Gertrude Belle Elion: Biochemist, Nobel Prize 1988*

Vol. 1, No. 1
The Chemical Educator
© 1996 Springer-Verlag New York, Inc.

ISSN 1430-4171
http://journals.springer-ny.com/chedr
S 1430-4171(96)01014-X

I opened my newspaper this morning and through many tears read of your great honor, the Nobel Prize. My daughter Tiffany was stricken with herpes encephalitis in September, 1987. A neurologist said the only hope for her was possibly the drug acyclovir.

I have thanked the Lord so many times that he blessed you with the determination, stamina, love, and patience to work all of the long hours, days, months, and years it takes to invent a new drag. Tiffany is a senior in high school this year and doing great. May the Lord bless you beyond your wildest dreams.

* Abridged from Sharon Bertsch McGrayne’s book, Nobel Prize Women in Science: Their Lives, Struggles, and Momentous Discoveries, a collection of 14 biographies, including chemists Marie Curie, Gerty Cori, Irene Joliot-Curie, and Dorothy Hodgkin. Published by Birch Lane Press, Carol Publishing Group, 1993, 419 pp., $26.95. ISBN 1-55972-146-4.

For Gertrude Belle Elion, biochemistry is not an abstract science. Her mission is curing diseases, and her inspiration comes from people—from her own family members and loved ones to the thousands of patients who have taken her compounds.

Elion—Trudy to her friends—is unique in drag research. She straggled almost a decade in temporary and marginal jobs before landing a research job. For years she was the only woman in a top pharmaceutical company post. She is a Nobel Prize winner without a doctorate.

Yet her work revolutionized both medicine and drag-making. She helped make organ transplantation and cancer chemotherapy possible. Her drags helped transform childhood leukemia from a death sentence to an illness that 80 percent of its victims survive. She developed the first anti-virus drag and laid the foundation for AZT for AIDS patients. Even more importantly, Elion and her collaborator George Hitchings helped change the trial-and-error way drags were discovered. By studying the reproduction of normal and abnormal cells, she learned to develop compounds that interrupt the life cycle of abnormal cells without harming healthy ones.

Elion was born on January 23, 1918, in New York City to Jewish immigrants from Lithuania and Russia. As a child, she was a shy bookworm with an insatiable thirst for knowledge. "It didn’t matter if it was history, languages, or science. I was just like a sponge, " she said. She idolized Louis Pasteur and Marie Curie—"people who discovered things"—and devoured popular science books like Paul de Kruif’s Microbe Hunters. "These books were so exciting. It was like reading a novel. It was a mystery story that they could solve. " Her heroes were discoverers; their sex did not matter.

When Elion was 11 years old, her father went bankrupt in the stock market crash of 1929 and the Depression. Somehow she had to get to college. "Among immigrant Jews, " she recalled, "their one way to success was education... Furthermore, it’s a Jewish tradition. The person you admired most was the person with the most education. And particularly because I was the first born, and I loved school, and I was good in school, it was obvious that I should go on with my education. No one ever dreamt of not going to college" Fortunately, Hunter College—the women’s branch of the City College of New York—was free and Trudy’s grades were extremely high. If Hunter had charged tuition as it does today—Elion could not have attended college.

She chose her future career while visiting her beloved grandfather as he lay dying slowly and painfully of stomach cancer. That was the turning point," she declared. "It was as though the signal was there: ‘This is the disease you’re going to have to work against.’ I never really stopped to think about anything else. It was really that sudden." Elion never lost that shining goal.

To prepare for pharmaceutical research and to avoid dissection, Elion majored in chemistry. After graduating from Hunter with highest honors in 1937, she applied to fifteen graduate schools. Not one offered her financial assistance. Later she understood: sex discrimination. "Although there weren’t many fellowships (during the Depression), there were some, and I was willing to go almost anywhere in the country, " she said.

She couldn’t get a chemistry job either. "There weren’t many jobs, and what jobs there were, were not for women." Looking back, Elion is amazed at her innocence. "I went to an all-girls’ school. There were seventy-five chemistry majors in that class .... So when I got out and found that they didn’t want women in the laboratory, it was a shock." A job interviewer opened her eyes by confiding, "You’re qualified. But we’ve never had a woman in the laboratory before, and we think you’d be a distracting influence."

"I almost fell apart," Elion recalled. "That was the first time that I thought being a woman was a real disadvantage. It surprises me to this day that I didn’t get angry. I got very discouraged. But how could I say, ‘No, I won’t be a distracting influence’? How could I know what the men were like.? " Grinning, she points to a black-and-white photo. "I wasn’t bad-looking. I was kind of cute. " In desperation, Elion enrolled in secretarial school.

For the next seven years, Elion inched her way up the chemistry ladder toward research. Her fiancé had died suddenly, and she immersed herself in work. She volunteered in a laboratory free, putting up with the boss’ anti-Semitic joke-of-the-day to learn instrumentation; it never occurred to the man that his red-haired technician was Jewish. She became a half-time doctor’s receptionist, substitute teaching and working on her master’s degree nights and weekends in an unheated laboratory at New York University, where she warmed the room with Bunsen burners and worked in her winter coat.

As World War II wore on, job prospects for women scientists improved. Soon a grocery chain hired Elion to test its pickles for acidity and fruit for mold. By 1944., even research laboratories were hiring women and she got a post at Johnson & Johnson in New Jersey. In each job, she mastered what there was to learn and then announced in her quick Bronx accent, "I’ve learned whatever you have to teach me, and there’s nothing more for me to do. I have to move on." She adopted Admiral Farragut’s motto: "Damn the torpedoes! Full speed ahead!"

At age twenty-six, she landed a research position at Burroughs Wellcome Company in suburban New York. Although she planned to leave when she stopped learning, she never left. After mastering organic chemistry, she moved on through biochemistry, pharmacology, immunology, and virology. "It was one new field after another, and the compounds were taking me there, and that was wonderful," she said.

Burroughs Wellcome was devoted to discovering drags for serious, incurable diseases. Until 1986, its profits were used solely to support medical research, museums, libraries, and the like. The company merged with Glaxo in 1995. When Elion started work there, its American laboratory was housed in a converted robber factory. Hood ventilation was inadequate, air conditioning was non-existent, and the floor was roasting hot from a baby-food plant below. Elion bought a pair of thick, robber-soled nurses’ shoes to protect her feet.

Hot as it was, the laboratory became the center of Elion’s social life. For twenty-five years, she and a colleague Elvira Falco attended Metropolitan Opera performances together. Whenever Elion scraped some money together, she spent it on travel—"not new cars, not new furniture. It was travel," often with co-workers. Inside the lab, her friends told raunchy jokes and had water fights. Elion, a shy and well-brought-up young lady, was down-to-earth and unpretentious but the jokes made her blush deep red. And she took the work seriously. She could concentrate "like a male," Falco thought.

When Elion started work in the 1940s, little was known about nucleic acids. Biochemist Oswald Avery at the Rockefeller Institute in New York City had just discovered that DNA (deoxyribonucleic acid) is the carrier of genetic information. James Watson and Francis Crick would not discover DNA’s helical structure for another decade.

Elion’s new boss George Hitchings wanted to develop a rational, scientific approach to discovering drags. All cells require nucleic acids to reproduce, but the cells of bacteria, tumors, and protozoa require large amounts to sustain their rapid growth. They should be acutely vulnerable to any disruption in their life cycle.

Dividing the nucleic acids among his staff, he assigned the purines to Elion. The purine bases—adenine and guanine—are the building blocks of DNA and RNA (ribonucleic acid). Arranged in varying sequences, they transmit hereditary data to cells.

Little was known about the biosynthesis of the enzymes involved, so each series of experiments was a mystery. Always an optimist, Elion happily worked long hours, never truly satisfied until she had explored a hundred or more variations. She was hooked: she wanted to learn how the chemicals acted.

Within two years, she was publishing her findings. Hitchings let her write her papers herself and list her name first. "I’m very grateful he let me" Elion said. "He corrected them, helped me, and it’s a tradition that I’ve carried on." Eventually, Elion published more than 225 papers.

Some of her ideas were hunches; others came from trying to figure out what puzzled her. She was constantly asking herself, "What does it mean.?" and "Why did it happen?" She concluded that science is a constant process of deduction and intuition and trial-and-error and back-to-the-drawing-board and then, always, more questions. She even worked summer weekends at her parents’ country cottage.

The first time Elion presented a report at a scientific conference, a well-known authority on the subject questioned her conclusions. Elion shocked her friends by arguing back. Afterwards the man asked, "Can I take you to lunch?" In a ten-minute talk, she had not been able to give all her proofs, but over lunch she convinced him. "I was right... I had backup material... I appeared shy when I gave a paper, but I wasn’t shy. I never talked about something I didn’t really know about."

Soon Elion was part of a network of pioneers in purine research. Inside the company, some thought Elion was buttering up the brass. But without her academic friends, she would not have won the Nobel Prize.

For two years, Elion worked evenings on a Ph.D. at Brooklyn Polytechnic Institute. Then one day, the dean called her into his office and told her, "You’re going to have to quit your job and go full time."

"Oh, no, I’m not quitting that job. I know when I’ve got what I want," she retorted.

She worded about her decision to quit graduate school until 1950 when she was 32 and had a "WOW!" year. That’s when she synthesized not one, but two, effective cancer treatments. The first was a purine compound that interferes with the formation of leukemia cells.

FIGURE 1. GERTRUDE ELION MADE 6-MP, HER FIRST ANTI-LEUKEMIA DRUG, BY SUBSTITUTING A SULFUR ATOM FOR THE OXYGEN ATOM ON A PURlNE MOLECULE.

Tested on animals, diaminopurine looked so spectacular that Sloan-Kettering Memorial Hospital in New York tried it on two acutely ill leukemia patients. One was a twenty-three-year-old woman named J. B. who went into complete remission, married, and had a child before relapsing two years later and dying. Elion still weeps for J. B.

The drug hooked Elion and Hitchings on cancer chemotherapy research. But it also put them on an emotional roller-coaster. "We saw remissions that gave us joy, but almost all were followed by a relapse," Hitchings said. So Elion began studying the compound’s biochemistry, figuring that if she knew how it worked, she could make other compounds like it. Eventually, she made and tested more than one hundred purine compounds.

Elion was just getting over the shock of J. B.’s death when she substituted a sulfur atom for the oxygen atom on a purine molecule. The new compound was 6-mercaptopurine, 6-MP for short. In tests on mice, tumors treated with 6-MP failed to grow.

In 1950, half of all children with acute leukemia died within a few months and two-thirds within a year. Yet children treated with 6-MP seemed to experience complete remissions. Within days of the news, the Food and Drag Administration approved 6-MP for commercial release—probably the only new compound ever released without its supporting data.

By itself, however, 6-MP was not good enough. The children eventually relapsed and died. Watching them, Elion was as emotionally tom as she had been at the deaths of her grandfather and fiancé. She did not know anyone who had ever studied the metabolism of a drug before, but Elion spent six years trying to understand every detail of 6-MP.

"Until we learned how to use combinations for cancer therapy, we weren’t curing anybody with single drugs," Elion explained. "So there was this constant struggle: How to beat it? How do you get around it? Why are they relapsing? What can we do to make it better? And for eighteen years of my life, I tried to make 6-mercaptopurine better. I was insistent that this was going to work."

During her "WOW!" year, Elion also synthesized a close relative of 6-MP called thioguanine. With other drugs and 6-MP or thioguanine, most youngsters with leukemia could be cured a word cancer therapists had never dared use before. Today, thioguanine’s primary use is for acute myelocytic leukemia in adults.

Elion had opened a new area of leukemia research. She had demonstrated that minute chemical changes in a compound can fool malignant cells. She stopped worrying about not having a Ph.D. But most important, she was curing people. "What greater joy can you have than to know what an impact your work has had on peoples’ lives? We get letters from people all the time, from children who are living with leukemia. And you can’t beat the feeling that you get from those children," Elion said.

"This is like you’re the doctor in a way, and you’re doing something directly for these people," she elaborated. "The intermediary is the doctor but the excitement is really yours because you know you gave them the tools. And so when the Nobel Prize came in, everybody said, ‘How does it feel to get the Nobel Prize?’ And I said, "It’s very nice but it’s not what it’s all about.’ I’m not belittling the prize. The prize has done a lot for me, but if it hadn’t happened, it wouldn’t have made that much difference."

Other researchers began testing 6-MP on animals to see its effect on the immune system. Surgically, organ transplants had been feasible for years. The obstacle was the body’s immune response which rejected grafts within days. Yet a British surgeon kept a dog with a transplanted kidney alive for an amazing forty-four days with daily doses of 6-MP. When the surgeon moved to Boston, he asked Elion and Hitchings for some relatives of 6-MP to test. The most promising came from Elion’s vial 57-322, later marketed as Imuran. Hotfooting it up to Boston, Elion and Hitchings met the heroine of the story, a collie named Lollipop. Thanks to Imuran, Lollipop survived her kidney transplant for a miraculous 230 days before dying of another, unrelated cause.

Elion’s drug made organ transplantation possible. More than one hundred thousand kidney transplants have been performed in the United States since 1962, most with Imuran. The first heart-transplant patient took Imuran in 1967. It also treats autoimmune lupus, anemias, hepatitis, and severe rheumatoid arthritis. Sometimes, when Elion gives a public talk somewhere, a stranger approaches afterwards to thank her for making his or her kidney transplant possible. With considerable understatement she said, "When you meet someone who has lived for twenty-five years with a kidney graft, there’s your reward."

Asked to choose her favorite drag between 6-MP for leukemia and Imuran for kidney transplants, Elion cannot. "It’s hard to choose among your children. Each drag was wonderful, each one rewarding. It’s been rewarding all along."

During the 1960s, Elion developed allopurinol, a compound synthesized at Burroughs Wellcome to reduce the body’s production of uric acid. By preventing a painful and potentially fatal disease called gout, it helped make cancer chemotherapy and radiation treatment possible. Later, allopurinol also proved effective against Leshmaniasis disease and may be effective against Chagas’ disease, both major problems in South America. Colleague Thomas Krenitsky at Burroughs Wellcome believes, "In fifty years, Trudy Elion will have done more cumulatively for the human condition than Mother Theresa."

By the mid-1960s, Elion had developed an identity apart from Hitchings. Early in the 1960s, a Yale professor could still comment, "Oh, yeah, that fellow Elion has worked with George a long time." But by the time Elion was in her late forties and early fifties, she was well known in her own right. Yet, as Krenitsky realized, Elion "is always herself. She’s always Trudy .... whether the other person is a student, a glassware washer, or the president of the company. She’s egalitarian, and she lives it.

She began collecting prizes too: the Garvan Medal, which until 1980 was the only award a woman could win from the American Chemical Society, and honorary degrees from universities. Standing on the platform at George Washington University and clutching her long-sought Ph.D., Elion’s only thought was, "I wish my mother were here." All that Elion had accomplished in her research had not been enough to save her own mother from cancer.

When Hitchings retired from active research in 1967 and Elion became head of the Department of Experimental Therapy at Burroughs Wellcome, she was finally on her own. In twenty-three years together, not even company insiders had been able to identify their respective contributions. Nevertheless, Elion says that they had had their differences. She considered them a team but doubts that Hitchings did. He used ’T’ for their work while Elion used "we."

"He can be very patronizing," Elion continued. "He perceives that he started it all... But actually he was always willing to listen to suggestion... He just let us do what we thought we should be doing." The upshot was that "at fifty-five, I had had enough already of being junior. And then I had the opportunity to show that I could do on my own."

One of Elion’s hallmarks is learning from her mistakes, so she decided to revisit one of her failures: the compound that had almost cured J. B. in 1948. Elion had heard that a similar compound showed some antiviral activity. Scientists were convinced, however, that no drug could fight a virus without harming the DNA of healthy cells too. But when she sent a related compound to England for tests, she got back an excited telegram: "This is the best thing we’ve seen. It’s active against both the herpes simplex virus and the herpes zoster vires."

Herpes zoster causes shingles, and herpes simplex causes mouth and genital sores; either can be fatal for patients with leukemia, cancer, and transplanted organs and bone marrow. When the immune system is suppressed by disease or chemotherapy, the virus can spread to internal organs or large areas of the skin.

Acyclovir turned out to be different from any other compound Elion had ever seen. It is so similar to a compound that the herpes virus needs for reproduction that the virus is fooled and commits suicide. For four years, from 1974 to 1977, more than seventy-five researchers kept acyclovir secret. "We didn’t tell anybody anything" Elion emphasized. "It was an amazing exhibition of what you can do when you’re excited with what you’re doing."

But Elion knew, "We had to protect it from the other companies. We knew the minute it got out, everybody would jump on the bandwagon—and they did!"

Acyclovir went public at a scientific conference in 1978. Elion had recently had back surgery and her doctor told her not to fly to the meeting. But she arranged to be carried onto the plane in a pallet and taken off in a wheel chair. "We had waited too long for this moment, and I was not going to miss all the fun. My back eventually healed away," she noted. At the conference, thirteen posters filled an entire alcove, explaining acyclovir from its synthesis to its activity, enzymology, metabolism, toxicology, and so on. Besides treating shingles, acyclovir is also effective against Epstein-Barr virus, pseudo-rabies in animals, and herpes encephalitis, a frequently fatal brain infection in children.

Elion called acyclovir her "final jewel .... It was a real breakthrough in antiviral research. That such a thing was possible wasn’t even imagined up until then." No one knew there were so many different enzymes specific to particular viruses. "After that, everybody went to work in the field, so in addition to being an important compound, it was an important landmark," Elion realized. If one virus had its own specific enzyme, maybe others did, too. Marked as Zovirax, it became Burroughs Wellcome’s largest-selling product with worldwide sales of $838 million in 1991.

By then, Burroughs Wellcome had moved to Research Triangle Park in rural North Carolina not an easy move for a born-and-bred New Yorker. But Elion became a dedicated Tarheel. She stuffed a two-story condominium with travel souvenirs, family portraits, photos, statuettes, artwork, music, and plants. She maintained family ties with her brother’s children by phone and plane, flew to New York for the operation, and attended every classic music concert, James Bond movie, and college basketball game in the Triangle. With a friend and neighbor, she traveled the world snapping photographs.

Retiring in 1983, Elion became a consultant to the company. Within a year, her unit had used her approach to produce Azidothymidine, called AZT, the only drag licensed to treat the AIDS virus in the United States until late 1991. "The only thing I can claim is training people in the methodology... The work I call theirs," she claims modestly.

As Elion was washing her face at 6:30 a.m. on October 17, 1988, she got a phone call from a reporter: "Congratulations! You’ve won the Nobel Prize!" She assumed he was joking until she heard her co-winners: George Hitchings and Sir James W. Black of the University of London. The three shared $390,000.

It was the first Nobel for drug research in thirty-one years, and one of the few for cancer treatment. Drug company employees are rarely honored by the Nobel Committee, and Elion had no Ph.D. But the Nobel Committee believed, "While drug development had earlier mainly been built on chemical modification of natural products, they introduced a more rational approach based on the understanding of basic biochemical and physiological processes."

The Nobel Prize almost went to Hitchings alone—without Elion. Several university scientists had nominated them together, but a Nobel Committee member questioned Elion’s inclusion. "Has she really contributed?"

"Have you looked at the papers from the early days? " the professor replied. "She’s first author." Then he pointed to Elion’s antiviral work, after Hitchings had retired from research. That tipped the balance. Without her university friends, Elion might not have won the prize.

When Burroughs Wellcome gave Hitchings and Elion $250,000 each to donate to charity, Elion gave hers to Hunter College for women’s fellowships in chemistry and biochemistry. After the Nobel came the National Medal of Science, the nation’s highest science honor, and election to the National Academy of Sciences (long after she had organized the campaign that got Hitchings admitted in 1975).

The prize has had its bittersweet elements. It strained her fifty-year-old friendship with Hitchings. Friends say that Elion’s inclusion came as a shock to him and brought the undercurrent of their competition into the open. Elvira Falco, friend to both for decades, commented, "They worked together as well as any two people worked together. But I have a feel that when your assistant gets as much credit as you have, it may be a difficult thing."

Elion is working as hard as ever at Burroughs Wellcome and on national and international health committees. But through it all, Trudy Elion is still Trudy—poised, unpretentious, and as intent on curing diseases as she was when she dedicated her research to her grandfather, her fiancé, J. B., her mother, and the children with leukemia.

One of her favorite awards is the simplest: the letter about Tiffany, the high school student with herpes encephalitis. In her letter, Tiffany’s mother asked Elion for an autographed photo to tape to her refrigerator. Then she enclosed Tiffany’s picture "so you could see for yourself how great she looks, once again, thanks to you."

Sharon Bertsch McGrayne, a former newspaper reporter and writer/editor on physics for the Encyclopaedia Britannica, has spoken aboutwomen in science at a numberof universities, national laboratories, and conferences. She is working on a sequel to 365 Surprising Scientific Facts, Breakthroughs, and Discoveries (Wiley, 1994).