Six Drugs, No Doctorate
The story of Gertrude Elion, chemist, pioneer, and the woman behind allopurinol. Rejected from every graduate fellowship she applied to, she built the world's most prescribed gout drug and the methodology that created modern medicine.
Written by Seth Collins, Pharm.D.
Updated on Jun 5, 2026
Drug History
3 viewsGertrude Elion was twenty-six years old in 1944. She had graduated summa cum laude from Hunter College at nineteen, earned a master's degree from NYU at night while teaching high school chemistry during the day, and applied to roughly fifteen graduate fellowships in chemistry. Every single one of them had rejected her. The rejections came back in different words but with the same reasoning. There was no place for a woman in a serious chemistry laboratory.
She spent the intervening years working jobs that universities considered acceptable for women with chemistry degrees. She tested the acidity of pickles for the A&P grocery chain. She taught high school. She took a temporary lab assistant job at Johnson and Johnson that ended when the position was cut. The only reason Burroughs Wellcome opened a research position to her in 1944 was that the men they would normally have hired were in Europe and the Pacific. She walked in.
She would never receive a PhD. She started doctoral coursework at Brooklyn Polytechnic Institute in the evenings while working full-time, made progress for several years, and was then told she would have to attend full-time or leave. She left. By the time the decision could have been reversed, the work she was producing at Burroughs Wellcome was the kind of work doctoral programs typically produce.
Over the next four decades, her research group developed 6-mercaptopurine for childhood leukemia, azathioprine for organ transplant rejection (which made modern transplant medicine possible), acyclovir for herpes (the first effective antiviral drug in medical history), pyrimethamine for malaria, trimethoprim for bacterial infections, and the methodology her team would later use to develop AZT for HIV. Her direct supervisor George Hitchings was thirteen years her senior, was listed as senior author on most of the publications, and was referred to in industry shorthand as the leader of "the Hitchings group" for most of Elion's career. When the Nobel Prize in Physiology or Medicine was finally awarded for the methodology their lab had built, in 1988, Elion was seventy years old and had been retired from active research for six years. Somewhere in the middle of all of this, she had also produced the most widely prescribed drug for chronic gout management in the world.
Allopurinol exists because she was trying to make a cancer drug work better.
Gout has been documented in the medical record for more than two thousand years. Hippocrates wrote about it. Egyptian physicians described it. Medieval European medicine called it the king's disease, the inevitable consequence of organ meats and rich wine, a condition of wealth and excess. Colchicine had been treating acute flares since the Ebers Papyrus, but colchicine treats the inflammatory cascade after uric acid crystals have already formed. It does nothing about the underlying problem, which is that some people produce more uric acid than their kidneys can clear, and the excess deposits in joints as crystalline urate.
For most of medical history the chronic management of gout was dietary. Patients were told to avoid meat, avoid alcohol, avoid the foods physicians associated with the disease. This worked imperfectly. Uric acid production is influenced by diet but not determined by it. Patients with severe disease produced uric acid in quantities their kidneys could not handle regardless of what they ate, and the result was recurrent acute flares, progressive joint destruction, and tophi, the chalky urate deposits that erode bone and disfigure hands and feet over decades.
The biology of uric acid production sat unexplained until twentieth-century biochemistry mapped the purine metabolism pathway. Purines are essential components of DNA and RNA, and the body recycles them continuously. The final step in their breakdown is performed by an enzyme called xanthine oxidase, which converts hypoxanthine through xanthine to uric acid. In most mammals this is not a problem, because most mammals produce a subsequent enzyme called uricase that breaks uric acid down further into a soluble compound that passes easily into urine. Humans and great apes lost the uricase gene somewhere in primate evolution. Uric acid is our terminal purine metabolite. We produce it constantly, we have to clear it through the kidneys, and when production exceeds clearance we develop gout.
Elion was not trying to solve this. She was trying to solve leukemia.
She and Hitchings had developed a drug called 6-mercaptopurine in the early 1950s that worked against childhood acute leukemia. The problem was that the body broke 6-MP down quickly through xanthine oxidase, the same enzyme that produces uric acid. Patients metabolized the drug before it could finish its work. Elion's team needed to inhibit xanthine oxidase to keep 6-MP active longer.
They synthesized allopurinol in 1956 for exactly this purpose. It was designed as a structural analog of hypoxanthine, similar enough to occupy the active site of xanthine oxidase but different enough that the enzyme could not process it normally. It bound the enzyme and shut it down. 6-MP stayed active longer. The leukemia application worked.
Then Wayne Rundles, a hematologist at Duke University who was running the 6-MP trials, noticed something his patients were not supposed to be doing. Their uric acid levels were dropping. The xanthine oxidase inhibition designed to keep 6-MP active was also reducing uric acid production at its source. Patients with high baseline uric acid, including several with concurrent gout, were getting better gout control as a side effect of cancer treatment.
Rundles proposed running allopurinol as a primary gout drug, separate from any cancer indication. Elion and Hitchings ran the trials with him through the early 1960s, and the FDA approved allopurinol for gout in 1966.
Within a decade it was the standard of care for chronic gout management worldwide, displacing older drugs (uricosurics like probenecid) for most patients. It worked at the source rather than at the symptom. Colchicine fought the inflammatory cascade after crystals formed. Allopurinol stopped uric acid from being produced in problematic amounts in the first place. Together the two drugs converted gout from a slowly progressive disease that destroyed joints over decades into a manageable condition that responded to oral medication.
The methodological achievement is the part most people miss. Allopurinol was designed with its mechanism already in hand. That is not how drug discovery worked before Elion and Hitchings. Most drugs in human history were stumbled upon through plant medicine, accident, or large-scale random screening. Colchicine was used for three thousand years before anyone understood tubulin. Aspirin was prescribed for decades before the prostaglandin mechanism. The Elion-Hitchings methodology, which the Nobel committee eventually called rational drug design, treated drug discovery as an engineering problem. Study the biochemistry of the disease. Identify a specific molecular vulnerability. Design a molecule to exploit it. The pharmaceutical industry that exists today exists because of this approach. It was developed by a woman who could not be hired as a chemist for the first six years of her career.
There are two things worth knowing about allopurinol if you take it.
The first is that allopurinol itself is not the primary active inhibitor. The body converts allopurinol to a metabolite called oxypurinol, which has a much longer half-life and performs most of the actual enzyme inhibition. This was not fully understood when the drug was approved. It was worked out over the subsequent decades and explains why allopurinol works as a once-daily medication despite its own short half-life. The parent drug is essentially a prodrug. The metabolite does the work.
The second is more serious. A small fraction of patients develop a severe hypersensitivity reaction that can be life-threatening. The risk is dramatically higher in people carrying a specific HLA-B*5801 genetic variant, which occurs at substantially higher frequency in Han Chinese, Korean, and Thai populations. This genetic association has been clearly established since 2008. Screening for the variant before starting the drug is now standard practice in much of Asia. It is still inconsistently applied in the United States, which is worth knowing if you or someone in your family is from an at-risk population and is being started on allopurinol.
The drug is also used for Lesch-Nyhan syndrome, a rare genetic disorder in which patients produce massively elevated levels of uric acid from birth, and for tumor lysis syndrome in cancer patients, where rapid cell death from chemotherapy releases enormous quantities of purines that overwhelm the kidneys. Both applications derive from the same xanthine oxidase mechanism in different clinical contexts.
Gertrude Elion died in 1999, at eighty-one. By then she had collected twenty-three honorary doctorates from institutions that had not, when she was twenty-two, been willing to admit her as a candidate. The Nobel had come eleven years earlier, after most of her contemporaries had already retired or died. She was the first woman inducted into the National Inventors Hall of Fame. She had testified before Congress. She had lectured at every major medical school in the United States. She had mentored a generation of researchers at Burroughs Wellcome who carried her methodology forward into the work that produced AZT during the worst years of the AIDS epidemic, when the federal government was refusing to act.
She published her last paper in 1995, at seventy-seven.
When she gave her Nobel lecture in 1988, she spoke about what it had been like to be turned away from laboratories for being a woman, to work without a doctorate in a field that demanded one, to spend a career proving that the credentials she could not obtain were not the same thing as the work she could do. She also spoke about the patients. The leukemia children who had survived because of 6-MP. The transplant recipients who had lived because of azathioprine. The gout patients whose joints had stopped destroying themselves because of allopurinol. She had received letters from those patients for decades.
It is worth asking what the field of medicine lost during the six years when she was testing pickle acidity for the A&P grocery chain. How many drugs went unmade because the people who could have made them were not allowed into the laboratory? How many patients did not survive what she might otherwise have invented earlier? These questions do not have answers, but they are not rhetorical.
Allopurinol costs between four and fifteen dollars for a month's supply at most pharmacies today. It has been generic since the 1980s. The molecule is the same one Elion and Hitchings designed in 1956, and the mechanism is the same one they used to design it.
If you are paying significantly more than that, the difference is not the drug. The difference is the system stacked around the drug: the office visit required to get the prescription, the insurance gating, the pharmacy benefit manager negotiations, the brand-name markups for products that are pharmacologically identical to the generic. None of this has anything to do with what allopurinol costs to make, or with the chemistry Gertrude Elion did, or with the decades of patient lives the drug has changed.
Pillar Drug Club was built on the premise that the people who take these medications every year should understand what they are actually taking, and should not pay more than what the molecule itself costs to manufacture and dispense. If you take allopurinol, you are taking a drug built by someone the academic system rejected for being a woman, designed as a side project to a cancer treatment, approved for gout almost by accident, and held in continuous clinical use across six decades because nothing better has come along. The price you pay for it should reflect that history, which is to say, it should be cheap.
Sources
1. Elion GB. (1989). The purine path to chemotherapy. Science, 244(4900), 41-47. https://doi.org/10.1126/science.2649979
2. Elion GB. (1988). Nobel Lecture: The Purine Path to Chemotherapy. https://www.nobelprize.org/prizes/medicine/1988/elion/lecture/
3. Elion GB, Callahan S, Nathan H, Bieber S, Rundles RW, Hitchings GH. (1963). Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochemical Pharmacology, 12(1), 85-93.
4. Rundles RW, Wyngaarden JB, Hitchings GH, Elion GB, Silberman HR. (1963). Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Transactions of the Association of American Physicians, 76, 126-140.
5. Pacher P, Nivorozhkin A, Szabo C. (2006). Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological Reviews, 58(1), 87-114. https://doi.org/10.1124/pr.58.1.6
6. Hung SI, Chung WH, Liou LB, et al. (2005). HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proceedings of the National Academy of Sciences, 102(11), 4134-4139. https://doi.org/10.1073/pnas.0409500102
7. McGrayne SB. (1998). Nobel Prize Women in Science: Their Lives, Struggles, and Momentous Discoveries. Joseph Henry Press.
The Drug Files is a series on the molecules behind modern medicine. Written by Seth Collins, PharmD.
She spent the intervening years working jobs that universities considered acceptable for women with chemistry degrees. She tested the acidity of pickles for the A&P grocery chain. She taught high school. She took a temporary lab assistant job at Johnson and Johnson that ended when the position was cut. The only reason Burroughs Wellcome opened a research position to her in 1944 was that the men they would normally have hired were in Europe and the Pacific. She walked in.
She would never receive a PhD. She started doctoral coursework at Brooklyn Polytechnic Institute in the evenings while working full-time, made progress for several years, and was then told she would have to attend full-time or leave. She left. By the time the decision could have been reversed, the work she was producing at Burroughs Wellcome was the kind of work doctoral programs typically produce.
Over the next four decades, her research group developed 6-mercaptopurine for childhood leukemia, azathioprine for organ transplant rejection (which made modern transplant medicine possible), acyclovir for herpes (the first effective antiviral drug in medical history), pyrimethamine for malaria, trimethoprim for bacterial infections, and the methodology her team would later use to develop AZT for HIV. Her direct supervisor George Hitchings was thirteen years her senior, was listed as senior author on most of the publications, and was referred to in industry shorthand as the leader of "the Hitchings group" for most of Elion's career. When the Nobel Prize in Physiology or Medicine was finally awarded for the methodology their lab had built, in 1988, Elion was seventy years old and had been retired from active research for six years. Somewhere in the middle of all of this, she had also produced the most widely prescribed drug for chronic gout management in the world.
Allopurinol exists because she was trying to make a cancer drug work better.
Gout has been documented in the medical record for more than two thousand years. Hippocrates wrote about it. Egyptian physicians described it. Medieval European medicine called it the king's disease, the inevitable consequence of organ meats and rich wine, a condition of wealth and excess. Colchicine had been treating acute flares since the Ebers Papyrus, but colchicine treats the inflammatory cascade after uric acid crystals have already formed. It does nothing about the underlying problem, which is that some people produce more uric acid than their kidneys can clear, and the excess deposits in joints as crystalline urate.
For most of medical history the chronic management of gout was dietary. Patients were told to avoid meat, avoid alcohol, avoid the foods physicians associated with the disease. This worked imperfectly. Uric acid production is influenced by diet but not determined by it. Patients with severe disease produced uric acid in quantities their kidneys could not handle regardless of what they ate, and the result was recurrent acute flares, progressive joint destruction, and tophi, the chalky urate deposits that erode bone and disfigure hands and feet over decades.
The biology of uric acid production sat unexplained until twentieth-century biochemistry mapped the purine metabolism pathway. Purines are essential components of DNA and RNA, and the body recycles them continuously. The final step in their breakdown is performed by an enzyme called xanthine oxidase, which converts hypoxanthine through xanthine to uric acid. In most mammals this is not a problem, because most mammals produce a subsequent enzyme called uricase that breaks uric acid down further into a soluble compound that passes easily into urine. Humans and great apes lost the uricase gene somewhere in primate evolution. Uric acid is our terminal purine metabolite. We produce it constantly, we have to clear it through the kidneys, and when production exceeds clearance we develop gout.
Elion was not trying to solve this. She was trying to solve leukemia.
She and Hitchings had developed a drug called 6-mercaptopurine in the early 1950s that worked against childhood acute leukemia. The problem was that the body broke 6-MP down quickly through xanthine oxidase, the same enzyme that produces uric acid. Patients metabolized the drug before it could finish its work. Elion's team needed to inhibit xanthine oxidase to keep 6-MP active longer.
They synthesized allopurinol in 1956 for exactly this purpose. It was designed as a structural analog of hypoxanthine, similar enough to occupy the active site of xanthine oxidase but different enough that the enzyme could not process it normally. It bound the enzyme and shut it down. 6-MP stayed active longer. The leukemia application worked.
Then Wayne Rundles, a hematologist at Duke University who was running the 6-MP trials, noticed something his patients were not supposed to be doing. Their uric acid levels were dropping. The xanthine oxidase inhibition designed to keep 6-MP active was also reducing uric acid production at its source. Patients with high baseline uric acid, including several with concurrent gout, were getting better gout control as a side effect of cancer treatment.
Rundles proposed running allopurinol as a primary gout drug, separate from any cancer indication. Elion and Hitchings ran the trials with him through the early 1960s, and the FDA approved allopurinol for gout in 1966.
Within a decade it was the standard of care for chronic gout management worldwide, displacing older drugs (uricosurics like probenecid) for most patients. It worked at the source rather than at the symptom. Colchicine fought the inflammatory cascade after crystals formed. Allopurinol stopped uric acid from being produced in problematic amounts in the first place. Together the two drugs converted gout from a slowly progressive disease that destroyed joints over decades into a manageable condition that responded to oral medication.
The methodological achievement is the part most people miss. Allopurinol was designed with its mechanism already in hand. That is not how drug discovery worked before Elion and Hitchings. Most drugs in human history were stumbled upon through plant medicine, accident, or large-scale random screening. Colchicine was used for three thousand years before anyone understood tubulin. Aspirin was prescribed for decades before the prostaglandin mechanism. The Elion-Hitchings methodology, which the Nobel committee eventually called rational drug design, treated drug discovery as an engineering problem. Study the biochemistry of the disease. Identify a specific molecular vulnerability. Design a molecule to exploit it. The pharmaceutical industry that exists today exists because of this approach. It was developed by a woman who could not be hired as a chemist for the first six years of her career.
There are two things worth knowing about allopurinol if you take it.
The first is that allopurinol itself is not the primary active inhibitor. The body converts allopurinol to a metabolite called oxypurinol, which has a much longer half-life and performs most of the actual enzyme inhibition. This was not fully understood when the drug was approved. It was worked out over the subsequent decades and explains why allopurinol works as a once-daily medication despite its own short half-life. The parent drug is essentially a prodrug. The metabolite does the work.
The second is more serious. A small fraction of patients develop a severe hypersensitivity reaction that can be life-threatening. The risk is dramatically higher in people carrying a specific HLA-B*5801 genetic variant, which occurs at substantially higher frequency in Han Chinese, Korean, and Thai populations. This genetic association has been clearly established since 2008. Screening for the variant before starting the drug is now standard practice in much of Asia. It is still inconsistently applied in the United States, which is worth knowing if you or someone in your family is from an at-risk population and is being started on allopurinol.
The drug is also used for Lesch-Nyhan syndrome, a rare genetic disorder in which patients produce massively elevated levels of uric acid from birth, and for tumor lysis syndrome in cancer patients, where rapid cell death from chemotherapy releases enormous quantities of purines that overwhelm the kidneys. Both applications derive from the same xanthine oxidase mechanism in different clinical contexts.
Gertrude Elion died in 1999, at eighty-one. By then she had collected twenty-three honorary doctorates from institutions that had not, when she was twenty-two, been willing to admit her as a candidate. The Nobel had come eleven years earlier, after most of her contemporaries had already retired or died. She was the first woman inducted into the National Inventors Hall of Fame. She had testified before Congress. She had lectured at every major medical school in the United States. She had mentored a generation of researchers at Burroughs Wellcome who carried her methodology forward into the work that produced AZT during the worst years of the AIDS epidemic, when the federal government was refusing to act.
She published her last paper in 1995, at seventy-seven.
When she gave her Nobel lecture in 1988, she spoke about what it had been like to be turned away from laboratories for being a woman, to work without a doctorate in a field that demanded one, to spend a career proving that the credentials she could not obtain were not the same thing as the work she could do. She also spoke about the patients. The leukemia children who had survived because of 6-MP. The transplant recipients who had lived because of azathioprine. The gout patients whose joints had stopped destroying themselves because of allopurinol. She had received letters from those patients for decades.
It is worth asking what the field of medicine lost during the six years when she was testing pickle acidity for the A&P grocery chain. How many drugs went unmade because the people who could have made them were not allowed into the laboratory? How many patients did not survive what she might otherwise have invented earlier? These questions do not have answers, but they are not rhetorical.
Allopurinol costs between four and fifteen dollars for a month's supply at most pharmacies today. It has been generic since the 1980s. The molecule is the same one Elion and Hitchings designed in 1956, and the mechanism is the same one they used to design it.
If you are paying significantly more than that, the difference is not the drug. The difference is the system stacked around the drug: the office visit required to get the prescription, the insurance gating, the pharmacy benefit manager negotiations, the brand-name markups for products that are pharmacologically identical to the generic. None of this has anything to do with what allopurinol costs to make, or with the chemistry Gertrude Elion did, or with the decades of patient lives the drug has changed.
Pillar Drug Club was built on the premise that the people who take these medications every year should understand what they are actually taking, and should not pay more than what the molecule itself costs to manufacture and dispense. If you take allopurinol, you are taking a drug built by someone the academic system rejected for being a woman, designed as a side project to a cancer treatment, approved for gout almost by accident, and held in continuous clinical use across six decades because nothing better has come along. The price you pay for it should reflect that history, which is to say, it should be cheap.
Sources
1. Elion GB. (1989). The purine path to chemotherapy. Science, 244(4900), 41-47. https://doi.org/10.1126/science.2649979
2. Elion GB. (1988). Nobel Lecture: The Purine Path to Chemotherapy. https://www.nobelprize.org/prizes/medicine/1988/elion/lecture/
3. Elion GB, Callahan S, Nathan H, Bieber S, Rundles RW, Hitchings GH. (1963). Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochemical Pharmacology, 12(1), 85-93.
4. Rundles RW, Wyngaarden JB, Hitchings GH, Elion GB, Silberman HR. (1963). Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Transactions of the Association of American Physicians, 76, 126-140.
5. Pacher P, Nivorozhkin A, Szabo C. (2006). Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological Reviews, 58(1), 87-114. https://doi.org/10.1124/pr.58.1.6
6. Hung SI, Chung WH, Liou LB, et al. (2005). HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proceedings of the National Academy of Sciences, 102(11), 4134-4139. https://doi.org/10.1073/pnas.0409500102
7. McGrayne SB. (1998). Nobel Prize Women in Science: Their Lives, Struggles, and Momentous Discoveries. Joseph Henry Press.
The Drug Files is a series on the molecules behind modern medicine. Written by Seth Collins, PharmD.
Tags
Issue 006
Allopurinol
Gout
Gertrude Elion
Drug History