The contemporary treatment for leukaemia is complex and is also specific for each type of childhood leukaemia, and usually involves chemotherapy carried out in different stages. Certain features of a child’s leukaemia, such as the child’s age and initial white blood cell count, are used in determining the intensity of treatment that is needed to achieve the best chance for cure. Often many chemotherapeutic drugs are employed in the regime, each directed at a certain aspect of the disease. The drug 6-MP is still used in combination therapy for patients with acute lymphoblastic leukaemia.
Treatment options can include bone marrow transplantation, another medical breakthrough, from other donors or other unaffected bone marrow sites that may be within the patient’s body. In addition, blood products and antibiotics may also be administered to try to normalise abnormal blood component levels and reduce the risk of infection.[24] The goal is remission—no evidence of cancer cells in the body. Once remission has occurred, maintenance chemotherapy is usually used in cycles over a period of two to three years to keep the cancer from recurring.
The multiplicity of treatments is a testament to the cumulative work of innumerable researchers including Gertrude Elion and George Hitchings and theirs is one of the success stories in the anti-cancer crusade.
ELION AND HITCHINGS BROADEN THEIR FOCUS
Using the same principle that had made 6-MP possible, Elion and Hitchings began work on developing other drugs. During their research they discovered that another form of leukaemia could be treated with 6-thioguanine and that 6-MP had wider applications than they had first anticipated.[25] As the research led by Hitchings and Elion expanded at Burroughs Wellcome so did the number of scientists who were involved. Always quick to collaborate, Elion and Hitchings began working with Dr Joseph Murray, a transplant surgeon at the Peter Bent Brigham Hospital in Boston. They provided him with their compounds including 6-MP to see if they might have an effect on organ rejection.
Dr Roy Calne, a pioneer of transplantation surgery who had come from England to work with Joseph Murray at the laboratory at the Harvard Medical School, found a new use for 6-MP. Calne performed kidney transplants on dogs and found that 6-MP and its analogues prevented rejection of the new organ.[26] This showed that 6-MP could not only interfere with the multiplication of white blood cells, but could also suppress the immune system. Calne became a key figure in establishing life-saving transplantation as part of routine clinical practice through his work on drugs to suppress organ rejection. The understanding of immunological tolerance and rejection and the development of immunosuppressant drugs is what has made organ transplantation successful. Organ transplantation can give decades of nearly normal life to people who would otherwise die.
Apparently Hitchings and Elion became frequent visitors to Murray’s laboratory and were referred to fondly as the ‘two chemists from Tuckahoe’. The story goes that they got to know most of the lab dogs by name. There is a photograph of Gertrude Elion on the front steps of the Harvard Medical School with Roy Calne, George Hitchings, Joseph Murray, two other doctors and the dogs Tweedledum, Tweedledee, Titus, and Lollipop, the last dog being the recipient of the first successful kidney transplant made possible by 6-MP.[27]
The discovery that 6-MP was an immunosuppressant led the Hitchings team to a new drug, azathioprine (Imuran), which although it was not effective against cancer cells advanced the field of organ transplantation for humans. Imuran suppresses the immune system by interfering with the growth of T-lymphocytes, the specialised white blood cells that are one of the main instigators of the rejection process, when the immune system reacts to the transplanted organ as if it were a harmful foreign invader.[28] This was, in fact, a great leap forward for medical science and suppression was to have huge implications for future developments in surgery. Imuran was one of the drugs Elion had synthesised while trying to improve upon 6-MP. Once again the prescient words of Pasteur are resurrected. In the case of Imuran chance did favour the prepared mind. Late in her career Elion pointed out that she had not on this occasion set out to rationally design a drug that would work as an immunosuppressant but, if ears and minds are open, then great advances can happen.
For the first time in history, patients could receive organ transplants without their bodies rejecting the new organs. The first successful kidney transplant had taken place between identical twins in Boston in 1954 but rejection thwarted all transplants other than those between twins. With Imuran, Joseph Murray performed the first kidney transplant between unrelated individuals in 1961 and it has remained an essential anti-rejection drug that people take after transplantation. Imuran is now used with prednisone and cyclosporine which all work in slightly different ways thus causing fewer side-effects.
Developments in drug design led to Roy Calne and his team pioneering the use of cyclosporine A, a drug so successful in preventing rejection that transplantation of hearts, livers and lungs became common. In 1990, when Joseph Murray was awarded a Nobel Prize, in his address he noted that more than 200,000 kidney transplants had been performed worldwide.[29]
***
In the 1960s Elion and Hitchings shifted their research to nucleic acid formation in lower animals and the differences between these processes in animals and in people. For the dynamic duo the swinging sixties became a roller-coaster of rational drug design. They determined that infectious diseases could be fought if drugs could be targeted to attack bacterial and viral DNA. This work resulted in pyramethamine, used to treat malaria, and trimethoprim (Septra) used to treat meningitis, septicaemia and bacterial infections of the urinary and respiratory tracts.[30] Allopurinal, another relative of 6-MP, was developed in Gertrude Elion’s lab and apart from being a treatment for gout it also proved effective for use during chemotherapy.
As a result of these overwhelming successes Hitchings became Vice President of Research at Burroughs Wellcome in 1967, a promotion that effectively ended his hands-on participation in research. Elion was promoted as well, to head of the Department of Experimental Therapy. In this position she was a ‘great minds magnet’, attracting young and gifted scientists to Burroughs Wellcome who became known as a research ‘dream team’.[31]
Despite her new responsibilities, Elion did continue her research work and was involved in the development of acyclovir, an antiviral drug effective against herpes. Originally acyclovir was synthesised by Dr Howard Schaeffer but Elion was instrumental in determining exactly how and why it worked. Acyclovir, marketed as the well-known Zovirax, interferes with the replication process of the herpes virus, but only the herpes virus, thus proving that drugs can be selective. It was the development of acyclovir that eventually led to the development of azidothymidine (AZT) by Elion’s colleagues, one of the very few drugs that has any effect on AIDS.[32]
In 1970, the Wellcome laboratory moved to Research Triangle Park in North Carolina and both Gertrude Elion and George Hitchings moved too. In the 1970s George Hitchings made a life-changing decision when he resigned from his job as a scientific director at Burroughs where he had spent most of his long and productive career. He did stay on as a research scientist, back to the coalface in a way, but he now had more time to devote to his own pursuits inside and outside the laboratory, particularly philanthropic work. Hitchings was committed to promoting research, and as one of the leaders of the charitable Burroughs Wellcome Fund, he helped support the medical research of other scientists. His concern for people extended beyond their physical wellbeing and in 1983 Hitchings founded the Triangle Community Foundation which not only provided healthcare to the poor but assisted in protecting battered women and gave disadvantaged children greater opportunities.[33]
Gertrude Elion retired in 1983, eight years after Hitchings, with the status of scientist emeritus. For the next sixteen years she remained active as an advisor to many professional organisations and as a consultant she maintained her association with her former employer, Burroughs Wellcome, while holding adjunct professorships at Duke University, the University of
North Carolina and Ohio State University. Indefatigable, she served on advisory committees for the National Cancer Institute, the American Cancer Society, the Leukemia Society of America and the tropical disease research division of the World Health Organization.[34] It could all have been so different. Whatever project she worked on, Gertrude Elion remained involved in the investigation of her old favourites, purines and purine analogues as chemotherapeutic agents and she continued to publish her findings throughout her life. Her first article had been published in 1939 and her last, in 1998, the year before her death. Elion admitted that work had become her vocation and she never felt a need for outside relaxation. But there were pastimes that she enjoyed—photography, travel and music, especially Puccini, Verdi and Mozart operas.
There were so many synergies between Gertrude Elion and George Hitchings. Like Hitchings, Elion was passionate about the importance of research. Every year after her retirement she would share her knowledge by mentoring a third-year medical student at Duke University. ‘I think it’s a very valuable thing for a doctor to learn how to do research, to learn how to approach research, something there isn’t time to teach them in medical school.’[35] When visiting academic institutions she often preferred spending time with students rather than their teachers. Gertrude Elion and George Hitchings were cut from the same cloth. Both were devoted to improving the wellbeing of humankind and both were selfless in doing so.
ACCOLADES AND AWARDS
In 1988 Gertrude Elion and George Hitchings shared the Nobel Prize in Physiology or Medicine for their work on drug design with a third scientist, Sir James Black, who did seminal work which led to beta-blockers for cardiovascular disease and to H2-antagonists for peptic ulcers. The Nobel Committee noted that the prize was awarded for their discoveries of ‘important principles for drug treatment, principles that have resulted in the development of a series of new drugs’. Jon Elion, one of Gertrude’s nephews, recalled the Nobel festivities in Stockholm. All the laureates and officials, who were seated on the stage, were men and all were dressed in their formal black suits and ties and white shirts. Elion described fondly how his aunt stood out in what he called her ‘Trudy blue chiffon dress’.[36]
Gertrude Elion expressed how she felt about receiving the Nobel Prize in a lecture she often gave afterwards to students. What thrilled her more, she said, was that her work led to the discovery of drugs that saved people who might otherwise have died from diseases such as leukaemia, kidney failure and herpes virus encephalitis. To Gertrude Elion, the Nobel Prize was only ‘the icing on the cake’. She was often asked if the Nobel Prize was what she had aimed for in life. Her answer was that if getting an award was someone’s goal in life and they did not achieve that goal, then their life would be negated. She never lost her original motivation, no matter how hard the road or how much success she achieved. What she and George Hitchings aimed for was to make people well, to save them from life-threatening diseases and that brought infinitely more satisfaction.
I think I’m most proud of the fact that so many of the drugs have really been useful in saving lives. I’ve run into people whose lives have been saved, and the kind of satisfaction that you get from having someone come up and say, ‘My child had acute leukemia and your drug saved him.’ Or, ‘My little girl had herpes encephalitis, and she is now cured, she is back at school. She is doing very well. People told me that she might be mentally affected, but she is not.’ I run into people who have had kidney transplants for twenty years who are still taking the drug. And I don’t think that anything else that happens to you can match that type of satisfaction.[37]By all accounts Gertrude Elion did not trade on her celebrity. In the customs hall, after flying back to America from the awards ceremony in Stockholm, she was asked by a customs official if she had any jewellery to declare. Jokingly she pulled out the Nobel Prize medallion.[38] This seems totally in keeping with a woman who was described variously as direct in manner, vigorous in debate, generous in crediting others for their achievements and wholly unpretentious. In fact there were many people with whom she collaborated and who contributed to the evaluation of her drugs, including Joseph Burchenal at Sloan Kettering Institute in New York; Roy Calne, the English surgeon from Cambridge; Joseph Murray at Harvard; and Dr Robert Schwartz and William Damashek at Tufts University in Boston who pioneered the use of 6-MP with patients.
George Hitchings, for his part, was surprised when he won the Nobel Prize. He had already received many other awards for his contribution to humankind—devising rational drug design. At 83 years of age, however, he thought he was too old to be considered for the Nobel although he was still hard at work for science and philanthropy as president of the Burroughs Wellcome Fund. Hitchings regretted that his wife of 52 years, Beverly Reimer Hitchings, could not be by his side when he received the award. Beverly had passed away in 1985.
In September 1988, shortly before the announcement of the Nobel Prize, Hitchings met Joyce Shaver, who was 26 years his junior. They were married in February 1989, after attending the award ceremonies in Stockholm together with members of Hitchings’ family and a man whose cancer had been cured by a drug that Hitchings developed.[39] In an interview just before her husband died, Joyce Shaver gave some insight into what the Nobel Prize meant to Hitchings. On the day he was presented with the award Hitchings said that the real gift was not the prize itself but the individual people whom his medicines had helped. It would come as no surprise that Hitchings gave all of his prize money to the Triangle Community Foundation.
After winning the Nobel Prize, Hitchings continued to travel and lecture. During his lectures, apparently, he would always show his favourite slide of a beautiful young Pakistani woman in her wedding dress. He would then tell the story of how her life had been saved by a free sample of an antibiotic that Hitchings had developed and that a Burroughs Wellcome salesman had left with her doctor.[40] Every life was precious to Hitchings and he too had never lost sight of his goal to help humankind and cure disease. During his 30-year career Hitchings had developed and patented 85 different drugs.
The woman who had begun as George Hitchings’ assistant and who became his respected colleague, Gertrude Elion, was the holder of 45 patents herself as a result of the discoveries she had made. Elion had synthesised and co-developed the first successful drugs for the treatment of leukaemia—thioguanine and mercaptopurine—as well as azathioprine (Imuran), which not only prevented the rejection of kidney transplants but was a treatment for rheumatoid arthritis; she had played a major role in the development of allopurinol, the treatment of gout, and acyclovir, the first effective treatment for herpes virus infections.
The first major award Elion won for this seminal work was the Garvan Medal in 1968 and she was thrilled to receive it.[41] The Garvan Medal, however, was the only American Chemical Society prize for which she could compete. Until 1980, women were ineligible for any other ACS awards. The Garvan Medal was established in 1936 to recognise outstanding US women chemists. Other awards did follow and in 1991 Gertrude Elion received a National Medal of Science, which was presented to her by the President of the United States. Elion did not rest in her retirement and continued her association with a plethora of academic societies and in 1991 she was elected to the Institute of Medicine.
Ironically, Gertrude Elion never completed her PhD. At the time that she had been forced to make the choice between her job and further study, Hitchings had assured her that she would not need the degree to do the work that she was doing with him at Burroughs Wellcome. And she didn’t. In the 1950s when Hitchings successfully sponsored her before the American Society of Biological Chemists, he dismissed any objections to her election before they arose. He summed up the situation Elion often faced when, according to Elion he quipped, ‘I know she has three strikes against her. She doesn’t have a PhD, she is a woman, and she works for industry. Nevertheless, I am going to tell you about her.’[42] There was certainly a lot to tell and the society need not have worried about Elion’s academ
ic qualifications. During her career she was awarded 23 honorary degrees which included not just one, but three PhDs.
Both scientists, Gertrude Elion and George Hitchings, had long and distinguished careers spanning more than half a century and their work was prodigious. But fate dealt a cruel hand to George Hitchings in the end. He became blind and he developed Alzheimer’s disease. Although he was well advanced in years, it is a tragedy for a great mind to be destroyed in this way. Today in laboratories throughout the world scientists like Hitchings are seeking a cure for Alzheimer’s, which is becoming an increasing problem as more of us live longer thanks to the myriad medical advances that have been made since Edward Jenner produced the first vaccine. There is something very paradoxical about this.
George Hitchings died on 27 February 1998. Almost a year later on Sunday, 21 February 1999, Gertrude Elion collapsed while out on her daily walk. She was taken to the University of North Carolina Hospital and died at midnight. She was 81 years old. Unlike her dear colleague, Elion’s mind was as sharp as ever. Only a week before her death she had participated in a project team meeting at GlaxoSmithKline discussing the development of a new cancer drug called Arranon .
Fifty-five years after she synthesised the first of her drugs and six years after her death, Elion’s legacy was evident when Arranon was licensed in the United States in late 2005. It was the product of many hands and minds. The drug has a role in treating certain rare forms of leukaemia and lymphoma when patients have exhausted standard treatment options. In the early 1980s Elion knew that among the compounds her laboratory had synthesised over the years there might be other things that would work against leukaemia or lymphoma. She had given two glass vials with black tops to Joanne Kurtzberg, a specialist in paediatric oncology at Duke University Medical Center.[43] In one of the vials was a precursor of Arranon .
Smallpox, Syphilis and Salvation Page 33