Gertrude Elion
(1918-1999)

Gertrude Belle Elion was an American biochemist and pharmacologist, and a 1988 recipient of the Nobel Prize in Physiology or Medicine. Born in New York City to immigrant parents, she graduated from Hunter College in 1937 and New York University (M.Sc.) in 1941. Unable to obtain a graduate research position due to her gender, she worked as a lab assistant and a high school teacher, before becoming an assistant to George H. Hitchings at the Burroughs-Wellcome pharmaceutical company (now GlaxoSmithKline). She never obtained a formal Ph.D., but she was later awarded an honorary Ph.D from George Washington University.

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Gertrude Belle Elion was born in New York City on January 23, 1918. Her father emigrated from Lithuania when he was twelve years old and went on to become a dentist in the United States. Her homemaker mother arrived in the United States from Poland at the age of fourteen. When Trudy was seven, the family moved from a Manhattan apartment-cum-dental office to the Bronx, where she continued her public school education. By the time she was twelve, she had been promoted two years ahead of her class. After receiving her bachelor's degree in chemistry from Hunter College in 1937, Trudy realized that neither she nor her family had enough money for her to attend graduate school. She began to look for a job, and immediately ran into the proverbial brick wall. "Nobody . . . took me seriously. They wondered why in the world I wanted to be a chemist when no women were doing that. The world was not waiting for me."

Secretarial school followed, and then teaching at a hospital and a high school. She finally landed a position, albeit nonpaying, with a chemist, just to keep busy in her field; during this period she decided to pursue her master-of-science degree, which she received in 1941 from New York University. During her graduate studies, she started teaching high school chemistry and physics as a "permanent substitute" for $7.50 a day. Her big break came when the United States entered World War II. Since there were few men around, women came to be seen as potential employees, and Trudy was hired as an analytical chemist; her job included the measurement of the acidity of pickles and the color of mayonnaise. After a while she tired of those functions and a spell of testing the tensile strength of sutures and sought more meaningful work. The most interesting opening was at Burroughs Wellcome, where biochemist George Hitchings was trying to make antagonists to nucleic acid derivatives. Hitchings, who would later become a member of the National Academy of Sciences, "talked about purines and pyrimidines, which I must confess I'd never even heard of up to that point, and it was really to attack a whole variety of diseases by interfering with DNA synthesis. This sounded very exciting." She accepted the position of biochemist in 1944 and spent the next 39 years at Burroughs Wellcome, becoming head of the Department of Experimental Therapy in 1967.

In 1988 Elion received the Nobel Prize in Medicine, together with Hitchings and Sir James Black. Other awards include the National Medal of Science (1991) and the Lemelson-MIT Lifetime Achievement Award (1997). In 1991 she became the first woman to be inducted into the National Inventors Hall of Fame.

Gertrude Elion died in North Carolina in 1999, aged 81. She had moved to the Research Triangle in 1970, and for a time served as a research professor at Duke University. She was unmarried.


 
Let Trudy explain how she started out making compounds and ended up eventually with the first effective drug that induced remission in childhood leukemia:

"At the beginning . . . it was my job to find out how to make (compounds). So I'd go to the library, look up the old literature to see if I could figure out how to do it . . . I would just go ahead and make the compounds, and then the question was, well what do we do with these compounds? How do we find out if they really do anything? [Working with a microorganism like Lactobacillus casei] you could throw it in a defined medium and you could tell when you added something that was a real growth antagonist, then analyze why it was an antagonist. We knew that this organism would grow and from that it could make DNA and folic acid . . . You could make everything just from the amino acids, medium, and folic acid, and so on. We knew folic acid was essential, or if you could replace folic acid with a purine, it would grow . . . It would make lactic acid. If the organisms didn't grow, we knew we had something and we might be antagonizing folic acid or it might be antagonizing the purine. So you could with that one organism really make an analysis of three different kinds. You could add purine or folic acid and reverse the antagonism . . . [We] didn't know the structure of DNA, because nobody did at the time, but [we] knew what the building blocks were, and so we were starting really at the very basic portion of the DNA and saying we don't know how it gets to be DNA . . . but let's find out how we can deal with it . . . One of the things we had in mind was to inhibit what kills cancer cells."
 
By 1949 Trudy had synthesized a purine that inhibited growth in mouse leukemia, which Joseph Burchenal at Sloan Kettering Institute in New York used to treat four patients with chronic granulocytic leukemia, two of whom went into remission. This was the forerunner of 6-mercaptopurine, which continues to be effective in some cancers.

Trudy never completed the requirements for a Ph.D. degree. Shortly after starting her new job at Burroughs Wellcome, she began night courses at Brooklyn Polytechnical Institute in pursuit of a doctor's degree. After two years the institute requested that she convert to full-time to prove she was serious about the degree, but she did not wish to relinquish her exciting work. "It was exactly the kind of job I wanted, and Dr. Hitchings was kind enough to say you won't need your Ph.D. to do the work we're doing."

In 1983 Trudy retired and assumed the status of scientist emeritus. For the next 16 years she remained active in her field as an advisor to many organizations, including the World Health Organization and the American Association for Cancer Research. As a consultant she was also able to maintain her association with her former employer, now Glaxo Wellcome, Inc., in Research Triangle Park, North Carolina. She attracted many associates who became known as a research dream team, some of whom invented azidothymidine (AZT), a mainstay drug for treatment of HIV (human immunodeficiency virus) infection.

A most rewarding activity was her mentoring each year of a third-year Duke University medical student, who would take a year off from courses and do research under her aegis. "I think it's a very valuable thing for a doctor to learn how to do research, to learn how to approach research, something there isn't time to teach them in medical school. They don't really learn how to approach a problem, and yet diagnosis is a problem; and I think that year spent in research is extremely valuable to them."

Nephew Jonathan Elion, M.D., recollects the wonder of his aunt's relationships. "She made herself available to students. While people tell me now she was an advocate to the advancement of women in science, this actually comes as news to me, as I always thought of her as advocating the advancement of ALL persons in science. She was active in the North Carolina School of Science and Math, did lots with Duke medical students, loved to have young students visit Burroughs Wellcome (and kept a stack of books about herself directed at kids to give away). When she was a visiting professor at Brown, she didn't want to meet with the VIPs and department heads, she asked to arrange for time with the students" (J. Elion, e-mail message, September 15, 1999).

Trudy was awarded the Nobel Prize in physiology or medicine in 1988 for her discovery of important principles for drug treatment. "People ask me often [whether] the Nobel Prize [was] the thing you were aiming for all your life, and I say that would be crazy. Nobody would aim for a Nobel Prize because, if you didn't get it, your whole life would be wasted. What we were aiming at was getting people well, and the satisfaction of that is much greater than any prize you can get."

The prize was shared with her long-time associate George H. Hitchings and English scientist James Black. Others who contributed to the evaluation of her drugs included Joseph H. Burchenal of Sloan-Kettering Institute in New York and Roy Calne, a Cambridge, England, surgeon who came to Boston to join Joseph Murray of Harvard in the hope of finding the answer to rejection of transplanted kidneys in dogs. Dr. Robert Schwartz and William Damashek of Tufts University, also in Boston, pioneered the use of 6-mercaptopurine in patients. In 1998 Joseph Murray and E. Donnall Thomas of Seattle received a Nobel Prize for furthering studies of immunosuppression with azathioprine and later cyclosporin in the 1960s and 1970s.

Trudy remained active in research and professional organizations and held adjunct professorships at Duke University, the University of North Carolina, and Ohio State University. Among her awards, in addition to the 1988 Nobel Prize, were the National Medal of Science, presented by President George Bush in 1991; the Garvan Medal from the American Chemical Society in 1968; the President's Medal from Hunter College in 1970; the Judd Award from Memorial-Sloan Kettering Institute in 1983; the Cain Award from the American Association for Cancer Research in 1984; the Ernst W. Bertner Memorial Award from the M. D. Anderson Cancer Center and the Medal of Honor from the American Cancer Society in 1990; and 23 honorary degrees.

She was elected to membership in the National Academy of Sciences in 1990 (and served on the Council) and to the Institute of Medicine in 1991. She was a fellow of the American Academy of Pharmaceutical Scientists and the American Academy of Arts and Sciences; a foreign member of the Royal Society; and an honorary member of the Spanish Academy of Dermatology and Venereology, among many others.

Trudy's favorite pastimes were photography, music (especially Puccini, Verdi, and Mozart operas), travel ("I'll climb a mountain to get a picture," she said in 1993 during an interview with the Tampa Tribune), and a passion for raspberries. "Over the years, my work became both my vocation and avocation. Since I enjoyed it so much, I never felt a great need to go outside for relaxation. Nevertheless, I became an avid photographer and traveler. Possibly my love for travel stems from the early years when my family seldom went away on vacation. Thus, my curiosity about the rest of the world did not begin to be satisfied until I began to travel. I have traveled fairly widely over the world, but there still remain many places for me to explore. Another major interest is music, not because I am musically talented, but because I love to listen to it. I am an opera lover and have been a subscriber to the Metropolitan Opera for over 40 years. I also enjoy concerts, ballet, and theater" (Les Prix Nobel, 1999).
 

Elion's inventions


6-mercaptopurine (Purinethol), the first treatment for leukemia

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Mercaptopurine (also called 6-Mercaptopurine, 6-MP or its brand name Purinethol) is an immunosuppressive drug used to treat leukemia. It is also used for pediatric non-Hodgkin's lymphoma, polycythemia vera, psoriatic arthritis, and inflammatory bowel disease (such as Crohn's Disease and ulcerative colitis).

Mercaptopurine inhibits purine nucleotide synthesis and metabolism. This alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.

Azathioprine (Imuran), the first immuno-suppressive agent, used for organ transplants

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Azathioprine is an immunosupressant used in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohn's disease and ulcerative colitis. It is a pro-drug, converted in the body to the active metabolites 6-mercaptopurine and 6-thioinosinic acid.

Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes. It is an effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Side effects are uncommon, but include nausea, HA and rash. Because azathioprine suppresses the bone marrow, patients will be more susceptable to infection. Caution should be exercised when it is used in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication.
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Allopurinol (Zyloprim), for gout Allopurinol

Allopurinol is a drug used primarily to treat conditions arising from excess uric acid, most notably chronic gout. Allopurinol does not alleviate acute attacks of gout, but is useful in preventing recurrence. Allopurinol has been used in the United States since 1964.

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Allopurinol is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and acts to inhibit xanthine oxidase. This enzyme is responsible for the successive oxidation of hypoxanthine and xanthine resulting in the production of uric acid, the product of human purine metabolism.[1] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, which are converted to closely related purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol therefore decreases both uric acid formation and purine synthesis.

Pyrimethamine (Daraprim), for malaria

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Pyrimethamine (Daraprim®) is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention), and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.

Pyrimethamine interferes with folic acid synthesis by inhibiting the enzyme dihydrofolate reductase. Folic acid is needed for DNA and RNA synthesis in many species, including protozoa.

Trimethoprim (Septra), for meningitis, septicemia, and bacterial infections of the urinary and respiratory tracts

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Trimethoprim (INN) (pronounced) is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoWellcome under trade names including Proloprim, Monotrim and Triprim; but these trade names have been licensed to various generic pharmaceutical manufacturers. In clinical use it is often abbreviated TRI or TMP; its common laboratory abbreviation is W.

Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Tetrahydrofolic acid is an essential precursor in the de novo synthesis of the DNA nucleotide thymidine. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) and are thus dependent on their own de novo synthesis. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication.

Acyclovir (Zovirax), for viral herpes

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Aciclovir (INN) (pronounced) or acyclovir (USAN, former BAN), chemical name acycloguanosine, is a guanine analogue antiviral drug, marketed under trade names such as Zovirax and Zovir (GSK). One of the most commonly-used antiviral drugs, it is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of herpes zoster (shingles). Aciclovir

Acylovir differs from previous nucleoside analogues in that it contains only a partial nucleoside structure: the sugar ring is replaced by an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases
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