Designing Drugs

A FEW DECADES AGO ALMOST EVERY CHILD RECEIVING A diagnosis of leukemia died within six months. Such a diagnosis is still frightening today, but parents now have hope. Because of Gertrude Elion, the inventor of 6-mercaptopurine (6-MP), nearly 8 out of 10 children are cured.

And 6-MP was only the beginning. Using the methods pioneered in its discovery, which were based on biochemical investigation rather than chance, Elion and her longtime colleague George Hitchings, with their co-workers, went on to develop drugs that could prevent organ-transplant rejections, treat herpesvirus infections and gout, and control the progression of HIV infections. Elion’s career was crowned when she, Hitchings, and James Black of England shared the 1988 Nobel Prize in physiology or medicine.

The life and work of Gertrude Elion is in many ways a classic American success story. Her father, Robert, emigrated from Lithuania around 1900. He attended New York City public schools, worked nights in a drugstore, and eventually became a dentist. Her mother, Bertha Cohen, emigrated shortly before World War I from a town that was in Russia at the time but is now part of Poland. She worked as a seamstress and studied English in night school before marrying Robert when she was 19. Gertrude Belle Elion was born nearly a year later, on January 23,1918. Always quick to use humor to embellish her stories, she wrote in her official Nobel Prize autobiography, “I was born on a cold January night when the water pipes in our apartment froze and burst. Fortunately, my mother was in the hospital rather than at home at the time.”

She said that her mother was the most important influence in her life. Although Bertha had very little formal education, she read and discussed the textbooks that Gertrude brought home from high school and college. “She had no higher education,” Gertrude recalled, “but had the most common sense of anyone I knew, and she wanted me to have a career.”

Once the family was settled, they helped Bertha’s father, a respected scholar who had been a watchmaker until his eyesight faded, to immigrate in 1921. He lived with the Elion family and developed a close relationship with his granddaughter. The time that the precocious child and her grandfather spent together, telling stories and walking in the park, would play a key role in her decision to become a research chemist.

Shortly after her brother, Herbert, was born, in 1924, the family moved from Manhattan to the comparatively rural Bronx. Living in the “country,” Gertrude attended public schools, played outdoors, and enjoyed the Bronx Zoo. Her parents encouraged both children to follow their interests in music, languages, science, and history. Gertrude, an enthusiastic student, graduated from the allgirls Walton High School at the age of 15. Herbert was also an outstanding student and went on to a distinguished career in engineering.

Many years later Elion explained, “Among immigrant Jews, their one way to success was education, and they all wanted their children to be educated. Furthermore, it’s a Jewish tradition. The person you admired most was the person with the most education.” This was especially true in the Elion family. Her father traced his ancestry through a line of rabbis going back more than a thousand years, and one of her mother’s grandfathers had been a rabbi as well.

The family grew fairly prosperous, but Gertrude’s father speculated in stocks and real estate, and the stock-market crash of 1929 pushed the Elions into bankruptcy. Fortunately, Gertrude could turn to New York City’s outstanding municipal university system, which was tuition-free. She was accepted into Hunter College, a highly regarded public institution for women that was sometimes called the “Jewish Radcliffe,” though students from many ethnic backgrounds attended.

Gertrude had been interested in many subjects in high school, but she had no particular inclination toward science until the summer before she enrolled at Hunter, when she watched her beloved grandfather die of stomach cancer. The experience made her resolve to seek a way to cure such diseases: “I decided that nobody should suffer that much.” At Hunter she found a nurturing environment with high academic standards. As she recalled much later, there were 75 chemistry majors in her Hunter class: “Women in chemistry and physics? There’s nothing strange about that.” Rosalyn Yalow, a 1941 Hunter graduate who went on to win the Nobel Prize in physiology or medicine in 1977, had a similar experience. “From junior high school through Hunter College,” she said, “I never had boys in my classes.”

When Elion received her Hunter diploma, in the spring of 1937, she faced a problem more challenging than any she had solved in her classes: finding a job in the midst of a nationwide depression. There was nothing like today’s technologybased economy to absorb bright young science graduates; her summa cum laude chemistry degree might as well have been in medieval literature for all the employment prospects it opened up.

She had applied to 15 graduate schools and was accepted at many of them, but tuition and expenses were an insurmountable obstacle. Neither high grades nor enthusiastic recommendations from her professors could persuade any of the schools to offer financial help. Assistantships and fellowships were hard enough to come by for men and much harder for someone who would presumably soon abandon her career to start raising children.

As she cast about for a job, the clever, lively 19-year-old found herself spending more and more time with Leonard Canter, a brilliant statistics student at City College. She was cautious about entering a serious relationship, but on New Year’s Eve, 1937, the two went to the opera to see Madama Butterfly , and she wrote in her diary the next day: “This was the first time I was ever kissed as the New Year made its entrance. Leonard’s the only one I have a thoroughly good time with. We laugh at the same things and I always feel in harmony with him. I feel well taken care of and proud when I’m with him. It worries me a little how much I could care if I only let myself.”

Shortly afterward Canter left with a fellowship to study abroad. The combination of distance and frequent correspondence allowed her guarded feelings to blossom. Upon his return, they made plans to marry. Then he became ill with endocarditis, a bacterial infection of the heart. It was an infection that penicillin could have cured, but penicillin would not be manufactured m quantity until several years later, during World War II. His death in 1941 left the 23-year-old Gertrude shattered.

Gertrude’s nephew Jon Elion, a physician, recalls finding among her personal effects after her death the New York Hippodrome Opera Company program from that evening, which she saved for 60 years. “All her life, Madama Butterfly was her favorite opera. No question about it. I cannot help but wonder in retrospect if she would sit there and remember that New Year’s Eve performance that she attended with Leonard.”

Though her family recollects that many men later vied for her attention, nobody ever took Canter’s place. “It was a heartbreaker, and she never fully recovered,” her brother said. She made no formal decision not to get married, but she explained to potential suitors that her work was all-consuming and she would not have time for a family. Lacking a family of her own, she became a second mother and grandmother to her brother’s children and grandchildren. Jon Elion remembers frequent visits, particularly during the holidays, when she always brought thoughtfully chosen presents and bad weather, which the family fondly called “Trudy weather.”

The traumatic deaths of her grandfather and fiancé helped focus her scientific drive, as would her mother’s painful death from cervical cancer in 1956. She later said, “It reinforced in my mind the importance of scientific discovery, and that it really was a matter of life and death to find treatments for diseases that hadn’t been cured before.”

Back when she first graduated from Hunter, Elion had applied for scientific jobs. Employers seemed impressed with her, but as she later recalled, she was usually told that “hiring a woman would be a distractive influence in the laboratory.” Without giving up her research aspirations, she bowed to reality and enrolled in secretarial school. After six weeks of typing and shorthand classes—“about as much as I could take”—she was happy to accept a temporary job as a laboratory assistant at New York Hospital’s nursing school.

It lasted three months, and then she was unemployed again. A scientist friend invited her to volunteer to work in his laboratory. Even without a salary, she accepted, figuring that the lab experience would be helpful: “He was a very good organic chemist. I worked for him for a year and a half. At the end of that time, he was paying me $20 a week.”

Living at home with her parents, she needed money only for carfare and lunches. Out of her meager salary she managed to save enough to enroll in graduate school. In 1939 she started a master’s program in chemistry at New York University. She worked during the days, first as a medical receptionist and then as a high school chemistry and physics teacher, and she took classes at night and spent weekends in the NYU laboratory.

In 1941 she graduated from NYU with a master’s degree in chemistry. She kept her teaching position while looking for a laboratory job. Then in December, after the Japanese attack on Pearl Harbor, men began flocking to the armed forces, and women took over many of the jobs they had left behind—not just “Rosie the Riveter” work, but in laboratories as well. Elion’s first job was as a food analyst for the Quaker Maid Company. Saddled with repetitive tasks like testing the acidity of pickles, inspecting berries for mold and vanilla beans for freshness, and measuring the color of mayonnaise, she left after 18 months to join Johnson & Johnson, the pharmaceuticals firm, in New Brunswick, New Jersey. Within six months of her arrival, the company disbanded its research laboratory. Johnson & Johnson offered her a position testing the tensile strength of sutures. She declined it.

SHE FOUND THE JOB THAT SHE WOULD STICK WITH FOR the rest of her career by chance. In 1944 her father received a sample of Empirin painkiller from Burroughs Wellcome and noticed that the company’s research facility was in Tuckahoe, New York, just up the Hudson from the family’s Bronx home. He suggested that she inquire about a job. Her phone call resulted in an interview the following Saturday.

Elion was interviewed by Dr. George Hitchings, head of the company’s biochemistry department. Hitchings, she wrote, “talked about purines and pyrimidines, which I confess I’d never even heard of up to that point.” His idea was “to attack a whole variety of diseases by interfering with DNA synthesis. This sounded very exciting.” The following week she accepted his offer of $50 a week to work as his assistant. Finally she would be doing real research. As she later recalled, Hitchings was “one of those unusual people that didn’t care whether it was a man or a woman, and gave us equal opportunity.”

His idea for a new class of drugs, and a new way of finding them, was particularly inspired because when he came up with it, scientists still didn’t know how DNA and its companion nucleic acid, RNA, worked, or even what they looked like. Biochemists had identified the basic components of nucleic acids, and Oswald Avery of the Rockefeller Institute for Medical Research had just shown that they carried hereditary information. But no one knew how they were put together or by what chemical processes they functioned. Hitchings was aware, though, that cancer and other diseases were associated with rapid cell division and increased DNA synthesis. Since purines and pyrimidines are involved in both processes, he thought that using them to disrupt DNA synthesis could be a way to halt those diseases.

It was known that DNA is made up of four building blocks, which come in two varieties. Adenine and guanine are among a large class of compounds called purines, while thymine and cytosine are pyrimidines. Many other purines exist besides these two, and some of them function as intermediates in the complex chemistry of cell division.

As developed by Hitchings and Elion, the lab’s basic approach was to synthesize a new compound that resembled one of the purines used in cell division but was slightly altered. Elion referred to such a drug as a “rubber doughnut”: The drug would substitute for the purine it was mimicking, but its chemistry would be different enough to stop the disease by interfering with DNA synthesis. (Another group in the Burroughs Wellcome laboratory tried the same approach with pyrimidines, somewhat less successfully.)

This method could potentially work against any type of rapidly dividing cells, including such microorganisms as bacteria and protozoa as well as the cells in cancerous tumors. The idea was simple; implementing it was not. First of all, the drug molecule might be unstable in the body. If it broke down or was metabolized too quickly, it could not do the job it was meant for. Also, it might interfere with beneficial nucleic-acid processes, or it might be toxic in some other way. And the researchers would have to find something in the target cells’ chemistry that made them more susceptible than regular cells to a drug’s attack.

At first, Elion’s job was simply to follow Hitchings’s directions. She researched purine analogues in the library and then figured out how to synthesize them. In a few years, however, she was making detailed investigations of purines’ chemical pathways inside a cell and publishing her results. Eventually she would have research assistants of her own, along with everincreasing managerial and administrative responsibilities.

Shortly after she started work at Wellcome, she enrolled in a doctoral program at the Polytechnic Institute of Brooklyn. It gave her an exhausting schedule. Three days a week she had to commute from the company laboratory in Westchester County to the campus in Brooklyn for classes and then, late at night, back to her family’s home in the Bronx. As a parttime student, she expected to spend 10 years getting her degree. After two years, however, the dean told her that to stay in the program, she would have to enroll full-time. By then the purine research was starting to show promise. Hitchings said she could do her job just as well, and learn just as much, without a doctorate. So she abandoned graduate school, knowing that she was taking a chance on her prospects if she ever had to find another job.

The Burroughs Wellcome researchers evaluated their drugs by seeing if they had any effect on a test microorganism. The first encouraging result came in 1948, when they found that 2,6-diaminopurine greatly slowed the reproduction of Lactobacillus casei . ( L. casei is found naturally in the mouth and digestive tract, and as the name suggests, it causes milk to ferment.) Elion and Hitchings sent a sample to Dr. Joseph Burchenal at Memorial Sloan-Kettering Institute in New York City for testing. He found that it killed bacteria in vitro, shrank tumors in animals, and produced temporary clinical remission in two of four adult leukemia patients. Unfortunately, problems with intense nausea, vomiting, and bone-marrow suppression showed that it was too toxic. Still, it demonstrated the basic validity of the approach they were taking.

In 1951 Elion and co-workers found that replacing an oxygen atom with sulfur in a purine called hypoxanthine produced even better results. The resulting compound, 6-mercaptopurine, stopped tumor growth in animals with few serious side effects. When tumors from rodents treated with 6-MP were transplanted into other rodents, they did not propagate. With little delay, Burchenal began using 6-MP to treat acute lymphoblastic leukemia, a common type in children. At the time, clinicians were making limited progress using steroids and the cancer drug methotrexate to prolong the lives of these acutely ill children, but even so, only 30 percent survived as long as a year. The 6-MP treatments greatly increased the one-year survival rate. There were even cautious reports of a few cases in which 6-MP was believed to have produced a cure.

THIS WAS BIG NEWS. LEUKEMIA IS A CANCER THAT DOES not create solid tumors; instead, it affects white blood cells, causing them to multiply rapidly. Overproduction of new white blood cells leaves the body less able to make other vital blood components. The resulting lack of mature white blood cells leaves the body susceptible to infection; the lack of red blood cells makes patients tired because their cells are not getting enough oxygen; and the lack of blood-clotting platelets causes bruises and bleeding. Although physicians could diagnose leukemia, they couldn’t do anything about it. A popular medical textbook of the mid-1940s devotes several pages to leukemia diagnosis, but the section on treatment is one sentence long: “There is nothing to describe.”

An enormous outpouring of media attention and letters from desperate parents motivated the Food and Drug Administration to approve 6-MP quickly for acute lymphocytic and acute lymphoblastic leukemia. In an unprecedentedly brief time—less than 10 months after the initial clinical trials began—Burroughs Wellcome started producing 6-MP for commercial use in 1953. After this success and the publication of Elion’s twentieth research paper, Hitchings used his influence to help get her accepted into the prestigious American Society of Biological Chemists despite her lack of a doctorate.

The development of 6-MP was Elion and Hitchings’s first great success, but in most cases it produced only temporary remission. They wanted a cure. Toward that end, they and other researchers looked into the drug’s biochemical mechanisms to learn exactly how 6-MP interfered with cancers such as leukemia. This work stretched over the rest of the 1950s and into the 1960s.

As the two continued investigating 6-MP, researchers in their laboratory and elsewhere made great progress in elucidating the basic questions of what nucleic acids were and how they worked. The biggest step came in 1953, when James Watson and Francis Crick announced the helical structure of DNA. Once that basic and extremely important question was answered, scientists began teasing out the details of how DNA reproduces itself and transmits genetic information.

At the same time, new instruments and techniques greatly increased the ease and reliability of biochemical research. As Elion pointed out at the beginning of her Nobel lecture, when she joined Burroughs Wellcome, the laboratory used primiteve spectroscopes with carbon-arc lights and photographic plates to record absorption at different wavelengths; tritium and phosphorous-32 were the only readioactive isoltopes commonly available, and they had to be detected with Geiger counters instead of much more sensitive scintillation counters; and now-standard methods of chromatography had not been invented.

A major step forward came when Elion and Hitchings isolated a strain of bacteria that was resistant to 6-MP and found that this strain was also unable to use hypoxanthine for growth. The investigators surmised, and subsequently verified, that 6-MP and hypoxanthine were acted upon by the same enzyme. Hypoxanthine was an important intermediate in DNA replication, and when 6-MP took its place, that replication—and thus the multiplication of bacteria, or tumor cells—was disrupted.

Further work revealed that this disruption took several forms. The 6-MP stopped new purine molecules from being synthesized, it prevented interconversions between one purine and another, and it got itself incorporated into DNA molecules, which kept them from functioning properly. It did this in healthy cells too, of course, but it disrupted tumor cells more than healthy ones because tumor cells tend to have lower enzyme levels. A properly chosen dose of 6-MP will tie up the enzymes in tumor cells while leaving enough in healthy cells for them to function more or less normally.

Another question Elion had to solve was what happened to 6-MP inside the body. Did most of it go to work fighting cancer, or did it get consumed in other biochemical processes? A helpful technique that had recently become available was to give patients a special version of the test substance with a radioactive isotope substituted for one of the atoms. This substitution does not affect the substance’s chemical functioning but does make it easier to track. When the same radioactive isotope shows up later as part of a compound in the patient’s urine or blood, researchers know that it has come from a molecule of the test substance.

After much painstaking analysis, Elion and Hitchings found that 6-MP was often attacked in the body by unwanted compounds that removed the sulfur atom or attached new groups to it. They tried to protect 6-MP by adding attachments at other places on the molecule, but that usually nullified its antitumor properties. (There was one exception, in which an amino group was added at the 2 position. This compound, thioguanine, is used today to treat acute myelocytic leukemia in adults.)

Better results came from adapting to the unwanted compounds instead of fighting them. A modified form of 6-MP called azathioprine works as a “pro-drug,” meaning that it is inactive against cancer by itself, but after reacting with compounds present in certain types of tumors, it turns into 6-MP, which then acts against the tumor. Another weapon is to administer 6-MP in combination with protective agents that inactivate the compounds that attack 6-MP. More than a dozen such agents are now available.

While all this research was going on, scientists elsewhere were finding that 6-MP had applications beyond cancer. Robert Schwartz and William Dameshek, of Tufts University, noticed that certain white blood cells formed during an immune response were similar to those formed in patients with leukemia. They decided to investigate whether 6-MP could suppress the immune system. Finding that it could, Schwartz discovered that it was also possible to make the drug very precise in its action, suppressing immunity only to a specific antigen that was introduced to the body at the same time. He got Hitchings and Elion’s laboratory to work on the project, and they found new immunosuppressive drugs and drug combinations.

The point of suppressing the immune system was to make transplants possible. In the 1950s kidney transplants were just starting to be performed, but they were still quite rare because the patient’s immune system would usually reject any foreign material that was introduced. The odds could be improved if the patient had an identical twin to serve as the donor, and heavy doses of X rays followed by bone-marrow transplants could help patients get past the immediate aftermath of surgery. Still, survival for more than a few months was very rare. If the immune system could be suppressed, though, transplants would be much more promising.

After Schwartz and Dameshek announced their success at suppressing immune responses with 6-MP, an English surgeon named Roy Calne tested it with kidney transplants in dogs and got encouraging results, though no long-term survivors. He went to Boston to continue his research with Dr. Joseph E. Murray (who would win his own Nobel Prize in 1998) and others at Peter Bent Brigham Hospital. They worked closely with Elion and Hitchings, who, according to Murray, “were frequent visitors and knew most of our dogs by name.” Azathioprine turned out to be the most effective drug for this purpose.

In 1959 Calne successfully used azathioprine to transplant a kidney into a dog named Lollipop. After two failed attempts to duplicate the feat in humans, Calne performed the first successful human kidney transplant from an unrelated donor in 1962. Within a decade, several thousand kidneys were being transplanted per year. Today the procedure is considered routine, and other organs can be transplanted as well. New immunosuppressive drugs have been developed, but azathioprine is still a mainstay.

Meanwhile, the search for ways to make 6-MP more effective against cancer led to treatments for still more diseases. One of the main compounds into which 6-MP is converted in the body is 6-thiouric acid. This conversion keeps 6-MP from fighting tumors, so Elion and her co-workers looked for a way to neutralize the enzyme, xanthine oxidase, that causes it to happen. They found that the drug allopurinol inhibited this enzyme very well. When allopurinol was administered to patients along with 6-MP, the 6-MP became more effective against cancer cells. Unfortunately, the combination had serious and harmful side effects that kept it from being useful.

But allopurinol turned out to be valuable in other ways. Xanthine oxidase’s main job is to convert a pair of naturally occurring purines, xanthine and hypoxanthine, to uric acid. This suggested a promising approach to treating gout, a painful illness caused by uric acid crystals in the joints and excess uric acid in the blood: Tie up the xanthine oxidase with allopurinol, and production of uric acid would decrease. It worked, and allopurinol was later also found to be effective against the protozoan parasites that cause leishmaniasis and Chagas’ disease, two potentially deadly tropical afflictions that are transmitted by blood-sucking insects.

By the mid-1960s the rubber-doughnut approach of disrupting enzymatic processes had proved its value, and Elion and her colleagues were constantly looking for new diseases to use it against. She said, “It got to be almost a joke in the lab. ‘Now we have all the cures, we have to find the right diseases for them.’” Other ailments that Elion’s purines have been used against include malaria, rheumatoid arthritis, autoimmune hemolytic anemia, systemic lupus, and chronic active hepatitis.

In 1967 Hitchings retired from active laboratory work when he was elevated to vice president of research at Burroughs Wellcome. Elion took his place as head of the department of experimental therapy. She was the first woman at Burroughs Wellcome to lead a major research group and proved to be as talented a manager as she was a researcher. In a memorial tribute, a colleague said, “She was a team builder gifted with the ability to be critical and supportive simultaneously.”

The following year her group started investigating the possibilities of using purine derivatives against a new class of enemies: viruses. A virus is basically a core of nucleic acid encased in protein. Viruses are extremely tiny, much smaller than the smallest single-celled organisms, and must be in a living cell to reproduce. Biologists had distinguished them as a separate class of infectious agents early in the twentieth century and had learned to isolate and measure them in the days of World War I, but they had little knowledge about how they worked. New analytical techniques and new knowledge about nucleic acids led to greatly increased interest in virology at mid-century. Today, in addition to being targets of medical researchers, viruses have become indispensable tools for biochemical research and genetic engineering.

Way back in 1948 Elion’s first promising drug, 2,6diaminopurine, had shown activity against viruses, but it was too toxic and broke down quickly in the body. Two decades later Frank Schabel, at the Southern Research Institute, in Birmingham, Alabama, found another purine derivative that was active against viruses. When Elion learned about this, she remembered her tantalizing results from two decades earlier and decided to get back into virus research. Schabel’s compound, adenine arabinoside, did not last long enough in the body to be effective, but Elion thought an arabinoside of 2,6-diaminopurine would work as well or better against viruses and would last much longer.

SINCE BURROUGHS WELLCOME DID NOT HAVE A VIROL ogy laboratory, she sent a sample to one in England. After a few weeks the excited researchers told her by telegram that it was the best antiviral drug they had ever seen. As usual, the promising discovery had to be followed by years of research aimed at pinpointing how the drug worked and how it could be improved to make it safe and effective. Not wishing to tip her hand to competing firms, Elion kept Burroughs Wellcome’s antivirus project a secret. For nearly a decade, scores of researchers worked on the project, yet virtually no one outside the company knew what they were up to.

In 1970, in the midst of this work, the company decided it had outgrown its Tuckahoe location and moved its research facilities to North Carolina. Elion missed the area where she had spent her whole life, but the new laboratory was much more spacious and had modern, newly built facilities, including a virus lab. In 1972 her team found a purine that was 1OO times as effective as any previous drug against two very common and troublesome viruses, herpes simplex and herpes zoster. After much development work, it was announced in 1978 and eventually marketed under the name acyclovir. It was the first antiviral drug. Besides curing herpes infections, it also proved to be effective against shingles and Epstein-Barr virus.

Acyclovir worked so well because it closely resembled an important intermediate in the virus’s life cycle. This similarity led an enzyme to act upon acyclovir, and the resulting compound killed the virus. This technique opened up a fruitful way to make antiviral drugs: Find an enzyme that is characteristic of that virus, and then design a molecule that the enzyme will turn into something harmful. This method greatly reduces side effects because the enzyme in question is usually found only in the targeted virus. After Elion’s retirement, her laboratory used the experience it had gained with acyclovir to develop azidothymidine (AZT), the most effective drug yet against the virus that causes AIDS. It introduced a new class of drugs that has changed AIDS from a lethal disease to a chronic one.

By the time she retired in 1983, Elion had amassed more than 200 publications, 45 patents, and 26 honorary doctorates. Yet she did not see retirement as a time to slow down, and as an emerita member of the Burroughs Wellcome medicaltherapy department, she continued her research in drug discovery. On October 17, 1988, in an early-morning phone call from a reporter, Elion got the news that she had been awarded a Nobel Prize jointly with Hitchings and James Black (who had used rational drug-design techniques in a different area of biochemistry to develop drugs for heart problems, hypertension, and ulcers). With typical modesty, Elion did not believe the reporter and suspected him of pulling a prank.

The choice of Elion surprised her fellow scientists as much as it surprised her. While there was no doubting her brilliance, she was an industrial researcher, and the physiology or medicine prize usually goes to academics. Her age was another factor; most winners are in mid-career. Furthermore, she had never earned a doctorate. At the time, Elion was the only winner of a Nobel science prize without one. And, of course, she was a woman—among the more than 200 prizewinners in physiology or medicine, one of only 6. At the award ceremony in December 1988, she stood out in her blue chiffon dress among a sea of men in white ties and black tailcoats.

Through the years she won many other awards: the National Medal of Science, the Medal of Honor and the Cain Award from the American Cancer Society, the Judd Award from Memorial Sloan-Kettering Institute, and induction into the National Inventors Hall of Fame.

Because she loved working with students, teaching became almost a second career. When she gave presentations, she always insisted that her hosts schedule a block of time for her to spend with students. She was an adjunct professor at several universities and each year worked with a student from Duke’s medical school who was interested in research. She spoke to schoolchildren about the fun and excitement of scientific discovery with persuasive enthusiasm. She also was an active board member of the North Carolina School of Science and Mathematics, a residential high school for unusually able students.

Retirement also gave her the opportunity to travel and indulge her passion for photography. Her nephew recalls the family giving her a pair of long Johns to keep her warm on a trip to Antarctica: “She loved them and proudly showed us pictures where she was wearing them (but not visibly).”

Elion often received letters and photographs from her patients and their families. Some even wrote to her each year in commemoration of their kidney-transplant or cancer-remission anniversaries. She kept those letters in a file in her office and always sent back a heartfelt reply.

On February 21, 1999, Gertrude Elion collapsed and was taken to the University of North Carolina Hospital, where she died just before midnight. In going through her mail a few days after her death, Jon Elion found two letters. One was from a university president thanking her for being a visiting professor, and the other was from the mother of an elementary-school student who had played the role of Gertrude Elion in a school performance, complete with lab coat and tinfoil Nobel Prize. “I know that Trudy would have read the letter from the university president and put it aside with hardly a second thought,” Jon says. “The letter from the girl’s mother would have been very meaningful to her. She would have responded with a handwritten letter and made sure that the girl got proper attention. That’s the kind of thing that was important to her.”