvelles sur la nature des fermentations,” in Comptes rendus, 52 (1861), 1260–1264; and “Quelques fiats nouveaux au sujet des levures alcooliques,” in Bulletin de la Société Chimique de Paris (1862), 66–74.

Also see “Nouvel example de fermentation determinee par des animalcules infusoires pouvant vivre sans gaz oxygene libre, et en dehors de tout contact avec l’air de l’atmosphere,” in Comptes rendus,56 (1863), 416–421, of which an English version appeared in Annals and Magazine of Natural History, 3rd ser., 11 (1863), 313–317; “Examen du role attribute au gaz oxygene atmospherique dans la destruction des matieres animales et vegetales apres la mort,” in Comptes rendus, 56 (1863), 734–740, of which an English version appeared in Chemical News and Journal of Physical (Industrial) Science, 7 (1863), 280–282; “Recherches sur la putrefaction,” in Comptes rendus, 56 (1863), 1189–1194; “Des generations spontanees” in Reuve des course scientifiques, 1 (1864), 257–265; “Note sur un memoire de M. Liebig, relatif aux fermentations,” in Comptes rendus, 73 (1871), 1419–1424; “Sur la nature et l’origine des ferments,” ibid., 74 (1872), 209212; “Reponse a M. Fremy,” ibid., 403–404; “Faits nouveaux pour server a la connaissance de la theorie des fermentations proprement dites,” ibid., 75 (1872), 784–790, of which an English trans. appeared in Quarterly Journal of Microscopical Science, 2nd ser., 13 (1873), 351–356; “Nouvelles experiences pour demontrer que le germe de la levure qui fait le vin provident de l’exterieur des grains de raisin,” in Comptes rendus, 75 (1872), 781782; “Note sur la fermentation des fruits et sur la diffusion des germes des levures alcooliques,” ibid., 83 (1876), 173–176; “Note sur l’alternation de l’urine, a propos d’une communication du Dr Bastian, de Londres,” ibid., 176–180; “Sur l’alternation de l’urine. Reponse a M. le Dr Bastian,” ibid., 377–378; “Note sur l’alteration de l’urine, a propos des communications recentes du Dr Bastian,” ibid., 84 (1877), 64–66, written with Jules Francois Joubert; “Reponse a M. le Dr Bastion,” ibid., 206; “Sur les germes des bacteries en suspension dans l’atmosphere et dans les eaux,” ibid., 206–209, written with J. F. Jourbert; and “Note au suject de l’experience du Dr Bastian, relative a l’urine neutralisee par la potasse,” ibid., 85 (1887), 178–180. Also of interest are Pasteur’s papers on Claude bernard’s posthumous on fermentation. These papers, published in 1878 and 1879, are reproduced in the appendix to pasteur’s Examen critique d’un ecrit posthume de Claude Bernard (cited above).

The most important of pasteur’s papers on vinegar and acetic acid fermentation are “Sur la fermentation acetique,” in Bulletin de la Société chimique de paris (1861), 94–96, repr. in Oeuvres, III , 3–5; “Études sur les mycoderms. Rôle des ces plantes dans la fermentation acetique,” in Comptes rendus, 54 (1862), 265–270; “Suite a une precedente communication sur les mycodermes. Nouveau procede industrial de fabrication du vinaigre,” ibid., 55 (1862), 28–32; and “M#émoire sur la fermentation acetique,” in Annales scientifiques de l’École normale superieure, 1 (1864), 115–158. The last paper was combined with an otherwise unpublished lecture (delivered at Orleans in Nov. 1867) to yield Pasteur’s Études sur le vinaigre (cited above).

Of Pasteur’s papers on wine, the most important are “Études sur les vins. Premiere partie: De l’influence de l’oxygene de l’air dans la vinification,” in Comptes rendus, 57 (1863), 936–942; “Études sur les vins. Deuxieme partie: Des alterations spontanees ou maladies des vins, particulierement dans le Jura,” ibid., 58 (1864), 142–150; “Procede pratique de conservation et d’amelioration des vins,” ibid., 60(1865), 899–901; “Note sur les depots qui se forment dans les vins,” ibid., 1109–11’3; and “Nouvelles observations au sujet de la conservation des vins,” ibid., 61(1865), 274–278. These papers form the basis of and were developed into Pasteur’s Études sur le vin (cited above). Apart from his book Études sur la biere (cited above), Pasteur’s only important publication on beer is “Études sur la biere; nouveau procede de fabrication pour la rendre inalterable,” in Comptes rendus,77 (1873), 1140–1148.

In Études sur la maladie des vers a soie (cited above), Pasteur reproduced all his important papers on silkworm disease written between 1865 and 1869 with the exception of “Sur la nature des corpuscules des vers a soie. Lettre a M. Dumas,” in Comptes rendus, 64 (1867), 835–836. Of the post-1869 papers on silkworm disease, the most important are “Rapport adress#é a l’Académie sur les resultats des education pratiques de vers a soie, effectu#ées au moyen de grains preparees par les procedes de selection,” ibid., 71 (1870), 182–185; “Note sur l’application de la methode de M. Pasteur pour vaincre la pébrine,” in Annales scientifiques de l’École normale superieure, 2nd ser., 1 (1872), 1–9, written with Jules Raulin; and “Note sur la flacherie,” ibid., 11–21, written with Jules Raulin.

The most important of Pasteur’s communications on anthrax and septicemia are “Charbon et septicemie,” in Comptes rendus,85 (1877), 101–115, written with J. F. Joubert; [“Discussion sur l’#étiologie du charbon”], in Bulletin de l’Académie de medecine,6 (1877), 921–926; [“Discussion su l’etiologie du charbon. Poules rendues charbonneuses”], ibild., B (1878), 253–255, 259261; “sur le charbon des poules,” in Comptes rendus, 87 (1878), 47–48, written with J. F. Joubert and C. E. Chamberland; “Recherches sur l’#étiologie et la prophylaxie de la maladie charbonneuse dans le departement d’Eureet-Loir,” in Recueil de medecine veterinaire,56 (1879), 193–198; “Sur l’etiologie de l’affection charboneuse,” in Bulletin de l’Académie de medecine, 2nd ser., 8 (1879), 1063–1065, written with C. E. Chamberland and Emile Roux; “Etiologie du charbon [discussion],” ibid., 1152–1157, 1159, 1183–1186, 1222–1234; and “Sur l’etiologie du charbon,” inComberland and E. Roux, of which an English version appeared in Chemical News,42 (1880), 225–227

See also “Sur l’etiologie des affections charbonneuses,” in Comptes rendus,91 (1880), 455–457; “Sur la nonrecidive de l’affection charboneuse,” ibid., 531–538, written with C. E. Chamberland; “Sur la longue duree de la vie des germes charbonneux et sur leur conservation dans les terres cultivees,” ibid.,92 (1881), 209–211, written with C. E. Chamberland and E. Roux; “Note sur la constatation des germes du charbon dans les terres de la surface des fosses ou on a enfoui des animaux charbonneux,” in Bulletin de l’Académie de medecine, 2nd ser., 10 (1881), 308–311, written with C. E. Chamberland and E. Roux; “De la possibilite de rendre les moutons refractaires au charbon par la methode des inoculations preventives,” in Comptes rendus,92 (1881), 662–665, written with C. E. Chamberland and e. Roux; “Le vaccin du charbon,” ibid., 666–668, written with C. E. Chamberland and e. Roux; “Compte rendu sommaire des experiences faites a Pouilly-le-Fort, pres Melun, sur la vaccination charbonneuse,” ibid., 1378–1383d, written with C. E. Chamberland and E. Roux; “La Vaccinavtion charbonneuse. Reponse a un memoire de M. Koch,” in Revue scientifique, 3rd ser., 5 (1883), 74–84; “Sur la vaccination Charbonneuse,” in Comptes rendus,96 (1883), 967–982; “Les doctrines dites microbiennes et la vaccination charbonneuse,” in Bulletin de l’Académie de medecine, 2nd ser., 12 (1883), 509–514; and “La commission de l’École veterinaire de Turin,” in Comptes rendus, 96 (1883), 1457–1462.

Of Pasteur’s communications on fowl cholera, the most important are “Sur les maladies virulentes, et en particulier sur la maladie appelee vulgairement cholera des poules,” in Comptes rendus,90 (1880), 239–248, of which an English version appeared in Chemical News, 42 (1880), 4–7; “Sur le cholera des poules; Études des conditions de la non-recidive de la maladie et de quelques autres de ses caracter#és,” in Comptes rendus,90 (1880), 952–958, of which an English version appeared in Chemical News,42 (1880), 321–322, and 43 (1881), 5–6; “Exp#ériences tendant a demontrer que les poules vaccinees pour le cholera sont refractaires au charbon,” in Comptes rendus,91 (1880), 315; and “De l’attenuation de virus du cholera des poules,” ibid., 673–680, of which an English version appeared in Chemical News, 43 (1881), 179–180.

Of Pasteur’s papers on rabies, the most important are “Sur une maladie nouvelle provoquee par la saliva d’un enfant mort de la rage,” in Comptes rendus,92 (1881), 159–165, written with C. E. Chamberland and E. Roux; “sur la rage,” ibid., 1259–1260, written which C. E. Chamberland, E, Roux, and Louis Ferdinand Thuillier; “Nouveaux faits pour servir a la connaissance de la rage,” ibid.,95 (1882), 1187–1192, written with C. E. Chamberland, E. Roux, and L. F. Thuillier; “Nouvelle communication sur la rage,” ibid.,98 (1884), 457–463, Written with C. E. Chamberland and E. Roux; “Sur la rage,” ibid., 1229–1231, written with C. E. Chamberland nd E. Roux; “Methode pour Prevenir la rage aprds morsure,” ibid.,101 (1185), 765–773, 774; “Nouvelle communication sur la rage,” ibid.,103 (1886), 777–784; and “Lettre sur la rage,” in Annales de l’Institut Pasteur,1 (1887), 1–18. These communications, as well as two others, are trans. into English in Jean R. Suzor, Hydrophobia: An Account of M. Pasteur’s System (London, 1887). The two additional communications trans. by Suzor are “Resultats de l’application de la methode pour prevenir la rage apres morsure,” in Comptes rendus,102 (1886), 459–466, 468–469; and “Note complementaire sur les resultats de l’application de la methode de prophylaxie de la rage apres morsure,” ibid., 835–838.

Pasteur also published a number of papers on infectious diseases other than anthrax, fowl cholera, and rabies. The most important of these are [“Discussion sur la peste en Orient”} in Bulletin de l’Académie de m#édecine, 2nd ser., 8 (1879), 176–182; “Septicemie puerperale,” ibid., 256–260, 271–274, 488–493; “Commission dite de la peste,” ibid.,9 (1880), 386–390; “De l’extension de la theorie des germes a l’#étiologie de quelques maladies communes [1. sur les furoncles. II. Sur l’ost#éomyelite. III Sur la fievre puerperale],” in comptes rendus,90 (1880), 1033–1044; “Note sur la peripneumonie contagieuse des betes a cornet,” in Recueil de m#édecine veterinaire,59 (1882), 1215–1223; and “La vaccination du rouget des porcs a l’aide du virus mortel attenue de cette maladie,” in Comptes rendus,97 (1883), 1163–1169, written with L. F. Thuillier.

For Pasteur’s more general views on infectious diseases and vaccines, see especially “Observations verbales, a l’occasion du rapport de M. Gosselin,” in Comptes rendus,80 (1875), 87–95; “Discussion sur la fermentation,” in Bulletin de l’Académie de m#édecine, 2nd ser., 4 (1875), 247–257, 265–282,283, 284–290; “La th#éorrie des germes et ses applications a la medecine et la chirurgie, “ in comptes rendus,86 (1878), 1037–1043, written with J. F. Joubert and C. E. Chamberland; “De l’attenuation des virus et de leur retour #é la virulence,” ibid.,92 (1881), 429–435, written with C. E. Chamberland and E. Roux; “Vaccination in Relation to Chicken-Cholera and Splenic Fever,” in Transactions of the International Medical congress, Seventh Session Held in London… 1881, 4 vols. (London, 1881), I, 85–90; “Des virus-vaccins,” in Revue scientifique, 3rd ser., 3 (1881), 225–228; “De l’att#énuation des virus,” ibid.,4 (1882), 353–361, written with C. E. Chamberland, #é. Roux, and L. F. Thuillier; and “Microbes pathogenes et vaccins,” in Semaine medicale, 4 (1884), 318–320.

Of Pasteur’s nonscientific writings the most interesting are “Lavoisier,” in Moniteur universel, 4 Sept. 1865, 1198; “Claude Bernard. Idee de l’importance de ses travaux, de son enseignement et de sa m#éthods,” ibid., 7 Nov. 1866, 1284–1285; Quelques reflexions sur la science en France (Paris, 1871); Discours de reception a l’Académie francaise (Paris, 1882); Reponse au discours de M. J. Bertrand a l’Académie francaise(Paris, 1885); “Discours prononce a l’inaugurartion de l’Institut Pasteur, le 14 november 1888,” in Inauguration de l’Institut Pasteur (Paris, 1888), 26–30; and “Discours prononce par Pasteur, le 27 decembre 1892, a l’occasion de son jubile,” in Jubile de M. Pasteur (Paris, 1893), 24–26.

A major portion of Pasteur’s vast correspondence was assembled and published in his Correspondence, Pasteur Vallery-Radot, ed., 4 vols. (Paris, 1940–1951). Arranged chronologically over the period 1840–1895, these letters provide a detailed account of pasteur’s activities and vividly illuminate every aspect of his life and career. Pasteur’s own letters dominate the collection, but many letters to him and many by member of his family are included. For published versions of nearly 100 additional letters to or by Pasteur, as well as several other previously unpublished documents, see pages illustres de Pasteur, Pasteur Vallery-Radot, ed. (paris, 1968), 7–55; and Correspondence of Pasteur and Thuillier Concerning Anthrax and Swine Fever Vaccination, translated and edited by Robert M. Frank and Denise Wrotnowska with a preface by Pasteur Vallery-Radot (University, Ala., 1968).

Pasteur’s grandson, Pasteur Vallery-Radot, spent his life seeking and collecting his grandfather’s letters, MSS, and papers. In 1964 he gave most of his collection to the Bibliotheque Nationale. It comprises 7 file boxes of correspondence to Pasteur, 6 file boxes of correspondence by Pasteur, 1 file box of letters about him, and 22 packets containing MSS of his works and his laboratory and course notebooks. Although this material became generally accessible upon Pasteur Vallery-Radot’s death in 1971, the collection is not yet classified for use. Apart from this material, some letters or MSS by and relating to Pasteur are deposited in the Reynolds collection at the University of Alabama at Birmingham, the Institut Pasteur in Paris, the Maucuer family in Paris, the Carlsberg Foundation in Copenhagen, the Bayerische Staatsbibliothek in Munich, the Laboratoire Arago in Banyuls-Sur-Mer, the Royal Institution and the Wellcome Institute of the History of Medecine in London, the National Library of Medicine in Bethesda, Maryland, and the Burndy Library in Norwalk, Connecticut. Still other letters or MSS may be deposited in other libraries or may be privately owned. A number of official and administrative documents by and about Pasteur are deposited in French national and provincial archives. Many such documents have been extracted or otherwise put to use in the articles by Denise Wrotnowska (see below).

In addition to its small collection of Pasteur’s personal letters and the resplendent funeral chapel where Pasteur and his wife are interred, the Institut Pasteur houses the Musee Pasteur, which includes the following: Pasteur’s personal apartment, preserved as it was when he lived there; Pasteur’s personal library, including annotated volumes of his communications to the Académie des Sciences; about 1,000 pieces of Pasteur’s laboratory instruments and equipment, including chemical products with his labels, microscopes, wood models of crystals, flasks, and bottles; Pasteur’s medals, diplomas, and other personal souvenirs; several of the portraits and pastel drawings he did as a youth (including the superb portraits of his parents); an iconography of about 5,000 photographs, drawings, and portraits of pasteur, his disciples, and the Institut Pasteur; as yet uncataloged MS material on Emile Roux, Alexandre Yersin, Elie Metchnikoff, and Albert Calmette; documents concerning the Institut Pasteur; and a historical library. Pasteur museums also exist in Arbois, Dole, and Strabourg.

II. Secondary Literature. Perhaps no life in science has been so minutely described as Pasteur’s, and rarely does a biographer or historian have access to such a wealth of carefully preserved primary material. Nonetheless, no fully adequate scientific biography of Pasteur exists, and the vast majority of the literature on him is derivative and essentially useless. Only the most important and valuable of the literature can be listed here.

There are three basic sources for Pasteur’s life and work. The standard biography is Rene Vallery-Radot, La vie de Pasteur (Paris, 1900), trans. by Mrs. R. L. Devonshire as The Life of Pasteur, 2 vols. (London, 1901; 2nd, abr. ed., 1906)— references in the notes are to the 2nd ed. This biography, from which most of the literature on Pasteur derives, is distinguished for its extensive use of Pasteur;s correspondence (including some still not published) and for its extraordinary detail. But it is without scholarly apparatus, occasionally obscure about dates, weak on historical background, and too exclusively concerned with pasteur as an isolated genius at the expense of the more general context of his scientific work. Moreover, Vallery-Radot, who was Pasteur’s son-in-law, is often openly hostile toward Pasteur’s opponents and is so devoid of critical judgment as to approach hagiography. A second basic source is Emile Duclaux, Pasteur: Histoire d’un esprit (Paris, 1896), trans. by Erwin F. Smith and Florence Hedges as Pasteur: The History of a Mind (Philadelphia, 1920). Although also virtually devoid of scholarly apparatus, this book provides a lucidly brilliant and critical analysis of Pasteur’s work by one of his most celebrated students. Illuminated by a prescient historiography, it remains one of the most impressive and perceptive books ever written on the development of a scientist’s thought. The third basic source is Rene Dubos, Louis Pasteur: Free Lance of Science (Boston, 1950), trans. by Elisabeth Dussauze as Louis Pasteur: Franc-tireur de la science, with a preface by Robert Debre (Paris, 1955). Although sometimes almost embarrassingly dependent on Duclaux, and although virtually undocumented, this book is more sensitive to the larger context of Pasteur’s work and surpasses Duclaux’s by interweaving the evolution of Pasteur’s scientific thought with his other activities and attitudes. Distinguished by a lucid and graceful style, it offers insights and perspectives unavailable to Duclaux so soon after Pasteur’s death.

Of the remaining full-scale general accounts of Pasteur’s life and work, the most valuable are Hilaire Cuny, Louis Pasteur: L’homme et ses theories (Paris, 1963), trans. by Patrick Evans as Louis Pasteur: The Man and His Theories (London, 1965); Jacques Nicolle, Un maitre de l’enquete scientifique, Louis Pasteur (Paris, 1953), trans. as Louis Pasteur; a Master of Scientific Enquiry (London, 1961); and Pasteur: sa vie, sa methode, ses docouvertes (Paris, 1969); and Percy F. and Grace C. Frankland, Pasteur (New York, 1898). Rene Dubos, Pasteur and Modern Science (New York, 1960), is essentially an elegantly spare reworking of Dubos’s earlier full-bodied biography. Rene Vallery-Radot foreshadowed his later full-scale biography in the anonymously published Pasteur, histoire d’un savant par un ignorant (Paris, 1883), which appeared twelve years before Pasteur’s death. Also of interest is Rene Vallery-Radot, Madame Pasteur (Paris, 1941), a brief panegyric written in 1913 and eventually released for publication by Pasteur Vallery-Radot, whose own Lousi Pasteur: A Great Life in Brief, trans. by Alfred Joseph (New York, 1958), is perhaps the best short biography of Pasteur.

Of the remaining books on Pasteur, several deserve metion on rather more specialized grounds. Francois Dagognet, Methodes et doctrines dans l’oeuvre de pasteur (Paris, 1967), is a highly suggestive, sometimes brilliant, but essentially ahistorical account of Pasteur’s scientific work. Particularly valuable for their insights into the modern consequences of Pasteur’s program are Henri Simonnet, L’ieuvre de Louis Pasteur (Paris, 1947); and Albert Delaunay, Pasteur et la microbiologie (Paris, 1967). For a valuable account of some of the less familiar and essentially nonscientific aspects of Pasteur’s career, see Pasteur Vallery-Radot, Pasteur inconnu (Paris, 1954). Pasteur’s early life receives detailed scrutiny in E. Ledoux, Pasteur et la Franche-Comte: Dole, Arbois, Besancon (Besa#çon, 1941), an appealing attempt to elucidate the influences on him of the land, climate, and demography of his native region. Louis Blaringhem, Pasteur et le transformisme (Paris, 1923), approaches Pasteur’s work from an interesting perspective and seeks to trace to his work on fermentation, the genetic technique of “pure lines” and other intervening developments in biology. The Pasteur fermentation Centennial, 1857–1957 (New York, 1958) contains the contributions of Pasteur Vallery-Radot and Ren#é Dubos to a symposium held on the centennial of the publication of Pasteur’s first memoir on lactic fermentation. Among the books that reprint extracts or selections from Pasteur’s works are Les plus belles pages de Pasteur, Pasteur Vallery-Radot, ed. (Paris, 1943); Pasteur: pages choisies, Ernest Kahane, ed. (Paris, 1957) Louis Pasteur: Choix de textes, bibliographie, portraits, fac-similies, Hilaire Cuny, ed. (Paris, 1963); Louis Pasteur; recueil de travaux, Pasteur Vallery-Radot, ed. (Paris, 1966); and Louis Pasteur: Extraits de ses oeuvres, R. Dujarric de la Riviere, ed. (Paris, 1967).

Of the multitude of articles on Pasteur, the most generally valuable are those written by his students. Particularly informative with regard to Pasteur’s personality and interaction with his assistants are Emile Roux, “L’oeuvre medicale de Pasteur,” in Agenda du chimiste (Paris, 1896), trans. by Erwin F. Smith as “The Medical Work of Pasteur,” in Scientific Monthly,21 (1925), 365–389, to which version the notes refer; and Adrien Loir, “L’ombre de Pasteur,” in Mouvement sanitaire,14 (1937), 43–47, 84–93, 135–146, 188–192, 269–282, 328–348, 387399, 438–445, 487–497, 572–573, 619–621, 659–664; 15 (1938), 179–181, 370–376, 503–508.

See also Emile Duclaux, “Le laboratoire de M. Pasteur a I’École normale,” in Revue scientifique, 4th ser., 15 (Apr. 1895), 449–454; and “Le laboratoire de M. Pasteur.” in Le centenaire de l’École normale, 1795–1895 (Paris, 1895), 458 ff., and repro. in the centenary volume sponsored by the Institut Pasteur, Pasteur, 1822–1922 (Paris, 1922), 39–54. Also repro. in the centenary volume are Roux’s paper of 1896, “L’oeuvre medicale de Pasteur” (55–87); his “L’oeuvre agricole de Pasteur” (89–101), originally delivered to the Société Nationale d’ Agriculture on 22 Mar. 1911; and his “Madame Pasteur” (102–104), a speech Mar. 1911; and his “Madame Pasteur” (102–104), a speech originally delivered on 28 Sept. 1910, when she was interred in the Pasteur crypt at the Institut Pasteur. See also Elie Metchnikoff, “Recollections of Pasteur,” in Ciba-Symposium,13 (1965), 108–111; and The Founders of Modern Medicine: Pasteur, Koch, Lister (New York, 1939). For a lengthy list of obituary notices on Pasteur, see the Royal Society Catalogue of Scientific Papers, XVII, 726–727.

Of the more narrowly focused literature on Pasteur (including that cited in full in the notes above), several works deserve special mention. Pasteur’s religious position is explored in great detail in George (n. 25). On his handling of student discipline, see Glachant (n. 31). Various aspects of his career are explored in the articles of Denise Wrotnowska, among which the most significant are “Pasteur, professeur a Strasbourg (1849–1854),” in 92rd congres national des Sociétés savantes, I (Strabourg-Colmar, 1967), 135–144; “Candidatures de Pasteur a l’Académie des sciences,” in Histoire de la medicinem spec. no. (1958), 1–23; “Pasteur et Lacaze—Duthiers, professeur d’histoire nturelle a la Faculte des sciences de Lille,” in Histoire des sciences medicales (1967), no. 1, 1–13; “Pasteur, precurseur des laboratories aupres des musees,” inBulletin du Laboratoire du Musee du Louvre (1959), no. 4, 46–61; and “Recherches de Pasteur sur le rouget du porc,” in 90th Congres nationale des Sociétés savantes, III (Nice, 1965), 147–159. Pasteur’s work on crystallography and molecular asymmetry is explored in admirable detail in Huber (n. 44). Seymour Mauskopf, Crystals and Compounds (forthcoming), examines the French crystallographic tradition from which Pasteur emerged, and offers a novel interpretation of his discovery of optical isomerism, emphasizing Laurent’s influence and the issue of isomorphism. See also J.D.Bernal, “Molecular Asymmetry,” in Science and Industry in the Nineteenth Century )London, 1953), 181–219; and Nils Roll-Hansen, “Louis Pasteur—a Case Against Reductionist Historiography,” in British Journal for the Philosophy of Science,23 (1972), 347–361.

For an English trans. of nearly all of Pasteur’s first memoir on fermentation, together witha brief account of its genesis and impact, see James Bryant Conant, “Pasteur’s Study of Fermentation,” in Harvard Case Histories in Experimental Science, II (Cambridge, Mass., 1957), 437–485. On the relationship of Pasteur’s work on fermentation to Buchner’s discovery of zymase, see Kohler (n. 89). For an English trans, of significant portions of Pasteur’s prize-winning memoir of 1861 on organized particles in the atmosphere, together with a more general discussion of the controversy over spontaneous generation, see Conant, “Pasteur’s and Tyndall’s Study of Spontaneous Generation,” op cit., 487–539. For an attempt to show that Pasteur’s work on and public posture toward spontaneous generation were motivated in part by political factors, see John Farley and Gerald L. Geison, “Science, Politics and Spontaneous Generation in Nineteenth-Century France: The Pasteur-Pouchet Debate,” in Bulletin of the History of Medicine, 48 (1974). The same debate is treated at length by Pouchet’s disciple Georges Pennetier, Un debat scientifique: Pouchet et Pasteur, 1858–1868 (Rouen, 1907). More generally on spontaneous generation, see Crellin (n. 102 and n. 103) and Vandervliet (n. 102). On the larger historical context of Pasteur’s biological work, see William Bulloch, The History of Bacteriology, (London, 1938); and William D. Foster, A History of Medical Bacteriology and Immunology (London, 1970)

Gerald L. Geison

PASTEUR, LOUIS

(b. Dole, Jura, France, 27 December 1822; d. Villeneuve-l’Étang, near Paris, France, 28 September 1895), crystallography, organic chemistry, microbiology, immunology. For the original article on Pasteur see DSB, vol. 10.

By the end of the nineteenth century, Pasteur had no equal as a symbol of heroic and beneficent modern Western science. His theoretical and practical achievements in diverse areas of chemistry, biology, agriculture, industry, and medicine, combined with a pugnacious personality eager for fame, and an exceptional ability to stage and perform public controversies demonstrating his own claims, gave him an unrivaled public status. A vivid and suggestive account of Pasteur’s central role as a pioneer in the hygienic movement in the second half of the nineteenth century has been given by Bruno Latour (1988), and later balanced and filled in by other scholars (Löwy, 1995; Contrepois, 2002). It was not by accident that Pasteur’s work on fermentation and spontaneous generation were picked as two out of the three biological examples in the celebrated Harvard Case Histories in Experimental Science(Conant and Nash, 1957). His serious and somewhat pompous and fanatic personality also made Pasteur a natural object for the efforts to bring science down from the pedestal that started a decade later. This article will not attempt to replace the extensive and comprehensive overview provided by the original DSB article, but rather will concentrate on certain aspects of Pasteur historiography that have emerged since the 1970s.

The seven-volume Œuvres de Pasteur published by his grandson Pasteur Vallery-Radot from 1922 to 1939 is a representative and highly accessible selection of his main contributions, from the early work on molecular structure, through basic microbiology, to practical industrial, agricultural, and medical science. In breadth and significance Pasteur’s contributions were massive. His ability to move between basic theoretical and applied research and make the one stimulate the other is almost unique. Modern science policy is often torn by the dilemma of choosing between applied and basic theoretical research. Pasteur has inspired a tempting solution: instead of assessing projects either as applied (symbolized by Thomas Edison) or theoretical (symbolized by Niels Bohr) one should strive for the combination, namely Pasteur (Stokes, 1997). Whether this makes good sense in terms of evaluating individual research proposals is another question.

The Organismic Principle Despite its breadth, Pasteur’s science displays the quality of a coherent research program—a life project. His efforts were connected by a common idea sufficiently fundamental and sufficiently flexible to constitute a continuous and fruitful source of theoretical intuitions. Pasteur believed a special kind of physicochemical force to be responsible for the distinction between living and nonliving things.

Friedrich Wöhler’s synthesis of urea from ammonium cyanate in 1828 signaled the development of a chemistry of organic compounds based on the same methods and theories as that of mineral substances. But the idea that a special force or principle was responsible for the processes that distinguished living from nonliving things was not completely given up. The ability of substances in solution to rotate the plane of polarized light, for instance, had been found only in products of living organisms. The physicist Jean-Baptiste Biot, one of Pasteur’s teachers, was among those who thought this optical activity might point toward such a fundamental force of life (Dagognet, 1967).

Pasteur made his first major discovery in 1848, well before he was thirty. Among the crystals of the sodium ammonium salt of the optically inactive organic compound racemic acid, he distinguished two types of asymmetric crystals whose shapes were exact mirror images, like a right and a left hand. When dissolved in water, one type turned out to rotate polarized light to the right, precisely like the well-known isomer of racemic acid, tartaric acid. The other type rotated light the same number of degrees in the opposite direction, to the left. Pasteur’s discovery of this new “levoracemic acid,” as he called it (Œuvres, vol. 1, p. 83), amounted to the discovery of a new kind of isomerism. The process has been analyzed in great detail by Gerald Geison and James A. Secord (1988).

The production of the left-rotating tartaric acid from the optically inactive racemic acid inspired Pasteur to speculate on fundamental questions about the physical basis of life. His idea of a radical difference between living and nonliving, his organismic principle or “vegetalism” as it has been called (Dagognet, 1967), did not imply that there was no bridge between biological and physical science. It meant only that the construction of such a bridge needed physical principles of a new kind.

A Research Program in Organic Chemistry In organic chemistry Pasteur’s organismic principle was expressed in two basic ideas: chemical molecules can have either a symmetric or an asymmetric structure, and asymmetric structures have their origin in living organisms. This suggested the existence of four isomers of tartaric acids: the first two were the natural tartaric and the new left-rotating tartaric, which he had discovered. The third was inactive “by nature” (Œuvres, vol. 1, p. 346), while the fourth was inactive by internal compensation: each molecule had two asymmetric but opposite components, which resulted in overall molecular symmetry and hence no external effect on light. This last case was the racemic (or paratartaric) acid from which Pasteur had produced his new l-tartaric acid.

Pasteur explicitly stated this classification in a short note in 1861 (Œuvres, vol. 1, p. 346). But it is consistent with the way he discusses the relationship between racemic and tartaric acids in his 1850 account of the discovery. The sodium ammonium paratartrate was a special case. It was here, and a little later with the sodium potassium salt, that he was able to find and separate the two kinds of asymmetric crystals (Œuvres, vol. 1, pp. 86–120). In reporting this paper to the academy of sciences Pasteur’s mentor, Biot, explicitly described the racemic as a compound molecule and not as a mixture (Œuvres, vol. 1, p. 427).

Pasteur saw his twofold organismic principle as part of a general theory of organic chemistry. His idea was that the same four categories existing in tartaric acids would recur in other similar substances. Some early successes reinforced Pasteur’s belief in this scheme.

For instance, in 1850, Victor Dessaignes claimed that he had transformed maleic and fumaric acids into aspartic acid by purely traditional chemical means. Because fumaric and maleic acids were known to be inactive and Pasteur had recently shown naturally-occurring aspartic acid to be active, he immediately predicted that the synthesized aspartic acid must be optically inactive. After obtaining a sample he could proudly confirm that this was the case. At the same time he investigated the optical activity of malic acid regularly found together with tartaric. He speculated that these three acids, tartaric, malic, and aspartic, had similar molecular structures. It was a new, striking confirmation of his general theory when in 1853 he was able to produce the predicted tartaric acid that was inactive “by nature.”

The nature and origin of racemic acid intrigued Pasteur. In 1853 he was able to transform tartaric into racemic acid by heating a compound of tartaric acid with an optically active organic base. He also found a new way of transforming (splitting) racemic into the two tartaric acids by reacting it with optically active organic bases (Debré, 1998, pp. 72–73).

Pasteur’s clearest statement of this research program in organic chemistry was given in two lectures to the Société Chimique of Paris in 1860. He assumed the general existence of four isomers for organic compounds of similar nature to tartaric acid, for instance, succinic, malic, and aspartic acids. But by then Pasteur’s research program in organic chemistry was starting to degenerate.

William Henry Perkin and B. F. Duppa had produced a tartaric acid from inactive succinic acid. Pasteur first suggested that the product must be the internally compensated, inactive “by nature” tartaric acid. But it turned out to be the racemic variety, and Pasteur fell back on the ad hoc suggestion that either the succinic acid starting material was so weakly active that the activity had not been discovered, or it was, despite appearances, a racemic isomer (Œuvres, vol. 1, p. 347). He reacted to new, troublesome facts with ad hoc modifications of his own organismic theory, adjusting its basic principles without being able to produce any new discoveries himself.

The development of Pasteur’s research in structural organic chemistry supports Imre Lakatos’s theory of scientific research programs (Lakatos, 1970): after a first progressive phase of discoveries it degenerated to mere ad hoc modifications. But Pasteur was already deep into research on fermentation and spontaneous generation. The fundamental organismic idea, the “metaphysical hard core” in Lakatos’s terminology, was revitalized in new highly productive research programs in fermentation and various branches of microbiology, basic as well as applied (Dagognet, 1967; Roll-Hansen, 1972, 1974).

In the interpretation of Pasteur’s organic chemistry it is essential to take into account the difference between his ideas on molecular constitutions and present conceptions based on the tetrahedral carbon atom, which was introduced in the 1870s. In 1860 he considered various molecular possibilities, a right- or left-handed helix, a “fixed dissymmetric structure,” or an “irregular tetrahedron” (Kottler, 1978, p. 70; Œuvres, vol. 1, p. 327). It appears that he saw the production of the two tartaric acids from racemic acid as a transformation of the whole molecule, and not as a separation of a mixture of already existing mirror-image molecules, as is often assumed in historical accounts (e.g., Dubos, 1950, p. 105; Debré, 1998, p. 49). As the theory of the tetrahedral carbon atom became generally accepted and the structure of these acids well defined, Pasteur’s theorizing on molecular structure was made obsolete: there were only two malic and two aspartic acids, only one succinic acid (inactive “by nature” to use Pasteur’s terminology), and only three tartaric acids. The racemic no more existed as a separate molecular kind but became a mixture of the right and left rotating tartaric acids. Thus Pasteur’s organismic principle after a while failed in structural organic chemistry, but it continued to inspire his great successes in research on fermentation and microbiology.

Fermentation Amyl alcohol, an optically active byproduct of ordinary alcoholic fermentation, provided a link between Pasteur’s early research on molecular dissymmetry and the research on fermentation starting in the

1850s. In 1849 Biot had told him of the optical activity of amyl alcohol and Pasteur had tried to make crystals, hoping to confirm the correspondence between crystal form, molecular structure, and optical activity. This project failed. But after he had given up the idea that asymmetric crystal form was closely correlated to asymmetric molecular structure, he continued research on amyl alcohol. In 1855 he claimed to have revealed the existence of two isomers, an optically active and an optically inactive amyl alcohol. The production of these alcohols by fermentation became an important starting point for his research in this area (Œuvres, vol. 2, pp. 3–4, 25–28; Geison, 1995, pp. 95–103).

In the early 1850s Pasteur was obsessed by the ideas of an asymmetric physical force, molecular asymmetry, and optical activity as the basis of life. He even constructed elaborate experiments to test the possibility that asymmetric “cosmic” forces due to the revolution of Earth could create dissymmetric molecules. His loyal wife described Pasteur’s romantic hubris in private letters: if Louis succeeds, the world will have “a Newton or a Galileo” (Dubos, 1950, pp. 40–41). Depression followed when these hopes did not materialize. Colleagues did their best to dissuade him from these pursuits, which many considered ill-advised (Debré, 1998, pp. 76–80).

In December 1854, Pasteur became professor of chemistry and dean of the new faculty of sciences at Lille, an industrial center in the north of France. Contacts with the brewing industry stimulated his interest in fermentation. In August 1857 he published a paper on lactic acid fermentation sketching his new organismic research program in fermentation. His idea was that the different kinds of fermentation were caused by the growth of specific microorganisms, for example, lactic fermentation by a specific lactic “yeast” that he was able to isolate and cultivate in a precisely defined chemical medium. Pasteur formulated his theory explicitly in opposition to the widely accepted “chemical” theory of fermentation, namely that “ferments” and well-defined chemical substances, although produced by living organisms, could be isolated and made to work without their presence.

The idea that specific kinds of organisms cause specific kinds of effects was connected to the problem of “diseases” in brewing and wine making. When beer or wine went bad, Pasteur argued, it was due to the presence of unwanted kinds of microbes. The remedy for such a disease was to prevent the intrusion of the specific microbes responsible. Thus Pasteur’s organismic principle of fermentation opposed currently popular views of micro-organisms as highly pleomorphic and variable, without stable species like higher organisms. From the start of his work on fermentation Pasteur was interested in the origin and propagation of microbes. The organismic principle set him on a collision course with scientists claiming to have observed the spontaneous origin of microbes under various conditions.

Status of Spontaneous Generation As cytology developed, the question of spontaneous generation of microscopic organisms became accessible in a new way. Introduction of effective achromatic lenses for microscopes during the 1830s paved the way for cell theory, pioneered by Matthias Schleiden and Theodor Schwann around 1840. Within a period of about seventy years the detailed mapping of cell structures and processes—life cycles, fertilization, cell divisions, structure and behavior of cell organelles such as chromosomes, and so forth— would lay the foundations for a deeper understanding of the nature of living organisms, culminating with the founding of genetics.

Cytology was still in its beginnings when Pasteur first entered the debates over spontaneous generation at the end of the 1850s, but important discoveries were made at a rapid pace. The discovery of new structures and processes quickly made earlier theories about fertilization and sexual and asexual propagation obsolete. Cryptogamic plants, internal parasitic worms, and infusoria were areas of intensive research. The French Académie des Sciences announced a number of prizes in these fields between 1837 and 1862 (Gálvez, 1988).

Pasteur’s main opponent in the debates about spontaneous generation, Félix-Archimède Pouchet, received a prestigious physiology prize in 1845 for his work on ovulation in animals, demonstrating that egg cells were produced in females independently of contact with males. According to Pouchet’s theory of “spontaneous ovulation” the ova (egg cells) developed in the ovary because of a “plastic force.” In 1849 he was elected corresponding member of the academy. Pouchet’s ideas about the interaction of sperm and ova were contradicted by the discovery in the early 1850s that sperm entered the ova as part of the fertilization process. By this time Pouchet was more interested in the study of medieval science than in empirical cytological investigations.

He did not give up his theory of spontaneous ovulation, however, but developed it into a general theory of “spontaneous generation.” In 1864 he argued that the opponents of this theory had lagged behind in the development of “philosophical sciences.” Pouchet’s disregard of empirical developments in cytology and embryology produced a highly critical attitude in the academy (Gálvez, 1988, pp. 358–361). His theory of spontaneous generation conflicted with the most recent discoveries in the field.

Pasteur did not take part in the first confrontation over spontaneous generation between Pouchet and the academy. In December 1858 Pouchet claimed to have repeated a classical experiment by Schwann with the opposite result. Oxygen was often thought to have a crucial role. Organic matter could be kept sterile indefinitely by heating it in a closed vessel, but microbes quickly appeared when fresh air was let in. Schwann had shown in 1836 that heating of the introduced air prevents this. His result indicated that something in the air was destroyed by heating, probably “germs” of microbes. Pouchet consistently got the opposite result and argued that germs in the air could not be the source of microbes. But his claims met strong and unanimous criticism from members of the academy. They found his theory incompatible with general biological knowledge, and his experiments technically unconvincing (Roll-Hansen, 1979, pp. 281–282).

The Pouchet-Pasteur Controversy Pouchet’s Hétérogénie ou traité de la génération spontanée was published in October 1859, and in January 1860 the academy announced a prize for the best experimental contribution to “throw light on the question of spontaneous generation.” It was the wish of the commission named by the academy that “candidates focus on the effects of heat and other physical factors on the vitality and development of germs and lower animals and plants” (Gálvez, 1988, p. 349). Already at the following meeting Pasteur presented his first results. He clearly had been working on the problem for some time. Between February 1860 and January 1861 Pasteur made altogether five short presentations.

In a series of experiments Pasteur demonstrated how germs could have entered Pouchet’s experiments, and how any organic matter could be kept indefinitely sterile in contact with fresh air in a swan-necked flask. Most significant perhaps were his experiments of opening and closing a series of sterile flasks in different locations, thus taking small samples of fresh air and observing the effect on the sterile organic medium. The result was systematic statistical differences in the proportion of flasks containing microbial growths. The more polluted the air with dust particles the greater the chance of microbial growth: high in the streets of Paris and lower in a quiet basement room, relatively high in country fields, and decreasing in ascending high mountains. Of twenty flasks opened on a glacier 2,000 meters above sea level, only one was fertile (Roll-Hansen, 1979, pp. 283–284). Pasteur had thus invented a method of measuring the density of germs in the air.

During the same period, Pouchet also made a series of presentations to the members of the academy, which demonstrated at the same time that he was not well updated. For instance, he assumed that “all physiologists unanimously agree that no egg, no animal, no plant can resist a humid temperature of 100 degrees” Celsius, while Pasteur had shown a month before that heating milk to 100 degrees did not kill all microbes. Pouchet also described how alcoholic yeast developed into a mold, Aspergillus, and claimed that yeast globules never propagated by budding (Roll-Hansen, 1979, pp. 285–287). In the early 1860s, however, medical and biological scientists generally thought microorganisms to be highly polymorphic and changeable. The belief in specific and stable kinds of microbes was still a minority view that Pasteur shared with other pioneers such as the German botanist Ferdinand Cohn. Only with the foundation of bacteriology in the following two decades did it become the generally accepted view (Mazumdar, 1995, Gradmann, 2000).

In November 1862 Pouchet withdrew from the competition, and on 29 December Pasteur was awarded the prize. But in September 1863 Pouchet, together with two colleagues, challenged Pasteur’s key experiment of sampling fresh air with sterile flasks. At more than 2,000 meters altitude in the Pyrenees they opened four flasks in a glacier crevice and four in a nearby village. Their paper to the academy described how two flasks from each location had given rise to an Abūndance of microorganisms.

Pasteur was not impressed. He found the argument poor and doubted the technical quality of the experiment as a repetition and challenge to his own: Four flasks at each location was insufficient for statistical analysis, and the report described only half of them, showing that Pouchet and the others had not grasped the point of the experiment. That Pouchet after consulting with his collaborators confirmed growth in all flasks did not invalidate this methodological criticism.

Pasteur now used his opponents’ claim to have disproved his experiment for all it was worth, for they were now obliged to accept his challenge to a careful and precise repetition under closely controlled circumstances.

Pasteur had a penchant for staging such crucial experiments, or “duels” as he called them, with his opponents. He had a typically nineteenth-century excessive faith in the possibility of reaching a final verdict in this way. Nevertheless, this sort of adversarial procedure could stimulate focused and fruitful research.

Pouchet’s two collaborators picked up “the gauntlet” and promised

to conform even more scrupulously than before to all the minute details which he points to as absolutely indispensable. If a single one of our flasks remains unaltered in contact with air taken at Toulouse, we will loyally concede our defeat. If all are populated with infusoria and mould, what will Mr. Pasteur answer and do? (Joly and Musset, 1863, p. 845 [translated by author]).

Two weeks later Pouchet assented to their proposal that the academy name a commission to oversee and judge the experimental claims. He defiantly proclaimed that a decimeter of air taken anywhere on Earth will always be able to generate living organisms from organic matter (Roll-Hansen, 1979, p. 289).

But Pouchet and the others resigned before the “duel” was consummated. The commission asked that both parties carry out an experiment opening about twenty flasks prepared according to Pasteur’s method in each of three different locations. Pouchet’s party would use hay infusion and Pasteur’s yeast extract. This was the experiment that Pouchet had challenged and that needed testing. However, Pouchet’s party asked to start with other investigations, such as a microscopic analysis of the air in the room or of a liter of beer. The commission believed such investigations were doomed to be inconclusive and insisted that first the experiment of opening sterile flasks had to be repeated. Pouchet’s party then withdrew and left Pasteur to carry out his part with the same result as before. Thus Pouchet’s party had produced no evidence that Pasteur’s experiment was faulty, reported the commission. But it was careful not to reject Pouchet’s claim with respect to hay infusion, and said it ventured to repeat his experiment (Flourens et al., 1865).

The difference in their preferred growth mediums, yeast extract for Pasteur and hay infusion for Pouchet, is widely presented as a crucial point. The hay bacillus produces spores that can survive heating to 100 degrees Celsius, a fact that was only discovered some years later. Thus growth in all flasks with hay infusion would probably have occurred even following the strict procedures of Pasteur. So if Pouchet and the others had not lost their nerve they might well have won their point (Duclaux, 1896, p. 141; Geison, 1995, pp. 131–132). However, both the commission and Pasteur were well aware of this possibility, and there is no reason not to assume that such a result would have been followed up quickly by Pasteur, introducing more rigorously sterile methods.

In hindsight the descriptions that Pouchet and his collaborators give of the content of the flasks indicate serious weaknesses in their experimental techniques. The presence of “touffes de Mycelium,” “Mucédinées articulées,” “bacteries,” “amibes,” and so forth (Pouchet et al., 1863, p. 560) is clear evidence that not only spores of the hay bacillus were at work. Because a belief in the strong polymorphy of microorganisms was still dominant among biologists, Pasteur’s belief in a high degree of specificity was not in itself a passable argument. But it could fruitfully guide his own investigations. By forcing Pouchet and others to repeat their experiments under controlled circumstances, and in strict parallel to the experiments they claimed to contradict, Pasteur assumed that he would be able to spot the holes in their presumed disproof of his claims. That is, he would be able to show where the specific organisms that grew up in their flasks had come from, whether they were due to germs introduced through careless techniques in opening and closing the flasks or whether the broth contained some kind of heat-resistant stage of the organism in question (Roll-Hansen, 1998).

An Alternative Interpretation The preceding is a rough outline of the scientific issues and institutional framework of the Pasteur-Pouchet debate of 1859 to 1864. In traditional rationalist accounts it is a paradigmatic example of how experimental science can reveal superstitions and advance human understanding of the world (Duclaux, 1896; Bulloch, 1938; Dubos, 1950; Debré, 1998). The scientifically superior quality of Pasteur’s experiments, it is said, established facts and supported principles that pointed toward conclusions that would be generally accepted within a few decades.

However, in a 1974 paper John Farley and Gerald Geison claimed that Pasteur’s victory in the controversy with Pouchet was due to external factors—to cultural, political, and institutional power—rather than to sound scientific evidence and argument. They claimed to have revealed the “very real significance of the extra-scientific, political aspects of the debate” (p. 162) and they were “persuaded that external factors influenced Pasteur’s research and scientific judgment more powerfully than they did the defeated Pouchet” (p. 197). With the Académie des Sciences as the judge, Farley and Geison said that the outcome was more or less inevitable given the cultural and political ideologies that the academy shared with ruling groups.

Farley and Geison argued that the outcome was in harmony with the interests of cultural and political conservative elites who feared the influence of radical materialist views about the nature of human beings, where the demonstration of spontaneous generation could be taken as further supporting evidence. But as both men were confessional Christians, Pasteur a Catholic and Pouchet a Protestant, and neither had a radical political profile, a clear effect of such factors appears hard to substantiate. Farley and Geison also point out that Pasteur was an insider in the academy, while Pouchet was a minor figure in the French scientific establishment, but suggestions concerning the effects of social loyalty or elite networks on the knowledge claims of scientist need to be scrutinized carefully. In the Pouchet-Pasteur case the conclusions of the French academy’s commission were carefully limited to rather uncontroversial statements on the experimental results, not stating any further generalizations on the possibility or impossibility of spontaneous generation. Leading members of the commission had expressed a clear preference for the germ hypothesis but took care to proceed in a reliably objective manner. They can be understood as genuinely interested in pinpointing clear evidence in conflict with the germ hypothesis.

Pasteur’s Scientific Method However, the salient point in the argument of Farley and Geison was a critique of Pasteur’s scientific method. By claiming that Pasteur’s method had serious weaknesses and was no better than Pouchet's, they depicted a situation where it appears more likely that “extrascientific” factors were decisive. According to Farley and Geison, Pasteur violated fundamental precepts of experimental method, for instance, failing to repeat and falsify Pouchet’s experiment in the Pyrenees. However, as shown above, that experiment was modeled on an earlier set of experiments by Pasteur in which Pouchet claimed to have shown that the conclusion Pasteur had drawn from them was mistaken. Thus Pouchet had taken on a burden of proving Pasteur wrong on the experimental level. If the modified experiment of Pouchet and others, with hay infusion instead of yeast extract, had been verified under strictly controlled and analogous experimental circumstances it would have been Pasteur’s challenge to explain the difference in terms of his own germ theory. But his opponents withdrew and Pasteur had a walkover.

Farley and Geison further argued that there was a basic methodological asymmetry in the debate based on the logical difference between proving and disproving a universal claim. While a universal claim can be disproved by a single counterinstance, it can never be conclusively proved however large a number of positive instances are found. Farley and Geison argued that the proponents of a spontaneous generation theory such as that of Pouchet “needed only to show that the feat was possible” while opponents had to demonstrate the general claim that it never happens (1974, p. 192; Farley, 1978, p. 144). But, as shown, there was hardly any difference in the level of generality in their claims. Pasteur held that it was always possible to draw a sample of air that would not provoke growth of microorganisms—with his methods. Likewise, Pouchet claimed it was always possible to draw a sample that would provoke growth—with his methods.

Implications of the pervasive dependence of observation on theory was perceived by thoughtful methodologists long before twentieth-century philosophers of science began to develop more explicit ideas about competing theories, paradigms, and research programs. Pasteur explicitly promoted a sophisticated hypothetico-deductive method where both sides in a controversy have an obligation both to substantiate their generalizations and to undermine their opponent’s interpretation of specific experimental and observational results (Latour, 1992). Pasteur was more successful than Pouchet in both respects, in producing new striking experimental phenomena and in showing that his opponent’s experiments on closer examination did not show what Pouchet claimed. Even in his famous public lecture on spontaneous generation at the Sorbonne in April 1864, at the height of the controversy with Pouchet, Pasteur was very circumspect in his conclusion, avoiding any dogmatic universal claim about the impossibility of the phenomenon: “there are no circumstances known today in which one can affirm that microscopic organisms come into the world without germs, without parents similar to themselves” (Œuvres, vol. 2, p. 346). Nevertheless, the assumption of a deep asymmetry between proponents and opponents of spontaneous generation has continued in historical accounts of the Pasteur-Pouchet debate (Geison, 1995, p. 131).

Scientific Misconduct? Geison’s 1995 analysis of Pasteur’s “private science” emphasized his tendency toward secrecy about his intentions and technical methods. In publicly staged experiments in particular he was often reticent to reveal details. Geison suggested that sometimes Pasteur consciously created a false public impression, and Geison found some of the accusations of plagiarism plausible. For instance, in the famous anthrax experiment at Pouilly-le-Fort in 1881 Pasteur did not inform the public that the vaccine used was not the type that he had been developing, but rather had been made according to different principles by one of his collaborators, Charles Chamberland. Pasteur thus took the honor that really belonged to another person. His spectacular vaccinations against rabies also met with strong contemporary criticisms and were replete with ethical dilemmas (Geison, 1995, pp. 171, 218–223). Though customary norms of scientific behavior were different in the late nineteenth century from what they are in the early twenty-first century, there may indeed be reasons to be critical of Pasteur. Geison’s analysis in connection with the approaching centennial of Pasteur’s death in 1995 triggered a public debate with a spirited French defense against Anglo-American hints at “fraud” (Debré, 1998, pp. xiiv, 537).

Bacteria, Specificity, and Vaccination Together with his German rival Robert Koch, Pasteur has a secure standing as a founder of bacteriology. In continuation of the work on fermentation and spontaneous generation Pasteur developed general ideas about bacteria and their various roles. And it was in particular his work on vaccination and immunology, both practical and theoretical, that made him world famous. Pasteur and Koch have traditionally been depicted as champions of the germ theory of disease against those who thought that microbes were too variable to be important explanations of specific diseases and looked instead to environmental conditions.

This picture has recently been further developed and nuanced by tracing how Pasteur and Koch interacted in shaping more precise ideas about the specificity and limits of variation in bacteria during the 1880s (Mazumdar, 1995, pp. 68–97; Mendelsohn, 2003). In accordance with his organismic principle Pasteur emphasized specificity, but in his fermentation studies he had also discovered how environmental conditions radically affected microbial processes, such as in his theory about fermentation as life without oxygen. When Pasteur announced his theory of “attenuation,” a way of making pathogens fit for vaccination, Koch was at first skeptical. But Pasteur would soon confirm the claims with own experiments.

Pasteur and his pupils were not as one-sided in their support of the germ theory as is often thought. Studies of diphtheria and tuberculosis showed how epidemics needed to be explained by complex causes. Differences in onset and course were due to many factors, from variation in environmental conditions like nutrition, to changes in virulence of the bacteria, to differences in the immunity of host populations. Bacteriology was a leading discipline in the trend toward laboratory-based experimental biology, and contributed importantly to the general concepts of “identity and stability of biological species” (Mendelsohn 2002, p. 27). There is remarkable continuity from the bacteriological and immunological studies of the 1880s to the identification of DNA as a “transforming principle” in the 1940s (Mendelsohn, 2002, pp. 29–30).

Experimental Method One merit of externalist criticism is to demonstrate more clearly the limited force and fragile nature of scientific rationality, how easily it can be invoked in favor of loose speculation and how dependent it is on the existence of stable institutions and actors with adequate understanding of scientific methods and their limitations. It took decades before the ideas that guided Pasteur in the controversy with Pouchet won general acceptance among scientists, and crucial general questions about the origin of life remain open in the early 2000s. For instance, it is still beyond the reach of empirical science to decide whether life originated on Earth in a distant past or whether the first germs came with meteorites from space (Fry, 2000).

Pasteur and the French Académie des Sciences were concerned with a more limited question of heterogenesis, whether microscopic living organisms can arise from dead organic matter. They were well aware that general claims about natural phenomena are never proven in a strict sense, but only tested and supported. The academy asked for experiments that would illuminate the question. Under public scrutiny, Pasteur undermined Pouchet’s purported results by analyzing his experiment and repeating modified versions, while Pouchet was unable to do the same to Pasteur’s main experiment. This outcome of experimental efforts was what the academy proclaimed as a fact in February 1865, neither more nor less.

When a young British medical scientist, Henry Charlton Bastian, claimed experimental demonstration of heterogenesis a decade later, the debate took a similar course. In the summer of 1870 he published a long paper in Nature describing various kinds of microorganisms that had grown up in hay infusion and other media under vacuum in flasks similar to Pasteur's. Throughout the paper he argued against Pasteur and in favor of Pouchet, invoking a methodological asymmetry similar to that claimed by Farley and Geison (Bastian, 1870, p. 228). Bastian set up experiments in which it appeared that a much more severe treatment than the usual boiling was insufficient to prevent bacterial growth. He argued that it was generally agreed that no “fungus-spore” could survive these conditions, and thus the result was strong evidence for de novo origin of life (Bastian, 1870, p. 219).

Thomas Henry Huxley had warned Bastian against publishing these claims because of weaknesses in experimental methodology and argumentation, and a protracted controversy ensued (Strick, 2000, pp. 84–91). Bastian was able to set up experiments that only later found a clear explanation, as the existence of highly resistant fungal spores was definitively demonstrated by Ferdinand Cohn in 1876. In the final phase of the controversy (1876–1877) when the physicist John Tyndall was Bastian’s main opponent, Pasteur also entered the fray (Strick, 2000, pp. 157–182); in his familiar incisive way he pointed to a neglected entry route for microbes in one of Bastian’s main experiments.

In July 1876 Bastian announced that by adding potash solution to sterile urine he could produce living bacteria. Pasteur quickly responded to this direct challenge from Bastian. Urine was a medium that Pasteur was familiar with and the reagent was a well-defined chemical substance. In other words, here was an experiment that promised an unequivocal answer. Pasteur repeated Bastian’s experiment and found that by making sure that the added potash did not contain living germs either by strongly heating the solid potash or heating the solution to 110 degrees the urine remained sterile (Nature 15, 8 February 1877, p. 314). But Bastian refused to accept Pasteur’s explanation, that germs were introduced with the potash. In Bastian’s own experiments the potash solution was just as potent after having been heated to 110 degrees. However, his reasoning appears in part unconvincing: “[I]t is to me incredible that a fluid so caustic as the strong liquor potassæ which I have employed could contain living germs after it has been raised to 100 degrees C.” He also suggested that Pasteur’s flask had remained sterile because of too much potash that made the urine alkaline instead of just neutralizing it (Nature 15, 8 February 1877, p. 314).

At a meeting of the French Académie des Sciences in January 1877, Pasteur pointed out that the issue was the effect of chemically “pure potash” and challenged Bastian to demonstrate this “in the presence of competent judges” (Nature 15, 1 March 1877, p. 380; Œuvres, vol. 1, p. 467). Bastian quickly accepted the challenge, adding that even heating to 110 degrees for 60 minutes or 20 hours made no difference. Once more the French Académie des Sciences set up a commission who clearly favored the germ theory (Nature 15, 1 March 1877, pp. 380–381).

As had happened a decade earlier with Pouchet, the commission and Bastian could not agree on the precise terms of the inquiry. Bastian insisted that the commission limited itself to report on “the mere question of fact” of the generative power of “liquor potassæ” (Nature 16, 2 August 1877, p. 277). The commission was reluctant to preclude a follow-up with further experiments. It apparently did not share Bastian’s implicit belief in a sharp separation of fact from interpretation. Bastian met with the commission and Pasteur in Paris in July 1877, but negotiations quickly broke down and Bastian returned to London without performing his experiment (Bastian, 1877). Pasteur then carefully repeated Bastian’s experiment under control of the commission and concluded that there were three sources of germs: the urine, the potash, and the glassware. Insufficient sterilization of the glassware had not been prominent in the earlier written exchange. When sufficient care was taken with all three sources the result was continued sterility in 100 percent of the flasks (Œuvres, vol. 2, pp. 471–473). After this Bastian soon withdrew from the public debate and the controversy between him and Tyndall petered out in a brief exchange in 1878 (Farley, 1977, p. 141). By then spontaneous generation had lost most of its support in the British medical community (Thomson, 1877, pp. 303–304).

What characterizes Pasteur’s unique ability with the experimental method is not only an exceptional technical performance in the laboratory but also a superior ability to focus experiments on theoretically crucial questions. Such experiments were crucial, not in determining the absolute truth of certain claims, but in their impact on the course of theoretical debate. Pasteur did not see Bastian’s challenge as trivial, but he waited for the right occasion, until an effective “crucial experiment” presented itself, before he entered the controversy. The Pasteur camp acknowledged Bastian had made an important contribution to scientific progress by forcing them to develop more effective techniques of sterilization (Duclaux, 1896, pp. 146–152).

Besides presenting an overview of some recent contributions to the historical understanding of Pasteur’s role in the history of science, the thrust of this article has been to suggest that internal aspects must be taken into consideration to achieve an adequate comprehensive understanding in the longer run. The controversies over spontaneous generation are given extensive treatment because they have been so widely appealed to in critiques of scientific rationalism. Following the well-justified insistence that “external” cultural, ideological, and political factors are important, there is a need to investigate more effectively how they interact with “internal” factors, such as experimental evidence and theoretical reasoning. It is problematic even to formulate clear and precise externalist claims without close attention to the questions that scientists posed and tried to solve. In particular, misunderstandings have resulted from simple assumptions that some historians have made with respect to scientific method.

SUPPLEMENTARY BIBLIOGRAPHY

Within the very large literature on Pasteur, the extensive and comprehensive article of Gerald Geison (1974) in the old DSB remains the most accessible and comprehensive overview.

WORKS BY PASTEUR

Œuvres de Pasteur. Edited by Pasteur Vallery-Radot. 7 vols. Paris: Masson, 1922–1939.

OTHER SOURCES

Bastian, H. Charlton. “Facts and Reasonings concerning the Heterogeneous Evolution of Living Things.” Nature (1870, 30 June, 7 and 14 July): 170–177, 192–201, 219–228.

——. “The Commission of the French Academy and the Pasteur-Bastian Experiments.” Nature 16 (2 August 1877): 276–279.

Bulloch, William. The History of Bacteriology. London: Oxford University Press, 1938.

Conant, James B., and Leonard Nash. Harvard Case Histories in Experimental Science. 2 vols. Cambridge, MA: Harvard University Press, 1957.

Contrepois, Alain. “The Clinician, Germs and Infectious Diseases: The Example of Charles Bouchard in Paris.” Medical History 46 (2002): 197–220.

Dagognet, François. Méthodes et doctrine dans l’œuvre de Pasteur. Paris: Presses universitaires de France, 1967.

Debré, Patrice. Louis Pasteur. Baltimore, MD: Johns Hopkins University Press, 1998. Translation from French, Paris: Flammarion, 1994.

Dubos, René. Louis Pasteur: Free Lance of Science. New York: Charles Scribner, 1950.

Duclaux, Émile. Pasteur: Histoire d’un esprit. Paris: Sceaux, 1896. Translated by Erwin F. Smith and Florence Hedges as Pasteur: The History of a Mind. Philadelphia: W.B. Saunders, 1920.

Farley, John. The Spontaneous Generation Controversy from Descartes to Oparin. Baltimore, MD: Johns Hopkins University Press, 1977.

——. “The Social, Political and Religious Background to the Work of Louis Pasteur.” Annual Review of Microbiology 32 (1978): 143–154.

——, and Gerald L. Geison. “Science, Politics and Spontaneous Generation in Nineteenth-Century France: The Pasteur-Pouchet Debate.” Bulletin of the History of Medicine 48 (1974): 161–198.

Flourens, Pierre, et al., and Jerôme Balard rapporteur. “Rapport sur les experiénces relative à la géneration spontanée.” Comptes Rendus de l’Academie des Sciences 60 (20 February 1865): 385–397.

Fry, Iris. The Emergence of Life on Earth: A Historical and Scientific Overview. New Brunswick, NJ: Rutgers University Press, 2000.

Gálvez, Antonio. “The Role of the French Academy of Sciences in the Clarification of the Issue of Spontaneous Generation in the Mid-nineteenth Century.” Annals of Science 45 (1988): 345–365.

Geison, Gerald L. The Private Science of Louis Pasteur. Princeton, NJ: Princeton University Press, 1995.

——, and James A. Secord. “Pasteur and the Process of Discovery: The Case of Optical Isomerism.” Isis 79 (1988): 6–36.

Gradmann, Christoph. “Isolation, Contamination, and Pure Culture: Monomorphism and Polymorphism of Pathogenic Micro-Organisms as Research Problem 1860–1880.” Perspectives on Science 9 (2000): 147–172.

Joly, N., and Ch. Musset. “Réponse aux observations critiques de M. Pasteur, relatives aux expériences exécutées dans les glaciers de la Maladetta.” Comptes rendus hebdomadaires des séances de l’Académie des sciences 57 (1863): 842–845.

Kottler, Dorian. “Louis Pasteur and Molecular Dissymmetry, 1844–1857.” Studies in the History of Biology 2 (1978): 57–98.

Lakatos, Imre. “Falsification and the Methodology of Scientific Research Programmes.” In Criticism and the Growth of Knowledge, edited by Imre Lakatos and Alan Musgrave Cambridge, U.K.: Cambridge University Press, 1970.

Latour, Bruno. The Pasteurization of France. Cambridge, MA: Harvard University Press, 1988.

——. “Pasteur on Lactic Acid Yeast: A Partial Semiotic Analysis.” Configurations 1 (1992): 129–145.

Löwy, Ilana. “Disciplines: The Pasteur Institute and the Development of Microbiology in France.” Studies in the History and Philosophy of Science 25 (1995): 655–688.

Mauskopf, Seymour H. “Crystals and Compounds: Molecular Structure and Composition in Nineteenth-Century French Science.” Transactions of the American Philosophical Society, n.s., 66, part 3 (1976): 1–82.

Mazumdar, Pauline M. H. Species and Specificity: An Interpretation of the History of Immunology. Cambridge, U.K.: Cambridge University Press, 1995.

Mendelsohn, Everett. “The Political Anatomy of Controversy in the Sciences.” Scientific Controversies: Case Studies in the Resolution and Closure of Disputes in Science and Technology, edited by H. Tristram Engelhardt Jr. and Arthur Caplan. Cambridge, U.K.: Cambridge University Press, 1987.

Mendelsohn, J. Andrew. “‘Like All That Lives’: Biology, Medicine and Bacteria in the Age of Pasteur and Koch.” History and Philosophy of the Life Sciences 24 (2002): 3–36.

———. “The Microscopist of Modern Life.” Osiris 18 (2003): 150–170.

Moreau, Richard. “Les expériences de Pasteur sur les générations spontanées. Le point de vue d’un microbiologiste.” La Vie des Sciences. Comptes rendus, série générale, 9 (1992): no. 3, pp. 231–226, and no. 4, pp. 287–321.

Pouchet, Félix-Archimède. Hétérogénie ou traité de la génération spontanée. Paris: J.B. Baillière et fils, 1859.

——, N. Joly, and Ch. Musset. “Expériences sur l’hétérogénie exécutés dans l’intérieure des glaciers de la Maladetta (Pyrénées d’Espagne).” Comptes rendus hebdomadaires des séances de l’Académie des sciences 57 (1863): 558–561.

Roll-Hansen, Nils. “Louis Pasteur: A Case against Reductionist Historiography.” British Journal for the Philosophy of Science 23 (1972): 347–361.

——. Forskningens Frihet og Nødvendighet. Pasteurs teorier I vekst og forfall [The freedom and necessity of research: Growth and decline of Pasteur’s theories]. Oslo: Gyldendal, 1974.

——. “Experimental Method and Spontaneous Generation: The Controversy between Pasteur and Pouchet, 1859–64.” Journal of the History of Medicine and Allied Sciences 34 (1979): 273–292.

——. “Pasteur: An Underestimated Hero of Science.” Review of The Private Science of Pasteur by Gerald Geison. Centaurus 40 (1998): 81–93.

Stokes, Donald. Pasteur’s Quadrant: Basic Science and Technological Innovation. Washington, DC: Brookings Institution Press, 1997.

Strick, James. Sparks of Life: Darwinism and the Victorian Debates over Spontaneous Generation. Cambridge, MA: Harvard University Press, 2000.

Thomson, Allen. “Inaugural address,” as newly elected president of the British Association for the Advancement of Science. Nature 16 (16 August 1877): 302–311.

Nils Roll-Hansen

PASTEUR, LOUIS

PASTEUR, LOUIS (1822–1895), French microbiologist.

The Pasteurian revolution may have been the final touch to an internal line of development in scientific thought and medical practice, but the most spectacular and far-reaching effects of Louis Pasteur's discoveries were in the field of public health. Pasteur the experimenter revolutionized public health by proving bacterial pollution, demonstrating pollution prevention through pasteurization, describing the microbial etiology of infectious diseases, and demonstrating that disease could be prevented through vaccination.

first lessons: from crystals to microbes

Louis Pasteur was born at Dole, France, into a modest family whose name had never shone in history. His father operated a tannery at Marmoz, Franche-Comté, where Pasteur spent his childhood. In October 1843 he entered the École Nationale in Paris and worked in the laboratory of Jérôme Balard. Pasteur built his first discovery on tartaric and para-tartaric acids: he showed that the two substances are identical but that their atomic positions are reversed. Pasteur defined what thirty-five years later Lord Kelvin (William Thomson), was to call chirality, from the Greek kheir, the hand, a symbol to designate a shape that cannot be super-imposed on its mirror image.

This success led Pasteur to study the optical activity of a whole series of substances. At the University of Strasbourg, where he was appointed as professor of chemistry in January 1849, Pasteur examined meticulously diverse kinds of molecules and was intrigued by a strange finding: asymmetry, it appeared, had its limits. All the substances composed of asymmetrical molecules came from plant, human, or animal models. Conversely, chemical substances that do not deviate light and possess an axis of symmetry are all of mineral origin. Pasteur deduced that the molecules of life are asymmetrical. Applying this discovery to fermentation, he went on to consider it as a natural biological occurrence, not as an artificial chemical synthesis. To prove that the fermentation was a germ of life he switched from crystals to microbes, from chemistry to microbiology and immunology.

bacterial pollution and pasteurization

Pasteur had begun his studies on fermentation in 1854 at the University of Lille, where he had been appointed dean of the science faculty two years earlier, and he soon turned his attention to incomplete distillation. He took a microscope to a beet sugar factory and spent days on end making alcohol. Looking through the eyepiece he watched the growth of the globules that were present as sugar was being turned into alcohol. Pasteur showed that minute organisms acted because they were alive and breathing. In holding his own against some of the greatest biochemical theories of the time, which maintained that fermentus was indispensable because of its capacity to disappear, Pasteur was going to give the germ its due importance in alcohol and lactic fermentation and then in the rotting process. Aerobic germs are necessary to the life cycle since they take in oxygen and expel carbon dioxide, which is absorbed by plants. Building on this, he held that microorganisms, both parasitic and useful ones, must be everywhere—in the water, the air, the ground. This hypothesis from the outset was waged against one of the major philosophical and biological problems of the nineteenth century: the theory of spontaneous generation, which claimed that germs are born directly in mineral matter.

To show that such theory was wrong and that spontaneous generation does not occur, Pasteur first had to develop a new experimental strategy. At the École Normale Supérieure, where he had been appointed director of scientific studies in 1857, he invented an external device used to pump air from the school's garden and filter it through a fluff of cotton. Microbes could be detected when the cotton was washed on a watch glass. This debate on spontaneous generation was to turn into an analysis of air and the first epidemiological analyses of the presence of microorganisms in the environment. Pasteur showed that germs vary in relation to place and season depending on climatic conditions and hygiene.

In 1865, upon orders from Napoleon III, Pasteur went to work on wine diseases, using heat as a source of prevention. He adopted Nicolas Appert's procedure for food keeping and recommended a new method for conserving wine: heating between 60°C and 100°C in an air-free environment for one to two hours. The pasteurization method circled the globe.

From 1865 through 1869 he investigated the pebrine disease that had been devastating the production of raw silk. He discovered that silkworms were contaminated when hatched, as the butterfly was already sick because of a minuscule parasite. Pasteur demonstrated that healthy eggs could be seen under a microscope and hatched. His cellular system helped end the disease by 1875.

asepsis and antisepsis

In France, by the end of the Franco-Prussian War of 1870–1871, a surgeon named Alphonse Guérin began to accept that infection could be caused by the microbes described by Pasteur. By applying a cotton dressing, Guérin was able to avoid microbial overinfection.

It was Joseph Lister from England, however, who was the first to officially apply Pasteur's discoveries to medicine. In 1865 Thomas Anderson, a chemistry professor in Glasgow, first showed Lister reports from Pasteur. Lister suddenly understood the link that might exist between the decomposition of organic matter and postoperative infections. He, like Pasteur, believed that the ambient air was one of the main pathways for the propagation of germs. He thought it would be possible to kill the germs using a substance that would not be toxic to human tissue but could prevent abscess formation, even in a nonsterile environment. In recounting the circumstances that convinced him of such hypothesis, Lister explained that he had been very impressed by a report on the remarkable effects of carbolic acid on sewer water. Understanding that carbolic acid not only removed the smells but also killed the germs, he discovered antisepsis.

Antisepsis (destruction of pathogenic microorganisms already present) was adopted before asepsis (prevention of such microorganisms from occurring); the latter only reached Paris toward the end of the 1870s and was not routinely used until the end of the 1880s. The application of asepsis progressed in parallel with hygiene.

the microbial theory of infectious diseases

The debate on aspesis and antisepsis only provided indirect arguments on the pathogenic effect of germs. The absence of germs indeed prevented the diseases, but it did not confirm the cause-and-effect link. Direct evidence came from Pasteur's work on anthrax.

Anthrax is a redoubtable infectious disease that wipes out whole herds of cattle and flocks of sheep. Sick animals soon collapse in the field. Scientists before Pasteur, such as Casimir-Joseph Davaine in France and Robert Koch in Germany, felt that bacteria were the cause but had not been able to prove it.

To demonstrate that bacteria transmitted the disease, Pasteur performed a simple experiment. All he had to do was dilute a drop of anthrax-infected blood and simulate microbial proliferation. By leaving to the bacteria the time they needed to multiply, a bacterial culture could soon be obtained that was nearly pure. The only thing then left to do was to inject a drop into an animal and demonstrate that such inoculation was as lethal as the anthrax-infected blood.

In the summer of 1878 the Ministry of Agriculture gave him a new assignment. He was to carry out a survey among cattle producers to find out how anthrax invaded the herds. Pasteur approached the problem using two clearly observed facts: the disease was transmitted by bacteria, and it depended on the grazing zone. Once again, proof involved field observation. Pasteur noticed that sharp, cutting leaves or barley beard caused abrasions in the animals' mouths. His conclusion was that the disease inoculation occurred when the cow or sheep cut its mouth or when it swallowed contaminated herbage.

But there was an outstanding question: How do anthrax spores rise to the surface when the dead animals have been buried deeply underground? In a flash of genius, Pasteur found the missing link in his anthrax transmission chain. "The worms are the carriers of the spore. As they dig galleries underground, they move near the animal graves, then transport and spread the spores."

vaccinations

For Pasteur, prevention was still the main therapy. Vaccination was soon to become one of the main concerns of his research.

Pasteur felt it would be possible to find a method of protection against each and every microbial strain. With the help of Émile Roux, in 1880, he applied his theory to chicken cholera. After a partly accidental discovery, Pasteur prepared a bacillus culture with attenuated virulence, which therefore offered protection against the fatal infection. Pasteur thus added a genuine biological reagent to Lister's antiseptic techniques. Such attenuated germs were not pathogenic but instead, acted as reagents to prevent the disease induced by virulent ones. It did not cause the disease but became a weapon to stimulate natural resistance.

By using the word vaccinate to mean inoculating the germ of attenuated virulence, Pasteur showed how much he owed to his predecessors, first and foremost the English physician Edward Jenner. However, Pasteurian vaccination is very different from Jenner's method of using a cow's udder because it includes biological experiments. Pasteur discovered the vaccine, not the vaccination. Indeed Jenner proposed a method to vaccinate against smallpox, but did not know how to make a vaccine. Pasteur did not discover the principle but instead described procedures to make vaccines, which, since then, have been applied with success.

Pasteur applied the vaccine to cattle diseases, chicken cholera, hog erysipelas, anthrax, and, although he used a different principle, to human rabies. These results automatically led the way to other vaccines, which were developed thereafter for numerous infectious diseases by many men and women of science and industry.

the pasteur institutes

Pasteur's contribution to public health, from the rules of hygiene to knowledge of germs and the development of vaccines, was not limited to scientific experimentation. Pasteur wanted to apply his ideas himself. The need for a place to combine instruction and industry became clear and led to the opening of the Pasteur Institute on 14 November 1888. He was also desirous of having his research findings serve the most underprivileged countries, and several other Pasteur Institutes were funded overseas from Asia to Africa.

When he died in 1895, Pasteur was judged one of humanity's most important scientists. By opening the way to the rational analysis of the elements of disease prevention, he changed the lives of people around the globe.

See alsoChemistry; Disease; France; Jenner, Edward; Koch, Robert; Lister, Joseph; Wine.

bibliography

Primary Sources

Pasteur, Louis. Oeuvres de Pasteur réunies. 7 vols. Paris, 1922–1939.

——. Correspondance générale. 4 vols. Paris, 1951.

Secondary Sources

Calmette, Albert. "Pasteur et les Instituts Pasteur." Revue d'hygiène 45 (1923).

Dagognet, François. Méthodes et doctrine dans l'œuvre de Pasteur. Paris, 1967.

——. Pasteur sans la légende. Le Plessis, 1994.

Debré, Patrice. Louis Pasteur. Paris, 1994.

Dubos, René. Le Leçon de Pasteur. Paris, 1988.

Geison, Gerald. "Pasteur." In Dictionary of Scientific Biography, edited by Charles Coulston Gillespie. Vol 1. New York, 1974.

Metchnikov, Elie. Trois fondateurs de la médicine moderne: Pasteur, Lister, Koch. Alcan, 1933.

Pasteur Vallery-Radot, Louis. "Les Instituts Pasteur d'Outre-Mer." La Presse Médicale 21 (1939).

Ramon, Gaston. "Ce que Pasteur doit aux vétérinaires et ce que le médecin vétérinaire doit à Pasteur." Revue Médicale et Vétérinaire 112 (1936).

Vallery-Radot, René. La vie de Pasteur. Paris, 1900.

Patrice DebrÉ

Louis Pasteur

The French chemist and biologist Louis Pasteur (1822-1895) is famous for his germ theory and for the development of vaccines.

Louis Pasteur was born on Dec. 27, 1822, in the small town of Dôle, the son of a tanner. He studied in the college of Arbois and at Besançon, where he graduated in arts in 1840. As a student preparing for the prestigious école Normale Supérieure of Paris, he did not doubt his ability. When he gained admittance by passing fourteenth on the list, he refused entry; taking the examination again, he won third place and accepted. For his doctorate his attention was directed to the then obscure science of crystallography. This was to have a decisive influence on his career.

Stereochemistry Investigations

Pasteur, under special dispensation from the minister of education, received a leave of absence from his duties as professor of physics at the lycée of Tournon to pursue research on the optical properties of crystals of the salts of tartrates and paratartrates, which had the capacity to rotate the plane of polarized light. He prepared 19 different salts, examined these under a microscope, and determined that they possessed hemihedral facets. However, the crystal faces were oriented differently; they were left-handed or right-handed, thus having the asymmetrical relationship of mirror images. Furthermore, each geometric variety of crystal rotated the light in accordance with its structure, while equal mixtures of the left-and right-handed crystals had no optical activity inasmuch as the physical effects canceled each other. Thus he demonstrated the phenomenon of optical isomers.

Pasteur was elated; he repeated his experiment under the exacting eyes of Jacques Biot, the French Academy's authority on polarized light who had brought Eilhardt Mitscherlich's work to Pasteur's attention. The confirmation was complete to the last exacting detail, and Pasteur, then 26, became famous. The French government made him a member of the Legion of Honor, and Britain's Royal Society presented him with the Copley Medal.

In 1852 Pasteur accepted the chair of chemistry at the University of Strasbourg. Here he found not only a wife but an opportunity to pursue another dimension of crystallography. It had long been known that molds grew readily in solutions of calcium paratartrate. It occurred to him to inquire whether organisms would show a preference for one isomer or another. He soon discovered that his microorganism could completely remove only one of the crystal forms from the solution, the levorotary, or left-handed, molecule.

Studies on Fermentation

In 1854, though only 31 years old, Pasteur became professor of chemistry and dean of sciences at the new University of Lille. The course of his activities is displayed in the publications which he gave to the world in the next decades: Studies on Wine (1866), Studies on Vinegar (1868), Studies on the Diseases of Silkworms (1870), and Studies on Beer (1876).

Soon after his arrival at Lille, Pasteur was asked to devote some time to the problems of the local industries. A producer of vinegar from beet juice requested Pasteur's help in determining why the product sometimes spoiled. Pasteur collected samples of the fermenting juices and examined them microscopically. He noticed that the juices contained yeast. He also noted that the contaminant, amyl alcohol, was an optically active compound, and hence to Pasteur evidence that it was produced by a living organism ("living contagion").

Pasteur was quick to generalize his findings and thus to advance a biological interpretation of the processes of fermentation. In a series of dramatic but exquisitely planned experiments, he demonstrated that physical screening or thermal methods destroyed all microorganisms and that when no contamination by living contagion took place, the processes of fermentation or putrefaction did not take place either. "Pasteurization" was thus a technique which could not only preserve wine, beer, and milk but could also prevent or drastically reduce infection in the surgeon's operating room.

Another by-product of Pasteur's work on fermentation was his elucidation of the fact that certain families of microbes require oxygen whereas others do not. Yeast, he showed, was a facultative anaerobe; when oxygen was not present, as in the vats of beer or wine manufacturers, it would derive its energy from the sugar, converting it to alcohol; under more favorable conditions (for the yeast) where oxygen was available, alcohol did not accumulate, and the process continued to the complete conversion of sugar to carbon dioxide and water. This insight divided the scientific community, and it was only in 1897, 2 years after the death of Pasteur, that the dispute was resolved, when a cell-free extract of yeast proved capable of fermenting a sugar solution. Thus it turned out that the living organism synthesized an enzyme which carried out the conversion.

Silkworms and Microbial Disease Theory

In 1865 Pasteur was called upon to assist another ailing industry of France—silk manufacture—which was being ruined by an epidemic among silkworms. He took his microscope to the south of France and in an improvised laboratory set to work. Four months later he had isolated the pathogens causing the disease, and after 3 years of intensive work he suggested the methods of bringing it under control.

Pasteur's scientific triumphs coincided with personal and national tragedy. In 1865 his father died; his two daughters were lost to typhoid fever in 1866. Over-worked and grief-stricken, Pasteur suffered a cerebral hemorrhage in 1868 which left part of his left arm and leg permanently paralyzed. Nonetheless, he pressed on, hardly with interruptions, on his study of silkworm diseases, already sensing that these investigations were but his apprenticeship for the control of the diseases of higher animals, including humans.

The Franco-Prussian War, with its trains of wounded, stimulated Pasteur to press his microbial theory of disease and infection on the military medical corps, winning grudging agreement to the sterilization of instruments and the steaming of bandages. The results were spectacular, and in 1873 Pasteur was made a member of the French Academy of Medicine—a remarkable accomplishment for a man without a formal medical degree.

Pasteur was now prepared to move from the most primitive manifestations of life, crystals and the simpler forms of life in the microbial world, to the diseases of the higher animals. The opportunity arose through a particularly devastating outbreak of anthrax, a killer plague of cattle and sheep in 1876/1877. The anthrax bacillus had already been identified by Robert Koch, and Pasteur now set about proving that the agent of disease was precisely the living organism and not a related toxin. He diluted a solution originally containing a source of infection of anthrax by a factor of 1 part in 100¹⁰⁰. Even at this enormous dilution, the residual fluid carried death, thus proving that it was the constantly multiplying organism that was the source of the disease.

In 1881 Pasteur had convincing evidence that gentle heating of anthrax bacilli could so attenuate the virulence of the organism that it could be used to inoculate animals and thus immunize them. In a dramatic demonstration of this procedure, carried out with the whole of France as witness, Pasteur inoculated one group of sheep with the vaccine and left another untreated. Upon injection of both groups with the bacillus, the untreated died; the others lived, and thus a scourge that had crippling economic effects was brought under control.

Pasteur's ultimate triumph came with the conquest of rabies, the disease of animals, particularly dogs, which gives rise to the dreaded hydrophobia of humans. The problem here was that the causative agent was a virus, hence an entity not capable of growth in the scientists' broth which nurtured bacteria. Pasteur worked for 5 years in an effort to isolate and culture the pathogen. Finally, in 1884, in collaboration with other investigators, he perfected a method of cultivating the virus in the tissues of rabbits. The virus could then be attenuated by exposing the incubation material to sterile air over a drying agent at room temperature. A vaccine could then be prepared for injection. The success of this method was greeted with jubilation all over the world. Animals could now be saved, but the question arose as to the effect of the treatment on human beings. In 1885 a 9-year-old boy, Joseph Meister, was brought to Pasteur. He was suffering from 14 bites from a rabid dog. With the agreement of the child's physician, Pasteur began his treatment with the vaccine. The injections continued over a 12-day period, and the child recovered.

Honors from the World

In 1888 a grateful France founded the Pasteur Institute, which was destined to become one of the most productive centers of biological study in the world. In the closing paragraphs of his inaugural oration, Pasteur said: "Two opposing laws seem to me now to be in contest. The one, a law of blood and death opening out each day new modes of destruction, forces nations always to be ready for the battle. The other, a law of peace, work and health, whose only aim is to deliver man from the calamities which beset him. The one seeks violent conquests, the other, the relief of mankind. The one places a single life above all victories, the other sacrifices hundreds of thousands of lives to the ambition of a single individual. The law of which we are the instruments strives even through the carnage to cure the wounds due to the law of war. Treatment by our antiseptic methods may preserve the lives of thousands of soldiers. Which of these two laws will prevail, God only knows. But of this we may be sure, science, in obeying the law of humanity, will always labor to enlarge the frontiers of life."

Pasteur's seventieth birthday was the occasion of a national holiday. At the celebration held at the Sorbonne, Pasteur was too weak to speak to the delegates who had gathered from all over the world. His address, read by his son, concluded: "Gentlemen, you bring me the greatest happiness that can be experienced by a man whose invincible belief is that science and peace will triumph over ignorance and war.… Have faith that in the long run … the future will belong not to the conquerors but to the saviors of mankind."

On Sept. 28, 1895, honored by the world but unspoiled and overflowing with affection, Pasteur died near Saint-Cloud. His last words were: "One must work; one must work. I have done what I could." He was buried in a crypt in the Pasteur Institute. There is a strange postscript to this story. In 1940 the conquering Germans came again to Paris. A German officer demanded to see the tomb of Pasteur, but the old French guard refused to open the gate. When the German insisted, the Frenchman killed himself. His name was Joseph Meister, the boy Pasteur had saved from hydrophobia so long ago.

Further Reading

The definitive biographies of Pasteur are René Dubos, Louis Pasteur, Free Lance of Science (1950), and Pierre Vallery-Radot, Louis Pasteur: A Great Life in Brief (trans. 1958). See also Jacques Nicolle, Louis Pasteur, a Master of Scientific Enquiry (1961). For the technical achievement in microbiology see Henry James Parish, A History of Immunization (1965). □

Louis Pasteur

Born: December 27, 1822
Dôle, France
Died: September 28, 1895
Paris, France
French chemist and biologist

The French chemist and biologist Louis Pasteur is famous for his germ theory and for the development of vaccines. He made major contributions to chemistry, medicine, and industry. His discovery that diseases are spread by microbes, which are living organisms—bacteria and viruses—that are invisible to the eye, saved countless lives all over the world.

The tanner's son

Louis Pasteur was born on December 27, 1822, in the small town of Dôle, France. His father was a tanner, a person who prepares animal skins to be made into leather. The men in Pasteur's family had been tanners back to 1763, when his great-grandfather set up his own tanning business. Part of the tanning process relies on microbes (tiny living organisms). In tanning, microbes prepare the leather, allowing it to become soft and strong. Other common products such as beer, wine, bread, and cheese depend on microbes as well. Yet, at the time Pasteur was a child, few people knew that microbes existed.

Pasteur's parents, Jean-Joseph Pasteur and Jeanne Roqui, taught their children the values of family loyalty, respect for hard work, and financial security. Jean-Joseph, who had received little education himself, wanted his son to become a teacher at the local lycée (high school). Pasteur attended the École Primaire (primary school), and in 1831 entered the Collège d'Arboix. He was regarded as an average student, who showed some talent as an artist. Nonetheless, the headmaster encouraged Pasteur to prepare for the École Normale Supérieure, a very large training college for teachers located in Paris. With this encouragement he applied himself to his studies. He swept the school prizes during the 1837 and 1838 school year.

Pasteur went to Paris in 1838 at the age of sixteen. His goal was to study and prepare for entering the École Normale. Yet, he returned to Arboix less than a month later, overwhelmed with homesickness. In August of 1840 he received his bachelor's degree in letters from the Collège Royal de Besançon and was appointed to tutor at the Collège. In 1842, at age twenty, he received his bachelor's degree in science. He then returned to Paris, and was admitted to the École Normale in the autumn of 1843. His doctoral thesis (a long essay resulting from original work in college) was on crystallography, the study of forms and structures of crystals.

Investigations into crystals

In 1848, while professor of physics at the lycée of Tournon, the minister of education granted Pasteur special permission for a leave of absence. During this time, Pasteur studied how certain crystals affect light. He became famous for this work. The French government made him a member of the Legion of Honor and Britain's Royal Society presented him with the Copley Medal.

Studies on fermentation

In 1852 Pasteur became chairman of the chemistry department at the University of Strasbourg, in Strasbourg, France. Here he began studying fermentation, a type of chemical process in which sugars are turned into alcohol. His work resulted in tremendous improvements in the brewing of beer and the making of wine. He also married at this time.

In 1854, at the age of thirty-one, Pasteur became professor of chemistry and dean of sciences at the new University of Lille. Soon after his arrival at Lille, a producer of vinegar from beet juice requested Pasteur's help. The vinegar producer could not understand why his vinegar sometimes spoiled and wanted to know how to prevent it.

Pasteur examined the beet juice under his microscope. He discovered it contained alcohol and yeast. The yeast was causing the beet juice to ferment. Pasteur then demonstrated that controlled heating of the beet juice destroyed the yeast, and prevented fermentation. This process, called "pasteurization," was eventually applied to preserve a number of foods such as cheese and milk. It also became the basis for dramatically reducing infection in the operating room.

Studies on silkworms

In 1865 Pasteur was asked to help the ailing silk industry in France. An epidemic among silkworms was ruining it. He took his microscope to the south of France and set to work. Four months later he had isolated the microorganism causing the disease. After three years of intensive work he suggested methods for bringing it under control.

The theory of microbial disease

Pasteur's scientific triumphs coincided with personal and national tragedy. In 1865 his father died. His two daughters were lost to typhoid fever in 1866. Overworked and grief-stricken, Pasteur suffered a cerebral hemorrhage (a bleeding caused by a broken blood vessel in the brain) in 1868. Part of his left arm and leg were permanently paralyzed. Nevertheless, he pressed on.

Pasteur saw the trains of wounded men coming home from the Franco-German War (1870–71; war fought to prevent unification under German rule). He urged the military medical corps to adopt his theory that disease and infection were caused by microbes. The military medical corps unwillingly agreed to sterilize their instruments and bandages, treating them with heat to kill microbes. The results were spectacular, and in 1873 Pasteur was made a member of the French Academy of Medicine—a remarkable accomplishment for a man without a formal medical degree.

Animal studies

A particularly devastating outbreak of anthrax, a killer plague that affected cattle and sheep, broke out between 1876 and 1877. The anthrax bacillus (a type of microbe shaped like a rod) had already been identified by Robert Koch (1843–1910) in 1876. It had been argued that the bacillus did not carry the disease, but that a toxic (poisonous) substance associated with it did. Pasteur proved that the bacillus itself was the disease agent, or the carrier of the disease.

In 1881 Pasteur had convincing evidence that gentle heating of anthrax bacilli could so weaken its strength that it could be used to inoculate animals. Inoculation is a process of introducing a weakened disease agent into the body. The body gets a mild form of the disease, but becomes immunized (strengthened against) the actual disease. Pasteur inoculated one group of sheep with the vaccine and left another untreated. He then injected both groups with the anthrax bacillus. The untreated sheep died and the treated sheep lived.

Pasteur also used inoculation to conquer rabies. Rabies is a fatal disease of animals, particularly dogs, which is transmitted to humans through a bite. It took five years to isolate and culture the rabies virus microbe. Finally, in 1884, in collaboration with other investigators, Pasteur perfected a method of growing the virus in the tissues of rabbits. The virus could be weakened by exposing it to sterile air. A vaccine, or weakened form of the microbe, could then be prepared for injection. The success of this method was greeted with excitement all over the world.

The question soon arose as to how the rabies vaccine would act on humans. In 1885 a nine-year-old boy, Joseph Meister, was brought to Pasteur. He was suffering from fourteen bites from a rabid dog. With the agreement of the child's physician, Pasteur began his treatment with the vaccine. The injections continued over a twelve-day period, and the child recovered.

Honors from the world

In 1888 a grateful France founded the Pasteur Institute. It was destined to become one of the most productive centers of biological study in the world.

In 1892 Pasteur's seventieth birthday was the occasion of a national holiday. A huge celebration was held at the Sorbonne. Unfortunately Pasteur was too weak to speak to the delegates who had gathered from all over the world. His son read his speech, which ended: "Gentlemen, you bring me the greatest happiness that can be experienced by a man whose invincible belief is that science and peace will triumph over ignorance and war.… Have faith that in the long run … the future will belong not to the conquerors but to the saviors of mankind."

On September 28, 1895, Pasteur died in Paris. His last words were: "One must work; one must work. I have done what I could." He was buried in a crypt in the Pasteur Institute. Years later Joseph Meister, the boy Pasteur saved from rabies, worked as a guard at his tomb.

For More Information

Dubos, René. Louis Pasteur: Free Lance of Science. Boston: Little, Brown, 1950. Reprint, New York, NY: Da Capo Press, 1986.

Geison, Gerald L. The Private Science of Louis Pasteur. Princeton, NJ: Princeton University Press, 1995.

Jakab, E. A. M. Louis Pasteur: Hunting Killer Germs. New York: McGraw-Hill, 2000.

Smith, Linda Wasmer. Louis Pasteur: Disease Fighter. Springfield, NJ: Enslow, 1997.