ELION, GERTRUDE BELLE

(b. New York, New York, 23 January 1918;

d. Chapel Hill, North Carolina, 21 February 1999),pharmacology, antimetabolites, immunosuppressors, anticancer drugs, antiviral drugs.

Elion shared the 1988 Nobel Prize in Physiology or Medicine with James Black, who discovered beta-blockers and H₂–receptor antagonists, and George H. Hitchings, with whom she had collaborated for more than forty years, the two being responsible for the discovery of many major therapeutic agents—anticancer, antiviral, antibacterial, immunosuppressive, anti-gout—whose common characteristic was that they were specifically targeted at nucleic acids. Elion may thus be considered a founder of molecular pharmacology. Although she was the fifth woman to receive the Nobel Prize in Physiology or Medicine, she was the first who was neither a physician nor the holder of a doctoral degree.

Elion was born in New York on 23 January 1918. Her father, Robert Elion, had immigrated from Lithuania at the age of twelve and studied dental surgery in New York. Her mother, Bertha Cohen, had arrived in the United States from the Russian-Polish borderlands at age fourteen. Their daughter graduated from Hunter College in 1937. Academia was scarcely welcoming to women in those days, and she was unable to pursue her studies immediately. She taught for a semester at the New York Hospital School of Nursing and volunteered at a chemistry laboratory. Only in 1939 did she embark on postgraduate studies at New York University, where, two years later, the sole female candidate, she was awarded a master of science degree in chemistry.

When her grandfather died of cancer, Elion began to dream of a career in medical research, but she was obliged to start out as a food analyst for the Quaker Maid Company. The American mobilization for World War II, by opening up many positions to women, gave her a chance to enter the pharmaceutical industry. In 1944, after a few months with Johnson & Johnson, she was offered employment with Burroughs Wellcome as an assistant chemist in the laboratory of Hitchings in Tuckahoe, New York. There she began, ten years before the discovery of the double helix, to investigate modifiers of nucleic-acid metabolism.

Contemporary advances in antineoplastic chemotherapy prompted the reorientation of this research toward cancer. The first concrete results began to appear in 1947, with the formulation of the antileukemics 6-mercaptopurine and 6-thioguanine. Elion and her colleagues subsequently developed azathioprine, a powerful immunosuppressive drug. Another line of inquiry led to allopurinol, a treatment for gout and hyperuricemia.

Elion’s work culminated in a great discovery, that of the strong antiherpetic action of acyclovir. From 1967 on, she headed Burroughs Wellcome’s Experimental Therapy Department. Her name appeared on forty-five patents. She received twenty-five honorary doctorates and was elected president of the American Association for Cancer Research. She entered semiretirement in 1983, but was invited to teach at Duke University (Durham, North Carolina) and at the University of North Carolina at Chapel Hill. She also worked for the World Health Organization and strove to increase support for young researchers, notably through the Wellcome Foundation. The Nobel Prize was a fitting coda to her remarkable career.

Gertrude Belle Elion, known to her friends as “Trudy,” died at the age of eighty-one on 21 February 1999 in Chapel Hill.

Research Program . In the mid-1940s, the idea of producing drugs designed to treat viral conditions seemed incongruous, for hitherto almost all efforts had been bent toward the development of vaccines capable of preventing such conditions. The aim now was to intervene early, at the beginning of the reproductive cycle of viruses. One of the difficulties facing Elion and her coworkers was the relative crudeness of the techniques available: Their physical and chemical apparatus was of the most basic kind, and they had little by way of spectroscopic or radiological equipment.

Antimetabolites . The theory of antimetabolites, conceived in 1940, was the brainchild of the Oxford biochemist Donald Woods, who argued that exogenous substances could compete with the natural substrates necessary to the anabolism of microorganisms and thus inhibit their replication. Woods observed that brewer’s yeast impeded the action of sulfonamides, and concluded that this yeast contained a substance closely resembling sulfanilamide and capable of competing with it. Based on this competition between sulfonamides and aminobenzoic acid (PABA), a natural substrate of bacterial metabolism, the term antimetabolite was applied to any substance capable of exercising such an inhibitory function.

Following a similar line of inquiry, Hitchings showed that different antimetabolites could prevent the growth of microorganisms. Thus pyrimethamine, a dihydrofolatereductase inhibitor in protozoa, was proposed as an anti-malarial agent.

In 1966 other chemical modifications brought about in the benzene cycle of 5-benzyl-2,4-diaminopyrimidine made it possible to obtain a derivative that was active against Proteus vulgaris. This was trimethoprim, an inhibitor fifty thousand times stronger than the human enzyme with respect to bacterial dihydrofolate reductase. A combination of trimethoprim with the sulfonamide sulfamethoxazole (co-trimoxazole) was offered by Burroughs Wellcome.

Hitchings was convinced that it should be possible to arrest the growth of rapidly dividing cells (bacteria or cancerous cells) by means of antagonists of the nucleic-acid bases their division depended on. The object was to exploit the high speed of their proliferation as compared with normal mammalian cells and ultimately to classify the biochemical differences between cell types according to the ways in which they responded to these antimetabolites.

The importance of dihydrofolate reductase inhibitors was recognized because this enzyme is an important rate-limiting step in the de novo folate synthesis pathway, which is an universal step in cell life cycle in eucaryote and procaryote cells as well. That is why the pharmacological targets of those inhibitors are so various: For instance, methotrexate is a cancer chemotherapeutic agent, whereas trimethoprim is an antibiotic. This is explained through the fact that despite both being dihydrofolate reductase inhibitors, methotrexate has a selective affinity for mammalian dihydrofolate reductase, while trimethoprim has a selective affinity for the bacterial enzyme.

Possible targets of research were provided by the various enzymes of nucleic acids then known: nucleases, nucleotidases, nucleosidases, deaminases, xanthine oxydase, and uricase. Hitchings and Elion began by studying guanase and xanthine oxydase in order to learn whether purines acted as substrates or as inhibitors of these enzymes. In 1948 they discovered that 2,6-diaminopurine was a powerful growth inhibitor for Lactobacillus casei, except when adenine was present. A strain of Lactobacillus casei resistant to diaminopurine made it possible to demonstrate that adenine and 2,6-diaminopurine were both modified by the same enzyme, namely adenylate pyrophosphorylase, described in 1955 by Arthur Kornberg (Nobel laureate, 1959).

Antileukemic Drugs . At the beginning of the 1950s, methotrexate was the only anticancer drug available. A leukemic child had a life expectancy of only three to four months once diagnosed, and only 30 percent of children survived for more than a year. In the late 1940s, the administration of 2,6-diaminopurine to leukemic mice (mice that are highly susceptible to development of spontaneous leukemias)and the exposure of tumor cells to it in vitro resulted in strong inhibitory activity. When it was tried out on patients, in 1951, impressive remissions of chronic myeloid leukemia were observed, as well as an in vitro inhibition of vaccinia virus. Unfortunately an excessive toxicity put an end to the clinical application of 2,6-diaminopurine.

In 1951 Elion and Hitchings synthesized and evaluated more than one hundred purine derivatives, finding that the replacement of the oxygen atom by a sulfur atom at the 6-position of guanine and hypoxanthine produced inhibitors of purine utilization, namely 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP). Following toxicological testing of these agents on animals, Joseph Burchenal of the Sloan-Kettering Institute in New York carried out clinical trials with children suffering from acute lymphoblastic leukemia. Some complete remissions were recorded, though most patients relapsed in the medium term. Consequently, in 1953, the U.S. Food and Drug Administration approved the use of 6-MP for acute leukemia in patients of this type, and the median survival rate for children thus treated rose from three to twelve months. A combination of thioguanine and cytosine arabinoside was later used to treat acute leukemias in adults.

Immunosuppression and Transplantation . In 1958 a team of Boston researchers led by William Dameshek and Robert Schwartz achieved an immuno-pharmacological breakthrough when they showed that prolonged and simultaneous administration of 6-MP and an antigen prevented the development of antibodies against the antigen in question. An immunological screening test allowed Schwartz and Elion to identify a new agent, 1-methyl-4-nitro 5-imidazolyl, or azathioprine (Imuran®), a prodrug for the 6-MP produced by the red blood cells under the influence of glutathion. At the suggestion of Schwartz and Elion, the British surgeon Roy Calne achieved a very good outcome when he replaced 6-MP by azathioprine in his already successful canine kidney homograft studies: With 6-MP, Calne had achieved a forty-four-day survival in a dog that had received a kidney from an unrelated donor— far longer than the nine- or ten-day graft survival expectation for control animals—furthermore, azathioprine proved to be even more effective in preventing rejection.

In humans, kidney transplantation from unrelated donors became possible in 1962, thanks to the use of immunosuppressive treatments combining azathioprine and cortisone derivatives. In the early twenty-first century, azathioprine was still a mainstay of transplantation. Its immunosuppressive properties are also called on in the treatment of a variety of autoimmune disorders.

Gout and Hyperuricemia . It was while searching for additional antileukemia agents that Elion and Hitchings came upon a treatment for gout. The biosynthesis of 6-thiouric acid, a product of the catabolism of 6-MP, is inhibited by xanthine oxydase. To evaluate the inhibition of xanthine oxydase in vivo, Elion and Hitchings used an analog of hypoxanthine, namely 4-hydroxypyrazolo-(3,4-d)-pyrimidine (allopurinol). They found that when allopurinol and 6-MP were administered simultaneously to mice, oxidation of the 6-MP was indeed inhibited. The antineoplastic and immunosuppressive properties of 6-MP were multiplied by a factor of three or four, whereas its toxicity was “only” doubled. Wayne Rundles studied leukemic patients on this basis, but found that in humans, unfortunately, toxicity increased in proportion to antitumoral action.

Another line of research with xanthine oxydase concerned the formation of uric acid from hypoxanthine and xanthine. It was found that treatment with allopurinol (a xanthine oxydase inhibitor) brought about a significant reduction in uric acid in blood and urine. This finding raised several questions. Would the pharmacokinetics of allopurinol ensure a durable impact on the metabolism of purines and uric-acid production? Would other metabolic products accumulate, such as hypoxanthine or xanthine? Did excess hypoxanthine and xanthine induce increased enzyme synthesis, thus indicating the administration of higher dosages of allopurinol? What would be the long-term effects of this drug?

All these questions were carefully explored, first with animals and then with human subjects. Allopurinol was determined to be a competitive inhibitor as well as a substrate of xanthine oxydase. Its oxidation produces the corresponding analog of xanthine, oxypurinol (or alloxantine), which is also a potent xanthine-oxydase inhibitor. Whereas allopurinol was found to have a plasma elimination half-life of just 90–120 minutes, that of oxypurinol was 18–30 hours: with a single daily dose of allopurinol, it was possible after a few days to maintain a roughly constant oxypurinol concentration. By adjusting the dosage, uric-acid concentration could be kept at the desired level. Completely absorbed after administration by mouth, allopurinol could become an ideal “prodrug.” It was the first radical treatment for gout.

Antiviral Drugs . In 1968, Hitchings and Elion and their team turned their attention once more to a working hypothesis—framed twenty years earlier but prematurely set aside—concerning the antiviral action of 2,6-diaminopurine. The idea of using this agent had been abandoned in view of its high toxicity, but the discovery of the antiviral properties of adenine arabinoside (ara-A) justified revisiting it and also considering 2,4-diaminop-urine-arabinoside, synthesized by Janet Rideout and subjected to virological study by John Bauer at the Wellcome Research Laboratories in the United Kingdom. This new derivative was effective not only against the vaccinia virus but also against herpes simplex, implicated in a variety of pathologies of the skin and mucous membranes. Furthermore, it was less cytotoxic than ara-A for eukaryotic cells. Hitchings and Elion had been right on target, and this was the beginning of what Elion called their “antiviral odyssey.” For several years they worked with purine arabinosides, investigating the relations between their structure and their action, searching for the best syntheses, and studying not only their metabolism but also their antiviral effectiveness. Among the most intriguing derivates of diaminopurine arabinoside (ara-DAP) were guanine arabinoside (ara-G), a more potent antiviral than the deami-nation product of ara-A, hypoxanthine arabinoside. Did this superiority warrant a full-scale development of araDAP? The answer was soon to come.

When Hitchings and Elion’s research laboratory moved to North Carolina in 1970, Howard Schaeffer, a specialist in analogs of adenosine, joined them as head of the organic chemistry department. Schaeffer had studied the effect of various changes on acyclic side-chains at the 9-position of adenine, and found that 9-(2-hydroxyethoxymethyl)-adenine was a constant substrate of adenosine deaminase. It followed logically that other enzymes too might likewise be able to mimic such side-chains and that nucleoside analogs of this kind might have antimetabolic properties. Research was therefore focused on acyclic nucleoside analogs. Schaeffer’s syntheses were followed by antiviral testing by Bauer and Peter Collins, while Elion’s group explored the mechanisms of action and conducted in vivo enzymological and metabolic studies. This was the context in which the potency of acycloguanosine (acyclovir) came to light.

Acyclovir . Elion’s most celebrated article was published in Proceedings of the National Academy of Sciences (PNAS) in December 1977, barely two months after she submitted it. The advent of acycloguanosine amounted to a therapeutic revolution. Acyclovir proved effective with respect to herpes simplex, just as, in the case of the purines, the analog of 2,6-diaminopurine had done. The big surprise was that acycloguanosine was more than one hundred times as active as the “diamino” compound. Four days after the Elion team’s pioneering article was sent to PNAS, they submitted to Nature a contribution that was largely concerned with clinical issues and already included, as well as recommendations on inhibitory dosages, some discussion of experimental pathology (experimental herpetic encephalitis and herpetic keratitis) and of pharmacokinetics. This was the start of the pharmacological career of acyclovir, an analog of guanine whose performance far surpassed that of 2,6-diaminopurine.

Acyclovir’s spectrum of action was found to cover herpes simplex virus types 1 and 2 and varicella zoster virus. It also had interesting properties in connection with Epstein-Barr virus (EBv). Unfortunately, it turned out to be less active with cytomegalovirus (CMV). Its great virtue was its very low toxicity. Acyclovir was manifestly more effective than all previously proposed antiviral agents. The utility of this new inhibitor resided not only in its potency but also in its very high selectivity, for it was not cytotoxic to mammalian cells in which herpes viruses grow.

The reasons for this selectivity were explored by the virologist Philip Furman. Although acyclic substitution at the 9-position did not, properly speaking, confer the structure of a nucleoside on it, acyclovir nevertheless behaved like an arabinoside-type derivative. Its chief chemical property lay in its ability to be triphosphorylated, an indispensable trait for any antimetabolite.

Ordinary derivatives can be phosphorylated by cellular kinases; in contrast, a viral kinase was solely responsible for the activity of acyclovir. Vero cell cultures, uninfected or infected in advance with strains of herpes simplex virus type 1 were incubated with radioactive acyclovir labeled with carbon 14 (¹⁴ C) at the 8-position of the guanine and with tritium (³ H) in the side-chain. Extracts of the cells were examined, after separation, by chromatography. The uninfected cells were found to contain only nonphosphorylated acyclovir. By contrast, three new radioactive compounds appeared on the chromatograms of the HSV-infected cells: these were identified as the monophosphate (ACV-MP), diphosphate (ACV-DP), and triphosphate (ACV-TP) of acyclovir.

Once the first phosphate had been added, the second was formed by a cellular guanylate kinase, while the third could be formed by several other thymidine kinases. Since the cellular thymidine kinase could not use acyclovir as a substrate, very little ACV-TP formed in noninfected cells. Once formed, the ACV-TP became a potent inhibitor of the viral DNA polymerase, which was also inactivated by the formation of an enzyme-template-acyclovirmonophosphate complex (an inactivation that did not occur with cellular DNA polymerase).

Pharmacokinetic and metabolic studies of acyclovir in several animal species and in humans revealed that it had a remarkable metabolic stability. Because its plasma half-life was about three hours, intravenous infusion of acyclovir (Zovirax®) was generally ordered on an eight-hourly basis. It was also possible to administer it via the genital, ophthalmic, or labial mucous membranes, or by mouth. Since the mid-1990s, the drug has been widely used to treat varied conditions in which herpes virus is implicated: first episodes of genital herpes infection, herpes zoster, prevention of herpes infection in immunode-pressed patients, herpetic encephalitis, and so on.

The discovery of acyclovir was a major therapeutic breakthrough per se, but the lessons learned from its history have also turned out to be extremely fruitful for subsequent research on antivirals, most notably in connection with AIDS. In-depth study of its mechanism of action has led to a better grasp of the enzymatic differences between healthy and virus-infected cells and helped assess the impact of the specific properties of enzymes on their therapeutic applications.

The introduction of acyclovir was undoubtedly the high point of Elion’s career. It is a remarkable fact that, more than fifty years after she began her work, the discoveries of this extraordinary pharmacologist were still indispensable and unsurpassed therapeutic tools.

BIBLIOGRAPHY

WORKS BY ELION

With George H. Hitchings, Gertrude B. Elion, Elvira A. Falco, et al. “Antagonists of nucleic acid derivatives. I. The lactobacillus casei model.” Journal of Biological Chemistry 183 (March 1950): 1–9.

With Sandra Callahan, R. Wayne Rundles, and George H. Hitchings. “Relationship between Metabolic Fates and Antitumor Activities of Thiopurines.” Cancer Research 23 (1963): 1207–1217.

With R. Wayne Rundles, James B. Wyngaarden, George H. Hitchings, et al. “Effects of a Xanthine Oxidase Inhibitor on Thiopurine Metabolism, Hyperuricemia, and Gout.” Transactions of the Association of American Physicians 76 (1963): 126–140.

“Enzymatic and Metabolic Studies with Allopurinol.” Annals of the Rheumatic Diseases 25 (1966): 608–614.

With S. Singer and George H. Hitchings. “Resistance to Inhibitors of Dihydrofolate Reductase in Strains of Lactobacillus casei and Proteus vulgaris.” Journal of General Microbiology 42, no. 2 (1966): 185–196.

With Vincent Massey, Hirochika Komai, and Graham Palmer. “On the Mechanism of Inactivation of Xanthine Oxidase by Allopurinol and Other Pyrazolo [3,4-d]-pyrimidines.” Journal of Biological Chemistry 245 (1970): 2837–2844.

With Paulo de Miranda, Lowrie M. Beacham III, and Teresa H. Creagh. “The Metabolic Fate of the Methylnitroimidazole Moiety of Azathioprine in the Rat.” Journal of Pharmacology and Experimental Therapeutics 187, no. 3 (1973): 588–601.

With Janet L. Rideout, Paulo de Miranda, Peter Collins, et al. “Biological Activities of Some Purine Arabinosides.” Annals of the New York Academy of Science 255 (1975): 468–480.

With Phillip A. Furman, James A. Fyfe, Paulo de Miranda, et al. “Selectivity of Action of an Antiherpetic Agent, 9-(2-hydroxyethoxymethyl)guanine.” Proceedings of the National Academy of Sciences of the United States of America 74, no. 12 (1977): 5716–5720.

With Howard J. Schaeffer, Lilia Beauchamp, Paulo de Miranda, et al. “9-(2-hydroxyethoxymethyl)guanine Activity against Viruses of the Herpes Group.” Nature 272 (1978): 583–585.

With Karen K. Biron. “In Vitro Susceptibility of Varicella-Zoster Virus to Acyclovir.” Antimicrobial Agents and Chemotherapy18 (1980): 443–447.

With Brenda M. Colby, James E. Shaw, and Joseph S. Pagano. “Effect of Acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein-Barr Virus DNA Replication.” Journal of Virology 34 (1980): 560–568.

With Marty H. St Clair, Phillip A. Furman, and Carol M. Lubbers. “Inhibition of Cellular Alpha and Virally Induced Deoxyribonucleic Acid Polymerases by the Triphosphate of Acyclovir.” Antimicrobial Agents and Chemotherapy 18 (1980): 741–745.

With Phillip A. Furman, Paulo de Miranda, and Marty H. St Clair. “Metabolism of Acyclovir in Virus-Infected and Uninfected Cells.” Antimicrobial Agents and Chemotherapy 20 (1981): 518–524.

With Paul M. Keller, James A. Fyfe, Lilia Beauchamp, et al. “Enzymatic Phosphorylation of Acyclic Nucleoside Analogs and Correlations with Antiherpetic Activities.” Biochemical Pharmacology 30 (1981): 3071–3077.

With Goerge H. Hitchings. “Layer on Layer: The Bruce F. Cain Memorial Award Lecture.” Cancer Research 45 (1985): 2415–2420.

“Nobel Lecture: The Purine Path to Chemotherapy.” In The Nobel Prizes 1988, edited by Tore Frängsmyr. Stockholm: Nobel Foundation, 1989.

With F. Chast, C. Chastel, N. Postel-Vinay, et al. Virus Herpès et pensée médicale, de l’empirisme au Prix Nobel [Herpes Virus and Medical Thought: From Empiricism to the Nobel Prize]. Paris: Imothep-Maloine, 1997.

OTHER SOURCES

Chast, François. Histoire contemporaine des médicaments [Contemporary History of Drugs]. Paris: La Découverte, 2002.

“Gertrude Belle Elion: A Lifeline.” Chemical Heritage Foundation. Available from http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/lifeline.htm

François Chast

Elion, Gertrude Belle (1918-1999)

American biochemist

Gertrude Belle Elion's innovative approach to drug discovery advanced the understanding of cellular metabolism and led to the development of medications for leukemia, gout, herpes , malaria , and the rejection of transplanted organs. Azidothymidine (AZT), the first drug approved for the treatment of AIDS , came out of her laboratory shortly after her retirement in 1983. One of the few women who held a top post at a major pharmaceutical company, Elion worked at Wellcome Research Laboratories for nearly five decades. Her work, with colleague George H. Hitchings, was recognized with the Nobel Prize for physiology or medicine in 1988. Her Nobel Prize was notable for several reasons: few winners have been women, few have lacked the Ph.D., and few have been industrial researchers.

Elion was born on January 23, 1918, in New York City, the first of two children, to Robert Elion and Bertha Cohen. Her father, a dentist, immigrated to the United States from Lithuania as a small boy. Her mother came to the United States from Russia at the age of fourteen. Elion, an excellent student who was accelerated two years by her teachers, graduated from high school at the height of the Great Depression. As a senior in high school, she had witnessed the painful death of her grandfather from stomach cancer and vowed to become a cancer researcher. She was able to attend college only because several New York City schools, including Hunter College, offered free tuition to students with good grades. In college, she majored in chemistry.

In 1937, Elion graduated Phi Beta Kappa from Hunter College with a B.A. at the age of nineteen. Despite her outstanding academic record, Elion's early efforts to find a job as a chemist failed. One laboratory after another told her that they had never employed a woman chemist. Her self-confidence shaken, Elion began secretarial school. That lasted only six weeks, until she landed a one-semester stint teaching biochemistry to nurses, and then took a position in a friend's laboratory. With the money she earned from these jobs, Elion began graduate school. To pay for her tuition, she continued to live with her parents and to work as a substitute science teacher in the New York public schools system. In 1941, she graduated summa cum laude from New York University with a M.S. degree in chemistry.

Upon her graduation, Elion again faced difficulties finding work appropriate to her experience and abilities. The only job available to her was as a quality control chemist in a food laboratory, checking the color of mayonnaise and the acidity of pickles for the Quaker Maid Company. After a year and a half, she was finally offered a job as a research chemist at Johnson & Johnson. Unfortunately, her division closed six months after she arrived. The company offered Elion a new job testing the tensile strength of sutures, but she declined.

As it did for many women of her generation, the start of World War II ushered in a new era of opportunity for Elion. As men left their jobs to fight the war, women were encouraged to join the workforce. "It was only when men weren't available that women were invited into the lab," Elion told the Washington Post.

For Elion, the war created an opening in the research lab of biochemist George Herbert Hitchings at Wellcome Research Laboratories in Tuckahoe, New York, a subsidiary of Burroughs Wellcome Company, a British firm. When they met, Elion was 26 years old and Hitchings was 39. Their working relationship began on June 14, 1944, and lasted for the rest of their careers. Each time Hitchings was promoted, Elion filled the spot he had just vacated, until she became head of the Department of Experimental Therapy in 1967, where she was to remain until her retirement 16 years later. Hitchings became vice president for research. During that period, they wrote many scientific papers together.

Settled in her job and encouraged by the breakthroughs occurring in the field of biochemistry, Elion took steps to earn a Ph.D., the degree that all serious scientists are expected to attain as evidence that they are capable of doing independent research. Only one school offered night classes in chemistry, the Brooklyn Polytechnic Institute (now Polytechnic University), and that is where Elion enrolled. Attending classes meant taking the train from Tuckahoe into Grand Central Station and transferring to the subway to Brooklyn. Although the hour-and-a-half commute each way was exhausting, Elion persevered for two years, until the school accused her of not being a serious student and pressed her to attend full-time. Forced to choose between school and her job, Elion had no choice but to continue working. Her relinquishment of the Ph.D. haunted her, until her lab developed its first successful drug, 6-mercaptopurine (6MP).

In the 1940s, Elion and Hitchings employed a novel approach in fighting the agents of disease. By studying the biochemistry of cancer cells, and of harmful bacteria and viruses , they hoped to understand the differences between the metabolism of those cells and normal cells. In particular, they wondered whether there were differences in how the diseasecausing cells used nucleic acids, the chemicals involved in the replication of DNA , to stay alive and to grow. Any dissimilarity discovered might serve as a target point for a drug that could destroy the abnormal cells without harming healthy, normal cells. By disrupting one crucial link in a cell's biochemistry, the cell itself would be damaged. In this manner, cancers and harmful bacteria might be eradicated.

Elion's work focused on purines, one of two main categories of nucleic acids. Their strategy, for which Elion and Hitchings would be honored by the Nobel Prize forty years later, steered a radical middle course between chemists who randomly screened compounds to find effective drugs and scientists who engaged in basic cellular research without a thought of drug therapy. The difficulties of such an approach were immense. Very little was known about nucleic acid biosynthesis. Discovery of the double helical structure of DNA still lay ahead, and many of the instruments and methods that make molecular biology possible had not yet been invented. But Elion and her colleagues persisted with the tools at hand and their own ingenuity. By observing the microbiological results of various experiments, they could make knowledgeable deductions about the biochemistry involved. To the same ends, they worked with various species of lab animals and examined varying responses. Still, the lack of advanced instrumentation and computerization made for slow and tedious work. Elion told Scientific American, "if we were starting now, we would probably do what we did in ten years."

By 1951, as a senior research chemist, Elion discovered the first effective compound against childhood leukemia. The compound, 6-mercaptopurine (6MP; trade name Purinethol), interfered with the synthesis of leukemia cells. In clinical trials run by the Sloan-Kettering Institute (now the Memorial Sloan-Kettering Cancer Center), it increased life expectancy from a few months to a year. The compound was approved by the Food and Drug Administration (FDA) in 1953. Eventually 6MP, used in combination with other drugs and radiation treatment, made leukemia one of the most curable of cancers.

In the following two decades, the potency of 6MP prompted Elion and other scientists to look for more uses for the drug. Robert Schwartz, at Tufts Medical School in Boston, and Roy Calne, at Harvard Medical School, successfully used 6MP to suppress the immune systems in dogs with transplanted kidneys. Motivated by Schwartz and Calne's work, Elion and Hitchings began searching for other immunosuppressants. They carefully studied the drug's course of action in the body, an endeavor known as pharmacokinetics. This additional work with 6MP led to the discovery of the derivative azathioprine (Imuran), which prevents rejection of transplanted human organs and treats rheumatoid arthritis. Other experiments in Elion's lab intended to improve 6MP's effectiveness led to the discovery of allopurinol (Zyloprim) for gout, a disease in which excess uric acid builds up in the joints. Allopurinol was approved by the FDA in 1966. In the 1950s, Elion and Hitchings's lab also discovered pyrimethamine (Daraprim and Fansidar) a treatment for malaria, and trimethoprim, for urinary and respiratory tract infections. Trimethoprim is also used to treat Pneumocystis carinii pneumonia , the leading killer of people with AIDS.

In 1968, Elion heard that a compound called adenine arabinoside appeared to have an effect against DNA viruses. This compound was similar in structure to a chemical in her lab, 2,6-diaminopurine. Although her own lab was not equipped to screen antiviral compounds, she immediately began synthesizing new compounds to send to a Wellcome Research lab in Britain for testing. In 1969, she received notice by telegram that one of the compounds was effective against herpes simplex viruses. Further derivatives of that compound yielded acyclovir (Zovirax), an effective drug against herpes, shingles, and chickenpox. An exhibit of the success of acyclovir, presented in 1978 at the Interscience Conference on Microbial Agents and Chemotherapy , demonstrated to other scientists that it was possible to find drugs that exploited the differences between viral and cellular enzymes . Acyclovir (Zovirax), approved by the FDA in 1982, became one of Burroughs Wellcome's most profitable drugs. In 1984, at Wellcome Research Laboratories, researchers trained by Elion and Hitchings developed azidothymidine (AZT), the first drug used to treat AIDS.

Although Elion retired in 1983, she continued at Wellcome Research Laboratories as scientist emeritus and kept an office there as a consultant. She also accepted a position as a research professor of medicine and pharmacology at Duke University. Following her retirement, Elion has served as president of the American Association for Cancer Research and as a member of the National Cancer Advisory Board, among other positions.

In 1988, Elion and Hitchings shared the Nobel Prize for physiology or medicine with Sir James Black, a British biochemist. Although Elion had been honored for her work before, beginning with the prestigious Garvan Medal of the American Chemical Society in 1968, a host of tributes followed the Nobel Prize. She received a number of honorary doctorates and was elected to the National Inventors' Hall of Fame, the National Academy of Sciences, and the National Women's Hall of Fame. Elion maintained that it was important to keep such awards in perspective. "The Nobel Prize is fine, but the drugs I've developed are rewards in themselves," she told the New York Times Magazine.

Elion never married. Engaged once, Elion dismissed the idea of marriage after her fiancé became ill and died. She was close to her brother's children and grandchildren, however, and on the trip to Stockholm to receive the Nobel Prize, she brought with her 11 family members. Elion once said that she never found it necessary to have women role models. "I never considered that I was a woman and then a scientist," Elion told the Washington Post. "My role models didn't have to be women—they could be scientists." Her other interests were photography, travel, and music, especially opera. Elion, whose name appears on 45 patents, died on February 21, 1999.

See also AIDS, recent advances in research and treatment; Antiviral drugs; Autoimmunity and autoimmune diseases; Immunosuppressant drugs; Transplantation genetics and immunology

Elion, Gertrude Belle

AMERICAN CHEMIST AND MEDICAL RESEARCHER
1918–1999

The Nobel Prize Committee rarely honors the work of scientists who develop new drugs. However in 1988, in awarding the Nobel Prize in physiology or medicine to Gertrude Elion and her colleague at the Burroughs

Wellcome Pharmaceutical Laboratories, George Hitchings, it recognized the work of this pair that led to the development of a series of important drugs, among these drugs used to treat malaria, the leukemias, viral infections, and some forms of impaired immune response.

Born on January 23, 1918, in New York City, Gertrude Elion graduated from Hunter College, in New York, in 1937 with an A.B. degree in chemistry. Unsuccessful in her efforts to enroll in graduate school, she worked for several years in pharmaceutical companies and as a teacher in New York City high schools while continuing her education part time. She earned an M.S. degree from New York University in 1941.

In 1944 Elion joined the Wellcome Research Laboratories, a subdivision of Burroughs Wellcome, as a senior research chemist; by 1967 she was head of their experimental therapy section. Probably the only woman to hold a top-ranking position in a major pharmaceutical company, in 1967 and for many years after, she is said to have felt that she experienced no discrimination at Burroughs Wellcome.

Her early work focused on the metabolism of nucleic acids. In 1944 little was known about these compounds beyond the fact that deoxyribonucleic acid (DNA ) is the main component of the cell nucleus, and that DNA is composed of repeating units, called nucleotides, whose structures incorporate heterocyclic bases (that is, organic compounds with rings containing nitrogen atoms; the four bases involved are adenine , cytosine , guanine , and thymine ). Elion's hope was that an understanding of the synthesis of nucleic acids in normal cells (and eventual comparisons with nucleic acid synthesis in malignant cells and in disease-causing microorganisms) would suggest ways to block selectively the metabolism of cancer cells or of pathogens without harming normal cells. She therefore proceeded to synthesize a number of compounds that resembled and that might mimic the substance used in DNA synthesis and in this way might block the formation of DNA in harmful cells.

Working with 2,6-diaminopurine (2,6-DAP), a derivative of adenine, Elion found that it inhibited nucleic acid synthesis in cancer cells and was effective in treating mouse leukemia. During the early 1950s, following the elucidation of the structure of DNA, interest in nucleic acid metabolism became intensified, and scientists investigating it, including Elion and her group, found themselves at the forefront of biochemical research. Elion synthesized 6-mercaptopurine (6-MP), another derivative of adenine, which also inhibited DNA synthesis. It was approved by the U.S. Food and Drug Administration in 1953 for the treatment of acute childhood leukemia. Its success led her to probe its exact mode of action using newly developed radiochemical techniques, a breakthrough in drug-related research that advanced considerably the rational design of therapeutic agents. Elion studied 6-MP as a possible inhibitor of antibody-forming cells. As a result, its derivative Imuran (azathioprine) has been used as an antirejection drug in kidney transplants.

Other notable research by Elion led to the development of the antiviral drug Acyclovir (acycloguanosine), which has been used to treat the herpes simplex viruses. Her studies during the 1970s showed that Acyclovir inhibited viral replication by interfering with viral DNA synthesis. The subsequent development of AZT (azidothymidine), which works in much the same way as Acyclovir against the human immunodeficiency virus (HIV), was carried out at Burroughs Wellcome after Elion retired in 1983 (although she worked after 1983 as a consultant).

In addition to the 1988 Nobel Prize (which she shared with Hitchings and British scientist Sir James Black), Elion received other awards and several honorary doctorates. Active in public service, she served on both national and international health committees. She died on February 20, 1999, in Chapel Hill, North Carolina.

see also Deoxyribonucleic Acid (DNA); DNA Replication; Nucleic Acids; Nucleotide.

Mary R. S. Creese

Bibliography

Alcamo, I. Edward (1997). "Gertrude Belle Elion (1918– )." In Women in the Biological Sciences: A Biobibliographic Sourcebook, ed. Louise S. Grinstein, Carol A. Biermann, and Rose K. Rose. Westport, CT: Greenwood Press.

Altman, Lawrence K. (1999). "Gertrude Elion, Drug Developer, Dies at 81." New York Times 148 (51,442; February 23):A21.

Goodman, Miles (1993). "Gertrude Belle Elion (1918– )." In Women in Chemistry and Physics: A Biobibliographic Sourcebook, ed. Louise Grinstein, Rose K. Rose, and Miriam H. Rafailovich. Westport, CT: Greenwood Press.

Gertrude Bell

Gertrude Bell (1868-1926) was the best known traveler in the Middle East and Arabia in the years before World War I. The British intelligence bureau in Cairo hired her as an advisor on Arabia. After the war, she was very involved in the political negotiations that divided the Arab world into new countries and established British political influence in the region.

Gertrude Bell was born into a wealthy family in the English county of Durham on July 14, 1868. Her father owned an iron works. Her mother died in childbirth two year after Bell's birth, and a stepmother raised the young child. At sixteen she attended Queens College and then went to Lady Margaret Hall, a womens college at Oxford University. She graduated with high honors in history.

First Trip to the Middle East

Bell traveled to the Middle East for the first time in 1892 to visit her uncle, who was the British ambassador to Tehran in Persia (now Iran). There she met a young diplomat and wrote to her parents asking for permission to marry him. They ordered her home instead (the young man died nine months later). She wrote a book about her experiences called Persian Pictures, A Book of Travels that was published in 1894.

In 1899 Bell studied Arabic in Jerusalem. During the spring of 1900 she went to visit the Druse in the mountains of southern Lebanon. Bell also visited Palmyra, the ruins of a Roman city in Jordan. She described it as "a white skeleton of a town, standing knee-deep in the blown sand." She then went mountain climbing in the Alps and took two trips around the world with her brother.

In January 1905 Bell made her first extended trip to the Middle East. She traveled through Syria to Cilicia and Konya in Asia Minor (Turkey). Bell was alone except for Arab servants and stayed in tents as well as in the houses of the wealthy, where her family could provide her with introductions. At the city of Alexandretta in southern Turkey she hired a servant, Fattuh, who was to stay with her for the rest of her life. She visited many ruins along the way and became interested in archeology. Bell wrote about her experiences in Syria: The Desert and the Sown, published in 1907.

Excavated Christian Churches

In 1907 Bell returned to Asia Minor with the British archeologist Sir William Ramsay to help excavate early Christian churches. The two of them collaborated on a picture book of their discoveries. In 1909 she left from Aleppo in Syria and traveled through the valley of the Euphrates River to Baghdad, visiting Babylonian sites along the way. She also went to the Shi'ite holy city of Karbala. Along the way Bell was robbed of her money and, most importantly, her notebooks. The whole countryside turned out to try to find the thieves, but the objects reappeared on a rock above her camp. When the Turkish soldiers of the Ottoman government arrived, they found a nearby village deserted, the inhabitants having fled for fear of retribution. Bell blamed herself for having been careless and causing all the difficulty.

Bell returned in 1911 to revisit the great castle at Kheidir and crossed the desert between Damascus and Baghdad. She then returned to England where she joined a movement that opposed women's suffrage. She also had an unhappy love affair with a married man.

Bell decided to return to Arabia to forget her unhappiness. This time she traveled to the city of Ha'il in the center of Arabia that had rarely been visited by Westerners. There, in 1913, Bell was held captive and robbed. When she was finally released, Arab hostility forced her to cut her journey short rather than continue to Riyadh as she had originally intended. Bell returned to Damascus in May 1914, having gained an unprecedented knowledge about the deserts of northern Arabia and the ruined cities that are found there.

Advisor to British Intelligence

This knowledge was to be of great value. When war broke out in Europe in August 1914, Turkey, which then controlled all of the Middle East, joined Germany in the fight against Great Britain. The British intelligence bureau in Cairo hired Bell as an advisor on Arabia. She became friends with T.E. Lawrence (the famous "Lawrence of Arabia") and helped formulate the British strategy of encouraging the Arabs to revolt against the Turks.

In 1916 Bell was sent to Basra in Iraq as an assistant political officer. She was transferred to Baghdad the following year, where she made her home for the rest of her life. Bell was very involved in the political negotiations that divided the Arab world into new countries and established British political influence in the Middle East. She also started and directed the Iraq Museum. Bell died of an overdose of drugs on the night of July 11-12, 1926 at her home in Baghdad.

Books

Burgoyne, Elizabeth. Gertrude Bell, from Her Personal Papers, 2 vols. E. Benn, 1958 and 1961.

Goodman, Susan. Gertrude Bell, Berg, 1985.

Kann, Josephine. Daughter of the Desert: The Story of Gertrude Bell, Bodley Head, 1956.

Tibble, Anne. Gertrude Bell, A. and C. Black, 1958.

Winstone, H.V.F. Gertrude Bell, Jonathan Cape, 1978. □