MACLEOD, COLIN MUNRO

(b. Port Hastings, Nova Scotia, Canada, 28 February 1909; d. London, England, 11 February 1972)

microbiology, medicine.

The son of a Presbyterian minister. MacLeod spent his youth in Canada, where the family lived a rather unsettled life moving between Nova Scotia, Saskatchewan, and Quebec. As a child prodigy he left secondary school in Richmond, Quebec, at the age of fifteen, but returned to teach there until he was old enough to enter medical school. At the age of twenty–three he received his medical degree at McGill University. Two years later, in 1934, he began medical research in New York City, where he was attached to the Pneumonia Service directed by Rufus Cole and O. T. Avery in the Rockefeller Institute Hospital. In 1938 he married Elizabeth Randol; they had one daughter.

Possibly MacLeod had been attracted to the idea of research at the Rockefeller Institute by his old friend Martin Henry Dawson, who worked there on bacterial transformation in 1928 and 1929. Cer tainly MacLeod had read F. Griffith’s famous paper describing bacterial transformation while he was a medical student at McGill.¹ On his arrival in New York he quickly settled to the task of repeating the experiments of Dawson and of J. L. Alloway. The former had achieved in vitro transformation, but with dead intact cells; the latter successfully sub stituted cell extracts for entire cells.

After three years devoted to this topic MacLeod had greatly improved the experimental procedures but had not made sufficient progress towards characterizing the transforming principle to justify pub lication. Discouraged, he dropped this research in order to collaborate with Frank Horsfall and Kenneth Goodner in their development of the antiserum treatment of pneumococcal pneumonia. No sooner had MacLeod switched to serum therapy than the superiority of chemotherapy over serum therapy began to emerge with the introduction of the sul fonamides. He promptly turned to the testing of sulfapyridine against pneumococcal infections and reported on the unpleasant side effects of this drug, which included nausea, vomiting, and the appearance of skin rashes. He also reported the development of drug resistance both in the host and in the test tube. Type I pneumococcus, he said,

can be adapted to growth in increasing concentrations of sulfapyridine until finally it will multiply freely in concentrations of the drug which inhibit the growth of organisms not so accustomed. Throughout the pro cedure of adaptation the pneumococcus retains not only its type–specific capsule but its virulence as well. This “drug–fast” strain, unlike the parent strain from which it was derived, does not respond to the ther apeutic effect of sulfapyridine in experimental infections².

MacLeod was describing this phenomenon in the language of the 1930’s, which assumed that bacteria acquire new adaptive characters in a Lamarckian fashion.

These studies were followed by an attempt, in collaboration with Avery, to identify the mysterious substance produced in the blood of patients with acute pneumonia infections. They called it the “C-reactive protein,” but why it is produced and what function it serves have remained an enigma. At this stage (1940) Avery and MacLeod judged it was time to return to bacterial transformation. Although in 1941 MacLeod left the Rockefeller Institute Hospital to become chairman of the Department of Microbiology at the New York University School of Medicine, he continued to follow the research that Maclyn McCarty took over on his arrival at the institute that year, and MacLeod’s name appeared as a coau thor on the world–famous paper (1944) describing the identification of the transforming principle.

The phenomenon of bacterial transformation was something of an oddity. Strains of pneumococcus had been grouped into a number of “types” based on their immunological reactions and the differing constitutions of their sugary protective coats or capsules. They could lose their coats to become “rough” (on account of the appearance of their colonies), and they could revert to the capsular form that produced “smooth” colonies. Such spon taneous reversion from R to S was always to the same capsular type. However, cultured with the dead cells of an S pneumococcus of another type, R cells could acquire the capsules of the dead type; they could be “transformed.”

Before MacLeod entered the field, the process of transformation, although in vitro, was erratic, and quantitative estimates of transforming activity were unreliable. MacLeod isolated a particular R strain of the type II pneumococcus (R36) that had no tendency to spontaneous reversion to S and was very susceptible to transformation by other pneu mococcal types. He also improved the medium, heating the chest fluid to inactivate enzymes that destroyed the transforming principle, and adapted the operations for achieving transformation on a large scale. As Walsh McDermott remarked, MacLeod “had taken an almost formless, erratic phenomenon and made it into something predictable and measurable.” ³ He had also achieved a scale of production sufficient for the isolation and chemical identification of the transforming principle.

MacLeod left the institute reluctantly. His ap pointment as an assistant resident physician and assistant in medicine had not been a tenured one. When the offer from New York University came, the institute’s director, Thomas Rivers, urged MacLeod to accept, for, as McCarty discovered later, Rivers was about to bring Frank Horsfall back to the institute as a full member to succeed Avery as director of the Pneumonia Service. Hence it was with some secret chagrin that MacLoed saw the transformation work taken up by McCarty in his place.

At the time of MacLeod’s departure from the institute, Avery had come to the conclusion that RNA, or yeast nucleic acid as it was then called, thought a prominent component of pneumococcal cells, was not necessary for transformation, but that the active extract contained a little DNA. MacLeod, however, made no mention of DNA, in his 1941 report to the board of science directors of the institute. Instead he pursued the alleged need for some of the specific soluble substance (the polysaccharide of the donor cell capsule) to be present to “prime” the enzyme produced as a result of transformation. Moreover, the success of transformation was still very variable due to the many factors influencing the process. After MacLeod left the institute, McCarty showed conclusively that carbohydrate was necessary for transformation, and gradually during 1942, together with Avery and MacLeod, he came to the conclusion that the active substance was DNA. They described it in 1944 as a “highly polymerized and viscous form of sodium desoxyribo nucleate.”⁴

During the fifteen years MacLeod spend at New York University he established an effective program of basic research in the medical school. In 1956 he became John Herr Musser Professor of Research Medicine at the University of Pennsylvania, and in 1960 he returned to New York University as professor of medicine. Finally, MacLeod became vice president for medical affairs of the Common wealth Fund.

From the entry of the United States into World War II, MacLeod served as a science adviser to the U.S. War Department, becoming president of the Army Epidemiology Board in 1945 and of the subsequently enlarged board for all the armed forces from 1949 until 1955. He also advised the National Institutes of Health, the president’s Sciences Advisory Committee, and the executive office of presidents Kennedy and Johnson. Among his many tasks as a science adviser were his direction of the U.S.-Japan cooperative of the technical committee of the Cholera Research Laboratory in Dacca, India, which had been set up by the South East Asia Treaty Organization. It was while on his way to Dacca in 1972 that he died.

NOTES

1. F. Griffith, “The Significance of Pneumococcal Types,” in Journal of Hygiene, 27 (1928), 113–159.

2. MacLeod, “Chemotherapy of Pneumococcic Pneumonia,” in Journal of the American Medical Association, 113 (1939), 1405.

3. McDermott, “Colin Munro MacLeod,” in Biographical Memoirs. National Academy of Science, 54 (1983), 187.

4. Avery, MacLeod, and McCarty, “Studies on the Chemical Nature of the Substance Inducing Transformation of Pneu mococcal Type,” in Journal of Experimental Medicine, 79 (1944), 152.

BIBLIOGRAPHY

I. Original Works. In his biographical memoir given below Walsh McDermott lists forty-five papers. Seventeen of these appeared in the Journal of Experimental Medicine and five in the Proceedings of the Society for Experimental Biology and Medicine. The remainder were scattered among a number of medical journals.

II. Secondary Literature. The most detailed obituary is by Walsh McDermott in Biographical Memories. National Academy of Sciences, 54 (1983), 183-219. Maclyn McCarty wrote two obituaries, to be found in the Yearbook of the American Philosophical Society, (1972), 222-230, and in the Transactions of the Association of American Physicians, 85 (1972), 31-34. MacLeod’s contribution to the work on bacterial transformation is discussed in René J. Dubos, The Professor, the Institute, and DNA (New York, 1976), and in Maclyn McCarty, Transforming Principle: Discovering Nun Genes are Made of DNA (New York, 1985)

Robert Olby

MacLeod, Colin Munro (1909-1972)

Canadian-born American microbiologist

Colin Munro MacLeod is recognized as one of the founders of molecular biology for his research concerning the role of deoxyribonucleic acid (DNA ) in bacteria . Along with his colleagues Oswald Avery and Maclyn McCarty , MacLeod conducted experiments on bacterial transformation which indicated that DNA was the active agent in the genetic transformation of bacterial cells. His earlier research focused on the causes of pneumonia and the development of serums to treat it. MacLeod later became chairman of the department of microbiology at New York University; he also worked with a number of government agencies and served as White House science advisor to President John F. Kennedy.

MacLeod, the fourth of eight children, was born in Port Hastings, in the Canadian province of Nova Scotia. He was the son of John Charles MacLeod, a Scottish Presbyterian minister, and Lillian Munro MacLeod, a schoolteacher. During his childhood, MacLeod moved with his family first to Saskatchewan and then to Quebec. A bright youth, he skipped several grades in elementary school and graduated from St. Francis College, a secondary school in Richmond, Quebec, at the age of fifteen. MacLeod was granted a scholarship to McGill University in Montreal but was required to wait a year for admission because of his age; during that time he taught elementary school. After two years of undergraduate work in McGill's premedical program, during which he became managing editor of the student newspaper and a member of the varsity ice hockey team, MacLeod entered the McGill University Medical School, receiving his medical degree in 1932.

Following a two-year internship at the Montreal General Hospital, MacLeod moved to New York City and became a research assistant at the Rockefeller Institute for Medical Research. His research there, under the direction of Oswald Avery, focused on pneumonia and the Pneumococcal infections which cause it. He examined the use of animal antiserums (liquid substances that contain proteins that guard against antigens) in the treatment of the disease. MacLeod also studied the use of sulfa drugs , synthetic substances that counteract bacteria, in treating pneumonia, as well as how Pneumococci develop a resistance to sulfa drugs. He also worked on a mysterious substance then known as "C-reactive protein," which appeared in the blood of patients with acute infections.

MacLeod's principal research interest at the Rockefeller Institute was the phenomenon known as bacterial transformation. First discovered by Frederick Griffith in 1928, this was a phenomenon in which live bacteria assumed some of the characteristics of dead bacteria. Avery had been fascinated with transformation for many years and believed that the phenomenon had broad implications for the science of biology. Thus, he and his associates, including MacLeod, conducted studies to determine how the bacterial transformation worked in Pneumococcal cells.

The researchers' primary problem was determining the exact nature of the substance which would bring about a transformation. Previously, the transformation had been achieved only sporadically in the laboratory, and scientists were not able to collect enough of the transforming substance to determine its exact chemical nature. MacLeod made two essential contributions to this project: He isolated a strain of Pneumococcus which could be consistently reproduced, and he developed an improved nutrient culture in which adequate quantities of the transforming substance could be collected for study.

By the time MacLeod left the Rockefeller Institute in 1941, he and Avery suspected that the vital substance in these transformations was DNA. A third scientist, Maclyn McCarty, confirmed their hypothesis. In 1944, MacLeod, Avery, and McCarty published "Studies of the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: Induction of Transformation by a Deoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III" in the Journal of Experimental Medicine. The article proposed that DNA was the material which brought about genetic transformation. Though the scientific community was slow to recognize the article's significance, it was later hailed as the beginning of a revolution that led to the formation of molecular biology as a scientific discipline.

MacLeod married Elizabeth Randol in 1938; they eventually had one daughter. In 1941, MacLeod became a citizen of the United States, and was appointed professor and chairman of the department of microbiology at the New York University School of Medicine, a position he held until 1956. At New York University he was instrumental in creating a combined program in which research-oriented students could acquire both an M.D. and a Ph.D. In 1956, he became professor of research medicine at the Medical School of the University of Pennsylvania. MacLeod returned to New York University in 1960 as professor of medicine and remained in that position until 1966.

From the time the United States entered World War II until the end of his life, MacLeod was a scientific advisor to the federal government. In 1941, he became director of the Commission on Pneumonia of the United States Army Epidemiological Board. Following the unification of the military services in 1949, he became president of the Armed Forces Epidemiological Board and served in that post until 1955. In the late 1950s, MacLeod helped establish the Health Research Council for the City of New York and served as its chairman from 1960 to 1970. In 1963, President John F. Kennedy appointed him deputy director of the Office of Science and Technology in the Executive Office of the President; from this position he was responsible for many program and policy initiatives, most notably the United States/Japan Cooperative Program in the Medical Sciences.

In 1966, MacLeod became vice-president for Medical Affairs of the Commonwealth Fund, a philanthropic organization. He was honored by election to the National Academy of Sciences, the American Philosophical Society, and the American Academy of Arts and Sciences. MacLeod was en route from the United States to Dacca, Bangladesh, to visit a cholera laboratory when he died in his sleep in a hotel at the London airport in 1972. In the Yearbook of the American Philosophical Society, Maclyn McCarty wrote of MacLeod's influence on younger scientists, "His insistence on rigorous principles in scientific research was not enforced by stern discipline but was conveyed with such good nature and patience that it was simply part of the spirit of investigation in his laboratory."

See also Bacteria and bacterial infection; Microbial genetics; Pneumonia, bacterial and viral