Elion, Gertrude B. (1918–1999)

American biochemist, pharmacologist, and Nobel laureate who developed drugs for treatment of leukemia and rejection of transplanted organs and laid the groundwork for the development of AZT in the fight against AIDS. Pronunciation: ELL-EE-un. Born Gertrude Belle Elion in New York, New York, on January 23, 1918; died at her home in Chapel Hill, North Carolina, on February 21, 1999; daughter of Bertha (Cohen) Elion and Robert Elion (a dentist); granted A.B., Hunter College, 1937; M.S.C., New York University, 1941; D.Sc., George Washington University, 1969; D.M.S., Brown University, 1969; never married; no children.

Awards:

Garvan Medal, American Chemical Society (1968); honorary D.Sc., University of Michigan (1969); honorary D.Sc., Columbia University (1969); Judd Award, Sloan-Kettering Institute (1983); Distinguished Chemist Award (1985); Bruce F. Cain Award, American Association of Cancer Research (1985); Berther Memorial Award, M.D. Anderson (1987); Nobel Prize in Physiology and Medicine with George Hitchings and Sir James Whyte Black (1988); honorary Doctor of Medical Science, Brown University (1989); honorary D.Sc., Ohio State University (1989); honorary D.Sc., State University of North Carolina (1989); Medal of Honor, American Cancer Society (1990); honorary D.Sc., Duke University (1990); honorary D.Sc., University of North Carolina (1990); National Science Medal (1991); honorary D.Sc., McMaster University (1990); National Inventors Hall of Fame (1991); National Women's Hall of Fame (1991); Engineering and Science Hall of Fame (1992); honorary D.Sc., Utah State University (1994).

Death of grandfather (1933); enrolled Hunter College (1934); became nursing assistant, New York Hospital (1937); hired as assistant organic chemist, Denver Chemical Company (1938); became analyst in food chemistry, Quaker Maid Company (1942); worked as researcher in organic chemistry, Johnson and Johnson (1943); worked as assistant research chemist, Burroughs Wellcome (1944); U.S. Food and Drug Administration approved 6-mercaptopurine (1953); synthesized azathioprine (1957); became assistant to the director of the chemotherapy division, Burroughs Wellcome (1963); headed experimental therapy, Burroughs Wellcome (1967); served as adjunct professor of pharmacology, University of North Carolina (1973); served as adjunct professor of pharmacology, Duke University (1973); synthesized acyclovir (1975); retired from Burroughs Wellcome as emeritus scientist (1983); was president of the Association for Cancer Research (1983).

Selected publications:

(with G.H. Hitchings) "Antagonists of Nucleic Acid Derivatives; Lactobacillus casei model," in Journal of Biological Chemistry(Vol. 183, 1950); (with Hitchings and Elvira A. Falco) "Antagonists of Nucleic Acid Derivatives: Reversal Studies with Substances Structurally Related to Thymide," in Journal of Biological Chemistry (Vol. 185, 1950); (with M.E. Balis, G.B. Brown, H.C. Nathan, and Hitchings) "The Effects of 6-mercaptop-urine on Lactobacillus casei," in Archives of Biochemistry and Biophysics (Vol. 71, 1957); (with S. Callahan, G. Bieber, Hitchings, and R.W. Rudles) "Experimental, Clinical, and Metabolic Studies of Thiopurines," in Cancer Chemotherapy Reports (Vol. 16, 1962); (with Hitchings) "Chemical Suppression of the Immune Response," in Pharmacological Review (Vol. 15, 1963).

In 1988, Gertrude Elion was awarded the Nobel Prize for Physiology and Medicine. Talent, ingenuity, and down-right stubbornness, account for her success.

Gertrude Elion was born in New York City on January 23, 1918, the daughter of Robert and Bertha Cohen Elion . Both parents were very supportive and "very anxious for me to have a career," writes Elion. The death of her grandfather from cancer in 1933 greatly influenced her decision to enter the field of chemistry. Her goal was to relieve the suffering of patients with terminal illness.

In 1937, 19-year-old Elion graduated with a bachelor's degree from Hunter College. Her choice of Hunter was fortuitous. Notes Sue Rosser :

With Elion's strong determination to become a scientist, she would probably have successfully pursued her major at any college, including a coeducational institution; statistics have shown, however, that women's colleges produce proportionately more women scientists than coeducational institutions and that a higher percentage of successful women scientists attended women's colleges.

After graduating, Elion was a nursing assistant at the New York Hospital. In 1938, she joined the Denver Chemical Company as an assistant organic chemist before returning to New York University to take her master's degree in 1940. Elion was rejected by a total of 15 graduate schools when she applied for a laboratory assistantship. As The New York Times noted in 1988, she had to "struggle against preconceived notions of what careers were suitable for women." Unable to secure a laboratory assignment, in 1941 Elion took a position teaching chemistry in the New York public-school system, while attending New York University as a part-time student. Following her graduation with a master's degree, she applied for several laboratory positions. Dr. Charles Frey, who interviewed her, recalled a bright young woman "who wanted to be a great research scientist." He also recalled the disappointment of Elion when all he could offer was a job washing test tubes.

The field of laboratory research had traditionally been a male preserve. With America's entry into World War II, however, a shortage of male researchers resulted. Elion found that positions were suddenly open to women. "It really was the war that gave women opportunities to get in the lab," she said. In 1942, Elion briefly held a position as an analyst in food chemistry with the Quaker Maid Company. The following year, she was hired by Johnson and Johnson as a researcher in organic chemistry. In 1944, she moved to the Burroughs Wellcome Company as a research assistant, where she worked for George Hitchings, doing research into nucleic acids. Far from treating her as an assistant, however, Hitchings considered her a colleague.

Nevertheless, her chosen career was not an easy one. "At the beginning it was a question of whether I'd get married or stay at the company," she commented. "In those days, women couldn't do both." As other professional women discovered, a stigma was attached to marriage. Employers felt that women should be in the home, taking care of their children. Thus, Elion was convinced that she could not marry and pursue a career at the same time. After a period of reflection, she decided to forsake marriage.

Elion felt that her lack of a doctorate might be an impediment to her career. Though she attempted to obtain her Ph.D. by attending night classes at Brooklyn Polytechnic, she withdrew from the program when told she must attend on a full-time basis—a proposition that would seem ludicrous years later. Thus, she achieved justifiable renown without the benefit of a doctorate.

The development of drugs prior to the Second World War had followed the well-worn path established by Paul Ehrlich, the German father of chemotherapy. Chemotherapy is the science of insinuating a poison into the body that attacks the infecting organism, without seriously harming the patient. Ehrlich advocated the un-systematic injection of a multiplicity of drugs into research animals, in order to discover the cure for specific illnesses. Others thought the animal trials were worthless. As Hitchings noted:

The world of chemotherapy was divided sharply between the screeners and the funda-mentalists. The screeners were dutifully poisoning infected mice with whatever came in hand or off the shelf. They hoped that if they tested enough compounds, sooner or later they would run across one that did more damage to the infecting organism than to the host. The fundamentalists disdained all this as being devoid of intellectual interest.

In their research, Elion and Hitchings wanted to develop "a middle course that would generate basic information which chemotherapy could then exploit," says Hitchings. The latitude that the research team was given by Burroughs Wellcome, he noted, was invaluable in their quest. "Our orientation was basic research and yet we turned out more drugs than people who were looking for them."

During the 1940s, knowledge of nucleic acids and purines was rudimentary at best, and the double-helical configuration of DNA had yet to be discovered by Rosalind Franklin . Elion and Hitchings focused their efforts on the cellular synthesis of nucleotides. Bacteria cells, they discovered, do not produce nucleic acid or DNA. Therefore, bacteria cells are incapable of division, except in the presence of certain purines or proteins, and folic acid. Elion and Hitchings postulated that it might be possible to develop a drug that inhibits the rapid division of cells, such as tumors, protozoa, and bacteria. By 1951, the pair had tested over 100 purines. As a result, Elion developed antimetabolite drugs designed to block the enzymes essential for the creation of cellular DNA.

In the early 1950s, Elion's antimetabolites were tested on patients with leukemia at the Sloan-Kettering Institute. It was hoped that the new drug would prevent the growth of white blood cells sufficiently to cause remission. The clinical challenge that the new drug faced was that it might also prevent the growth of red blood cells and prove toxic to the patient. During initial trials, the drug did indeed prove to be toxic. After refinements, however, it performed effectively and safely. Noted Elion, "With 6-mercaptopurine we knew we had to be on the right track." The development of 6-mercaptopurine was one of Elion's first research successes; the drug remains one of a dozen or so used in the treatment of leukemia. In 1953, the U.S. Food and Drug Administration formally approved its use.

In 1957, Elion synthesized azathioprine, a modification of 6-mercaptopurine. The drug proved ineffective in the fight against leukemia, but colleagues at Tufts University discovered that it acted to suppress antibodies produced by the immune system. Azathioprine proved invaluable in preventing the rejection of transplanted organs. As Paul Calabresi of Brown University noted, azathioprine "was the first immunosuppressive agent that allowed kidney and other transplants." The drug has also been used in the treatment of rheumatoid arthritis, a condition where the body believes itself to be under attack by its own tissue.

As well, Elion developed allopurinol, another modification of 6-mercaptopurine, to suppress enzymes. Her metabolic studies resulted in a new approach in the treatment of gout. The enzyme xanthine oxidase which is necessary for the body to synthesize uric acid was inhibited, and the formation of uric acid retained in the last stages of the metabolic pathway. Allopurinol is extensively used in the treatment of gout, an illness caused by an excessive build-up of uric acid in the joints. It is also employed in chemotherapy, where uric acid build-up is common in the treatment of cancer.

Elion and Hitchings' research into antitu-moral activity during the 1950s also laid the ground work for the development of Azidothymidine or AZT. The drug proved successful in the treatment of leukemia patients. Subsequently, it was also found to be the only effective drug in the fight against AIDS. Now, AZT is also used in the treatment of systemic lupus, chronic hepatitis, and autoimmune hemolytic anemia.

In the early 1960s, Elion began to focus her research efforts on nucleic acid synthesis in lower primates and contrasted her findings with similar tests done on humans. The research pointed to new ways of controlling infectious disease, by attacking viral DNA and bacteria. The drug pyrimethamine was developed, which is used to control the protozoa that causes malaria. As well, she developed trimethoprim, used to treat AIDS patients who develop pneumocystis carinii, a form of pneumonia which can prove fatal to those with immune-deficiency syndrome.

In 1963, Elion was appointed assistant to the director of the chemotherapy division of Burroughs Wellcome. During the next year, she and her colleagues began research into antiviral drugs. Elion was made head of experimental therapy in 1967. In 1970, Burroughs Wellcome moved their laboratories to North Carolina. Three years later, Elion was appointed adjunct professor of pharmacology at the University of North Carolina. She held the same position at Duke University.

In 1975, Elion and Hitchings synthesized the drug acyclovir, the first effective treatment for herpes. Eight years of clinical trials demonstrated its efficacy in reducing the suffering of patients with herpes encephalitis, shingles, and genital herpes. As well, the information gained from the development of acyclovir suggested new avenues of inquiry into AIDS research.

Elion retired as the head of experimental therapies at Burroughs Wellcome in 1983. She held the title of scientist emeritus and remained a consultant with the company. As well, she served as president of the Association for Cancer Research from 1983 to 1984. She also sat on the National Cancer Advisory Board until 1991.

Gertrude Elion was an acknowledged leader in the field of purine antimetabolites research for treating cancer. In 1988, she shared the Nobel Prize in Physiology and Medicine with George Hitchings, and Sir James Whyte Black. As Marcia Meldrum notes, the award recognized:

Their work in developing drugs for the treatment of many critical diseases. Elion and Hitchings, long-time collaborators at Burroughs Wellcome Research Laboratories, produced compounds that inhibit DNA synthesis and thus prevent the rapid growth of cancer cells. They then used their understanding of nucleic acid synthesis to develop immunosuppressives and antibiotics.

The Nobel committee acknowledged the multiple contributions made by Elion in the field of therapeutics. But the award was unusual in that it recognized the new drugs that she and Hitchings had created. "Only a few times in the 87-year history of the Nobel Prize has the medical award been granted to researchers who discovered drugs and worked for drug companies," noted The New York Times.

Gertrude Elion was only the ninth woman to be awarded the Nobel Prize in its history. Writes Meldrum: "Elion, unlike many other laureates, never expected to win the Nobel Prize. Her selection acknowledged the unheralded but important work of many women scientists whose careers, like her own, were artificially limited by their gender." In her Nobel lecture, entitled "The Purine Path to Chemotherapy," Elion outlined 40 years of research into purines and purine analogues, which led to her discovery of several drugs used in the chemotherapy treatment of various diseases.

The research done by Elion is notable not only for the development of particular drugs, but also for the insight it provided researchers into cellular DNA, and methods discovered to suppress certain pathways that form nucleic acids. Her successful development of various drugs grew out of research that created a better understanding of physiology and cell biochemistry. Her focus on sound research techniques, and her work on basic biochemical and physiological processes have been of incomparable benefit to other medical researchers. As one Nobel official said, "We are still harvesting the fruits of what they determined almost forty years ago." Indeed, as Sue Rosser wrote: "In exploring chemotherapeutic agents, she and her colleagues helped to unlock the mysteries of the interior of the cell. More significantly, she achieved her goal of finding ways to help alleviate human suffering from disease."

In 1991, Elion was honored by the Inventors Hall of Fame for her contribution to pharmacology and medicine, the first woman to be so honored. Her name now stands alongside the likes of Alexander Graham Bell and Thomas Edison. "I'm happy to be the first woman," Elion commented with a smile, "but I doubt I'll be the last." Gertrude Elion held over 40 patents, a rarity for a woman. Most of the drugs she invented are included in the World Health Organization's list of essential drugs. As well, Elion was inducted into the National Women's Hall of Fame and the Engineering and Science Hall of Fame.

Gertrude Elion was known for the care and precision she devoted to medical research. Her collaboration with George Hitchings resulted in ground-breaking advances in the treatment of disease. Upon receiving the Nobel prize, Elion commented: "The Nobel Prize is fine, but the drugs I've developed are rewards in themselves."

sources:

Adcock, Edgar, ed. American Men and Women of Science. Vol. 2. NJ: R.R. Bowker, 1994.

"Drug Pioneers with Nobel Prize," in New Scientist. Vol. 20, no. 1635. London: IPC Magazines, 1988.

Marx, Jean L. "The 1988 Nobel Prize for Physiology in Medicine," in Science. Vol. 248, no. 4878. Washington, DC: American Association for the Advancement of Science, 1988.

Meldrum, Marcia. "Gertrude Belle Elion 1988," in Nobel Laureates in Medicine or Physiology: A Biographical Dictionary. Daniel M. Fox, Marcia Meldrum, and Ira Rezak, eds. NY: Garland Press, 1990.

Miller, Jane A. "Women in Chemistry," in Women of Science. G. Kass-Simon and Patricia Farnes, eds. Bloomington, IN: Indiana University Press, 1990.

O'Neill, Lois Decker. The Women's Book of World Records and Achievements. Garden City, NY: Anchor Press, 1979.

suggested reading:

Rosser, Sue V. "Gertrude Belle Elion 1988," in The Nobel Prize Winners: Physiology and Medicine. Vol. 3. Frank N. Magill, ed. Pasadena, CA: Salem Press, 1991.

Hugh A. Stewart , M.A., University of Guelph, Guelph, Ontario, Canada