Apart from the personal challenges, there were other hurdles to face. After college, Elion knew that she needed to have a PhD if she wanted to proceed with her ambition to do laboratory research but her family could not afford to send her to graduate school. Despite her excellent academic record she was unable to get either a graduate fellowship or assistantship, so she did what many women were forced to do at a time in history when the glass ceiling was barely above the floor, and that was to look for a job in which her talents would be squandered. Elion described the experience as hitting a brick wall. She said that nobody took her seriously: ‘They wondered why in the world I wanted to be a chemist when no women were doing that. The world was not waiting for me.’[8] Things were doubly tough because jobs were scarce during the Depression and the few positions that existed in laboratories were not considered ‘women’s jobs’.
With little choice open to her Gertrude Elion embarked upon a more traditional career, but clung desperately to her goal. To get some practical skills she enrolled in a secretarial school and took on temporary work. She taught biochemistry to nurses in the New York Hospital School of Nursing for three months. Then by chance, she met a chemist who needed a laboratory assistant, and even though he was unable to pay any salary initially (not uncommon during the Depression), Elion stayed for a year and a half and gained valuable experience. Over this time she did begin to earn a wage and, using her meagre savings and some financial assistance from her parents, she was able to enter graduate school at New York University in 1939.
Gertrude Elion was a rarity, the only female in her chemistry class. Her recollection, however, is that she was accepted by her male classmates and did not feel out of place. Within a year Elion had completed the prerequisite courses to begin research for her Master’s degree. But there were bills to pay while she was studying and for two years she worked as a substitute teacher in secondary schools in New York City teaching chemistry, physics and general science and she also had a part-time job as a doctor’s receptionist. This left the evenings and weekends for research and study at New York University. Against the odds Gertrude Elion obtained her Master of Science degree in chemistry in 1941. World War II was ravaging Europe, and in December when Pearl Harbor was bombed by the Japanese, America joined the war. As the United States geared up for the war it entered a new era of economic prosperity and the Great Depression came to an end.
The war changed many things. Men were required in the armed services and suddenly there was a shortage of industrial chemists. Elion was finally able to get a job in a laboratory. It was not in research but it was in a lab. World War II made a difference to the thwarted aspirations of many women in countries like the United States, Britain and Australia. Unexpectedly women found themselves with careers that had previously not been an option for them. As more and more men enlisted, women filled the jobs that they vacated. Gertrude was hired as an analytical chemist for a major food company—a far cry from the groundbreaking medical work that she was destined to do. Her job included tasks such as measuring the acidity of pickles, testing the colour of mayonnaise and ensuring that the berries used in the manufacture of jam were not mouldy.[9] It’s a job that someone had to do.
It is hardly surprising that after a year and a half Elion became restless with the repetitive nature of the work; the only compensations were that she was using some of her scientific skills and learning a lot about instrumentation, but she must have felt that her brain was atrophying. In the end, the job was simply too mind-numbing for a woman of Elion’s intellectual capacity and she decided to make a move. Through an employment agency she applied successfully for a research job in pharmaceuticals at Johnson & Johnson in New Jersey, but even here the work was not all she had hoped for. Instead of synthesising medicines her time was mostly taken up with checking the strength of sutures.
In 1944, after Elion had been working in the laboratory for about six months it was disbanded. That was the bad news but the good news was that she was offered a number of positions in other research laboratories. The one which intrigued Elion most was a position as a biochemist assisting George Hitchings at the Burroughs Wellcome pharmaceutical company. The Wellcome Research Laboratories were located in Tuckahoe in New York. Elion suddenly found herself researching the metabolism of nucleic acids—the material that determines the genetic make-up of a cell and directs the process of protein synthesis—with a view to making substances that could attack diseases. This was a far cry from measuring the acidity of pickles.
In her autobiography, Gertrude Elion explained that she was not entirely sure what Hitchings was doing. She said that Hitchings ‘talked about purines and pyrimidines, which I must confess I’d never even heard of up to that point, and it was really to attack a whole variety of diseases by interfering with DNA synthesis’.[10] This all sounded extraordinarily exciting to Gertrude Elion and accorded with her mission to use science to fight disease.
The lifelong professional relationship between Hitchings and Elion would prove to be profoundly productive and successful. Elion was eager to learn and Hitchings was prepared to give her more responsibility than she thought herself ready for. Hitchings was impressed with his new assistant. He found her intelligent, hard-working and ambitious, the perfect combination for the ‘left-field’ research he was determined to do. Gertrude Elion had a real career at last, a career that took her from organic chemistry into the realms of microbiology, pharmacology, immunology and virology. Gertrude Elion would spend the next 39 years at Burroughs Wellcome, reaching the position of head of the Department of Experimental Therapy in 1967.
These two great minds were able to carry out all of their iconic work at Burroughs Wellcome, a British pharmaceutical company now known as GlaxoSmithKline. Times had changed and medical and scientific research were no longer the preserve of universities. Throughout the twentieth century drug companies became more and more involved in research. Today billions of dollars are at stake.
When George Hitchings joined Burroughs Wellcome in 1942 as a biochemist, after working for nine years in temporary positions at the Harvard School of Public Health and other universities, he finally found an environment in which he could conduct the research he wanted to do and this was a rare privilege. In 1944 when Gertude Elion began working with Hitchings, the two had no idea that they were about to embark on a pioneering scientific journey that would lead to cures for many diseases.
MAKING FALSE DNA BUILDING BLOCKS
The death of a close family member, combined with an abiding passion for science, similarly led George Hitchings to a career in the medical and chemical sciences. Hitchings was born on the Olympic Peninsula in Washington State in 1905. Because George’s father was a shipbuilder the family moved often from one place to another along the coast during George’s early years. Sadly, when George was only twelve his father died. It was a prolonged illness and this tragic experience turned the boy’s thoughts towards medicine.
Hitchings was unequivocal about the direction his life should take. He later explained that his determination to help save lives was all-consuming, even shaping his selection of courses at Seattle’s Franklin High School. Hitchings demonstrated his early resolve by focusing on science subjects and as salutatorian at his class graduation he chose the life of Pasteur as the subject for his oration.[11] The combination of Pasteur’s basic research principles and using science to achieve practical results for the common good remained a goal for Hitchings throughout his career. Gertrude Elion had also been influenced by Pasteur. While at school she had read Paul DeKruif’s Microbe Hunters and was fascinated by the achievements of Edward Jenner, Paul Ehrlich, Louis Pasteur and others in chemistry, physics and biology. She and Hitchings in their own way were to join the cohort of microbe hunters.
The next step for Hitchings was to enrol in a chemistry degree, which he did at the University of Washington in 1923. He followed this with a Master’s degree, which he began in 1928, and a PhD in biochemistry at Harvard, which he finish
ed in 1933. It was at Harvard that Hitchings became interested in research into the metabolism of nucleic acids, which we now know are the building blocks of DNA. His work centred on what to the lay person sounds arcane—the analytical methods used in physiological studies of purines, which are a class of compounds. In the same year that he was awarded his PhD, George Hitchings married Beverly Reimer, a woman he described as highly artistic, intelligent and empathetic but who was able to make accurate intuitive appraisals of people.
It is amazing to think that at the time Hitchings began his research into nucleic acids, the eventual discoverers of the DNA structure knew nothing about the subject. James Watson was three years old at the time and Francis Crick was a student at Mill Hill School in North London.[12] So in the 1930s nucleic acids were not considered to be a critical field in scientific research, ironically because not enough was known about them. This made it difficult for Hitchings to find a permanent appointment at an institution where he could indulge in this research. Hitchings was a little ahead of his time, and times were even tougher because the Great Depression had taken hold. Consequently George Hitchings wandered in the wilderness for the next nine years, going from one temporary position to another but wherever he went Beverly went with him. Hitchings worked at various universities including Western Reserve University (now Case Western Reserve) and the Harvard School of Public Health. When Hitchings joined Burroughs Wellcome in 1944 he too felt that at last his career had begun. He was able to concentrate his investigative energies on the metabolism of nucleic acids, the molecular carriers of genetic information.
Hitchings had been evolving the idea that it should be possible to make drug discovery more rational, less ‘hit and miss’. Although he was not entirely sure at the time how it could be achieved, the recent development of sulfa drugs that could interfere with the metabolism of microbes led Hitchings to believe that other substances could do the same. It was in that year that Oswald Avery at the Rockefeller Institute published a paper suggesting cautiously that deoxyribonucleic acid, DNA, was genetic material.[13] It was another nine years after this that Watson and Crick at Cambridge University discovered the double-helix structure of DNA, revealing how genetic information might be copied during cell replication.
In their work together George Hitchings and Gertrude Elion devised something akin in its conception to Emil von Behring’s Blood Serum Therapy and Paul Ehrlich’s ‘magic bullets’. Their brainchild was ‘rational drug design’, which meant doing things opposite to standard practice. Rational drug design was a controlled scientific process for creating new drugs by designing new molecules with specific molecular structures that would inhibit the replication of rapidly dividing cancer and bacteria cells in specific diseases rather than discovering new drugs and then trialling them against different diseases. Target the disease and design the drug accordingly.
Elion described the ‘rational drug design’ process as letting the drug lead the scientist to the answer that nature was trying to keep hidden.[14] This ingenious idea and the work that followed led to the development of the ‘designer drug’ 6-MP, their weapon against childhood leukaemia. Hitchings hypothesised that rapidly dividing cells like bacteria and cancer cells had to be making lots of nucleic acids, therefore it might be possible to stop the growth of these cells with ‘antagonists’ to the purine and pyrimidine bases, antagonists being the drugs that Elion and Hitchings would make through rational drug design.[15] The idea was that synthetic chemical compounds would be similar to the natural ones and would interfere with the body’s DNA production. They would be similar enough to those in nucleic acids so that they could integrate themselves into natural metabolic pathways. Once there, these ‘antimetabolites’ would be different enough to shut things down by interfering with the metabolism of nucleic acids, in particular purines and pyrimidines. It is this sort of science that is inconceivable to the non-scientific mind. The antimetabolites would look like the real thing but would be fake, the art-world equivalent of copying a masterpiece and tricking even the experts. They would make false DNA building blocks.
George Hitchings began examining nucleic acids, which are now known as DNA and RNA. Gertrude Elion was assigned to investigate and synthesise a large number of purines, including adenine and guanine. To find out how to make compounds she would go to the library and look up scientific literature, work out how to do it and then make them.[16] The next job, because so little was known about DNA and therefore nucleic acid structure and function, was to find out if the compounds actually did anything. For Hitchings and Elion it was like feeling their way in the dark. What they soon discovered was that without the presence of certain purines bacterial cells could not produce nucleic acids. So work began on the antimetabolite compounds that locked up enzymes necessary for the incorporation of these purines into nucleic acids. Elion later explained that when a microorganism like Lactobacillus casei was put in a defined medium, it was possible to tell if something was a real growth antagonist when it was added. Then it was necessary to analyse why it was an antagonist. ‘We knew that this organism would grow and from that it could make DNA and folic acid,’ she explained. She extrapolated:
You could make everything just from the amino acids, medium, and folic acid, and so on. We knew folic acid was essential, or if you could replace folic acid with a purine, it would grow ... It would make lactic acid. If the organisms didn’t grow, we knew we had something and we might be antagonising folic acid or it might be antagonising the purine. So you could with that one organism really make an analysis of three different kinds. You could add purine or folic acid and reverse the antagonism.[17]While Gertrude Elion was immersing herself in microbiology and synthesising compounds her ambition to get a doctoral degree was reignited. She began studying at night at the Brooklyn Polytechnic Institute, but after several taxing years of commuting, studying and working, she was informed that if she wished to continue she would have to convert to a fulltime program. Elion had come to a crossroads in her life and was forced into making a critical decision—stay with Hitchings and the job she found stimulating and fulfilling or commit entirely to the academic studies that meant so much to her. She stayed, and countless numbers of people have benefitted from what must have seemed an enormous sacrifice at the time.
***
In 1948 Hitchings and Elion found that a synthetic purine derivative, diaminopurine, inhibited the growth of bacteria. They tested it on the growth of mouse tumour cells and leukaemia cells in tissue culture and found that it did in fact inhibit growth.[18] The following year Joseph Burchenal at the Sloan Kettering Institute in New York used diaminopurine to treat four patients with chronic granulocytic leukaemia, two of whom went into remission, giving them and the researchers great hope. However, the other two patients improved initially but relapsed later and experienced severe bone marrow suppression. The results indicated that diaminopurine had toxic effects.
It was her disappointment over the failure of diaminopurine as a reliable cure for leukaemia that took Elion to the next phase of her research. The rigour she and Hitchings applied to their task is certainly reminiscent of Paul Ehrlich in his search for compound 606. By 1951 they had made and tested over 100 purine analogues, including diaminopurine and thioguanine. They found that the enzymes latched onto both of these analogues instead of adenine and guanine and both had activity against a wide variety of rodent cancers and leukaemias. It was in 1952 that Elion substituted an oxygen atom with a sulfur atom on a purine molecule and so created 6-mercaptopurine, a purine derivative also known as 6-MP.[19]
This new material, 6-MP, became the first purine antagonist to be useful in the treatment of acute lymphoblastic leukaemia in children. At that time children were treated with steroids and methotrexate but most survived only for a few months. Approximately 3 per cent survived for around a year. Children given the new drug went into complete remission. No abnormal cells could be detected in the bloodstream. The median survival time was extended to one year and a f
ew patients actually stayed in remission for years afterwards.[20] In 1999 when discussing her reaction to seeing leukaemia patients in remission due to her drug, Gertrude Elion said, ‘The first time that I went to the leukaemia clinic at Sloan Kettering, and saw the first children who had been treated with 6-mercaptopurine, who were in remission, I can remember then the feeling of, we’ve really done it, it really works.’[21]
The success of the drug 6-MP seemed miraculous and was reported in the press. Excitement about the designer drug was so great that within days the US Food and Drug Administration approved 6-MP for use late in 1953, only ten months after clinical trials began.[22] Sadly, though, there was a repetition of what had happened with diaminopurine and some children, after first improving, relapsed and died. What Elion had showed, however, by synthesising 6-MP, was that small changes in a compound that was essential to cell division could chemically ‘fool’ the malignant cells and thereby combat them. Elion decided to examine everything about 6-MP, devoting the next six years of her life to this research. As a result, by the 1980s an 80 per cent cure rate for childhood leukaemia was achieved using 6-MP in combination with one or more of about a dozen other drugs that act against leukaemia with a continuation of drug therapy during remission.[23] This method of treatment cures the majority of cases today, something that was beyond reach before Elion and Hitchings devised rational drug design.
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