Generally, our experience of a particular medicine is as a great faceless thing the name of which we do not know until we desperately need it, and the creation of which we assume is the end product of some unknowable corporate mixture of dark wizardry and exquisite micro pipetting. ‘Who made this?’ rarely crosses our minds, much less, ‘What did they sacrifice so that I might benefit from it now?’
Were we slightly more curious about these matters, we might find that a good number of the medications that save members of our species thousands of times over on a daily basis have their root in one remarkable human being: Nobel Prize winner Gertrude Elion (1918–1999). Her mind and approach to medical invention generated not only the first medication effective against leukaemia, but the first immuno-suppressing drug that allowed for organ transplants, the first drug to be effective against a virus, and an array of other compounds that fought (and continue to fight) gout, lupus, herpes, malaria and sepsis.
Her contribution to the betterment of human existence is truly incalculable, which is all the more amazing considering her late entry into pharmaceutical research. The daughter of Jewish immigrant parents, she grew up in an atmosphere where her love of learning and tendency to lionise the great scientific minds of the past were fostered and encouraged. She read Paul de Kruif’s Microbe Hunters, the 1926 classic that likewise inspired Jonas Salk in his choice of career, and knew that she wanted to find something new that might help people.
Her problem, however, was that of many talented young polymaths. Where ought she to concentrate her talents? She was just as quick at study of languages and history as she was of the natural sciences, and did not feel a definitive pull in any particular direction until her grandfather, whose attention and support had been so important to her as a child, fell ill with stomach cancer. At the time, she was a student at the City College of New York, which she had chosen because it was free and her family’s finances were all but wiped out during the Great Depression. She decided that chemistry, and in particular the connection between chemistry and disease, would be the main thrust of her life’s work.
Graduating in 1937 with highest honours, Elion set about the task of finding meaningful employment as a budding chemist during the long-lingering Depression, only to find all doors closed, not because no jobs were available but because no jobs were available for a woman chemist. As a result, one of the greatest scientific minds of her generation was compelled to fritter away seven long years in a series of secretarial, substitute teaching and flat-out temporary positions at anywhere that would take her. She did, however, manage to save up enough money as a result to attend graduate classes at New York University, gathering up the knowledge and experience that would prove essential when her nation was at last desperate enough to call upon her gifts.
The Second World War brought a whole new level of industrial-scale needs to the American landscape, needs which had to be filled by women if the requirements of intercontinental warfare were to be met. In such an atmosphere, it would have been odd for a single professional with Elion’s credentials to remain unutilised, but for two years, until 1944, that is precisely what happened. She was given laboratory work, certainly, but not precisely research of the first rank. Her first job was as a food tester for A & P grocery stores, checking vanilla bean freshness and pickle acidity, among other similarly workaday tasks.
After two years of that work, in which she learned how to use a variety of instruments but little else, she found work at Johnson and Johnson, but when she was offered a position as a suture tensile strength tester, she refused. Time was slipping through her fingers – nearly a decade had passed since her graduation and she was nowhere near realising the dreams of her youth or the vows she made by her grandfather’s deathbed.
A chance word from her father, however, placed her life suddenly on a brand-new trajectory. He was a dentist by trade, and one day he mentioned a company that had been sending him samples and which had a factory close to the family’s New York residence. The company was Burroughs Wellcome, founded in England in 1880 with the mission of discovering new drugs in the fight against humanity’s deadliest diseases. The company’s goal was original research, run by scientists who were given free rein to investigate whatever interested them. Elion invited herself over for an interview, secured a job, and began working under a scientist by the name of George Hitchings.
Together, Hitchings and Elion would revolutionise how new medicines are discovered, though the relationship was not always smooth. Hitchings could be egotistical and harsh, but he was also willing to let Elion follow her own instincts, and to place her name first on the papers announcing her discoveries (certainly not a universal practice, especially as regards women subordinate scientists in the early twentieth century). Hitchings was frustrated with the traditional approach to medicinal discovery, the random combing through nature for compounds that might, or might not, do something to some disease somehow. He wanted a more rigorous, biochemical-based approach, which looked at the life cycle of a disease and its chemical stages and crafted medications that interfered with that cycle without simultaneously interfering with the functioning of a human’s regular cells.
In Elion he found a perfect disciple, a scientist passionately and selflessly devoted to the eradication of disease, and willing to work appalling hours to determine the chemical cycles and metabolic processes of diseases in order to develop targeted medicines to combat them. He set her to work on purine research, which would dominate the first decades of her career. Purines and pyrimidines are the two types of bases that are found in RNA and DNA, and the cycle by which purines are degraded and recycled is central to the ability of any cell to function.
In the late 1940s, it was known that nucleic acids like DNA and RNA carried genetic information, and that purines and pyrimidines were important chemical components of nucleic acid structure, but that structure had yet to be fully elucidated by the work of Wilkins, Franklin, Watson and Crick in the 1950s. Elion’s task, then, was to determine the important intermediate chemicals in the life cycle of a purine, and to attempt to develop compounds that were like those intermediate chemicals (or that broke down into such chemicals), but chemically useless. The idea was that if you could flood a harmful cell with useless but similar versions of a chemical it needed to function, then it might be tricked into using those chemicals in place of the functional varieties, and would as such not be able to synthesise the basic compounds it needed to survive.
This was the compelling kind of work that Elion had dreamed of since her childhood, and it would ultimately bear the most rewarding possible results, but before she crossed the threshold into her years as a mature scientist, one terrible trial awaited her. She had been working on her PhD at the Brooklyn Polytechnic Institute for a number of years while simultaneously carrying out her research at Burroughs Wellcome when she was summoned by the BPI dean and told that, if she wanted to keep pursuing her PhD, she would have to quit her job at Burroughs. She was faced with a terrible decision – continue towards her PhD but at the cost of abandoning the meaningful work it had taken her so long to find, or leave BPI and thereby turn her back perhaps forever on the possibility of a doctorate. Would she always be treated as a subordinate, beneath consideration, if she did not have a PhD?
She decided to risk it. She abandoned a doctorate two years into the process and committed herself entirely to the creation of new drugs, and soon the discoveries began flowing from her laboratory in an unreal procession that proved the merit of the new metabolic-based techniques that she and Hitchings had been developing. In 1950, she took a critical component of a compound used in the formation of DNA nucleotides and replaced one of its oxygen atoms with a sulfur atom, creating 6-mercaptopurine (6-MP). 6-MP is converted in the cell into thioinosine monophosphate (TIMP), which is itself just one atom different from inosine monophosphate (IMP), a critical gateway compound in the recycling and creation of adenine and guanine, two of the major components of DNA.
6-MP, then, introduces a non-functional compound, TIMP, in place of the necessary compound, IMP, and thereby throws a wrench in the cycle of DNA formation, which is precisely the sort of thing one would like to do for cells that are multiplying beyond all reason and require large amounts of DNA to do so, i.e., cancerous cells. In 1950, if you were a child and had leukaemia, there was more than a 60 per cent chance that you would be dead within a year. Yet, 6-MP, given to child leukaemia patients, induced complete (though temporary) remission and on the strength of the preliminary data the drug was approved for release by 1953.
As it turned out, 6-MP by itself is insufficient to prevent relapse, as it needs to be combined in a cocktail with other drugs to target the cancer at several points, but in those combinations it is able not only to slow the progress of childhood leukaemia but to completely eradicate it in 80 per cent of cases.
Elion had found humanity’s first drug that effectively combated one of our oldest foes, but she was not one to rest on her laurels. She continued to tinker with 6-MP and in 1957 created a variant, azathioprine, to deal with one of 6-MP’s major shortcomings, the fact that it was broken down so quickly in the body. Azathioprine is not active until it is absorbed and slowly converted to 6-MP, thereby increasing the longevity of 6-MP within the relevant tissues. In 1958, a researcher named Robert Schwarz saw the potential of a purine-inhibiting drug like 6-MP to shut down the body’s immune response against transplanted organs, and visited Elion to see if she had a more potent version of it. She gave him azathioprine and in clinical tests it proved precisely what was needed to prevent organ rejection. In 1962, it was used in conjunction with prednisone in the world’s first successful kidney transplant operation, and was the central drug in organ transplants for the next two decades.
In 1967, Hitchings retired from Burroughs Wellcome and Elion had the chance to prove that her results were, in fact, the product of her own chemical insight. With characteristic daring, she decided to tackle a problem that the pharmaceutical industry had declared insoluble – developing an effective anti-viral medication. Two decades previously, in 1948, she had created a drug, aminopurine, before the discovery of 6-MP, that was effective against leukaemia but was so toxic it was not a feasible long-term treatment. It also had anti-viral characteristics, but at the time Elion was devoted to finding a leukaemia cure, and so let aminopurine lapse in obscurity until 1968, when she decided it might be a good starting point for developing the world’s first anti-virus drug. Over the coming years, Elion and her research team followed the same methods that Elion and Hitchings had invented two decades before – find something that works, investigate the chemical pathways that it partakes in, and produce variant compounds that target crucial parts in those pathways and just those pathways.
The result of their research, revealed to the world after years of secrecy in 1974, was acyclovir. It is essentially inactive until a virus invades a cell. Then, viral enzymes change it into a form that inhibits viral DNA polymerase, preventing the virus from producing more viral DNA and thereby from making copies of itself, without interfering in any way with the cell’s production of its own DNA. In effect, it tricks the virus into creating its own destroyer. It is cheap, non-toxic in most cases, and as of 2017 stands as the 166th most prescribed drug in the United States.
Elion retired in 1983, and in 1984 the team she had trained was responsible for the creation of AZT, the only drug available to treat AIDS until 1991. In 1988, she split the Nobel Prize in Physiology or Medicine with Hitchings and Sir James Black for their role in discovering new methods in the development of medications. Hitchings was none too thrilled to be sharing the award with somebody whom he considered to have been his subordinate, but the Nobel committee argued that her work after his departure in developing the world’s first anti-viral drug was a pretty good sign that she was at least an equal actor in the work Burroughs Wellcome did in the 1950s and early 1960s. Elion continued to act in an advisory capacity to Burroughs Wellcome as well as teach classes in methodology at Duke University after her official retirement. Her last paper was published in 1998, one year before her sudden death (after collapsing while out on her daily walk).
There are numbers that sum up Elion’s career – the forty-five patents, the over 231 scientific articles, the six decades of work, and there are numbers we can perhaps never calculate – the number of children cured of leukaemia, the number of lives saved due to a successful organ transplant, the number of people protected from opportunistic infections by an anti-viral drug, who owe their health to her dedication to investigating the fundamentals of biochemical interactions and her ability to see applications in new fields for variations of old compounds. She saw disease as a chain of chemical actions which could be tricked into self-termination by a sufficiently cunning series of cleverly disguised compounds, and spent her life getting the better of our most determined foes. Behind those drugs that save so many of us on a daily basis there was a determined and brilliant mind, and to that mind there belongs a face, one it is worth remembering, in times of sickness surely, but also in those of health.
FURTHER READING:
There is not yet, for variously unfathomable reasons, a full-length non-juvenile treatment of Elion’s life. Barring that, you can find a nice summary of her work in the as-ever indispensable Nobel Prize Women in Science by Sharon Bertsch McGrayne, and in various memorial articles written upon her death, such as the National Academy of Sciences biographical memoir by Mary Ellen Avery or the Royal Society biographical memoir published in Volume 54 in 2008.
Elion's story is also one of 140 stories of women in Medicine I told in A History of Women in Medicine and Medical Research, available on Amazon and from Pen and Sword books US or UK!
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