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75th stories: Rational drug design – Gertrude Elion and George Hitchings

16 Jun, 2011
George Hitchings and Gertrude Elion.

George Hitchings and Gertrude Elion. Credit: Wellcome Library

To mark the 75th anniversary of the death of Henry Wellcome and the founding of the Wellcome Trust, we are publishing a series of 14 features on people who have been significant in the Trust’s history. In our eighth piece, science writer Jon Turney looks at Gertrude Elion and George Hitchings, who shared a Nobel Prize for their rational drug design work at the Burroughs Wellcome Research Laboratories in the USA.

When Sir Henry Wellcome died in 1936, he left two legacies: his pharmaceutical company, the Wellcome Foundation, and his charity, the Wellcome Trust, which was the sole shareholder of the company. A decade later, however, and these legacies were in jeopardy. During World War II, the UK company had focused on supporting the war effort, and had suffered a punishing war tax regime. It was nearly bankrupt.

The company’s fortunes had a direct impact on the Trust, which relied on a dividend from the company to fulfil its charitable objectives of supporting research to improve human health. In its first 20 years, the Trust’s total charitable expenditure was only £1.17 million.

That the company survived at all was due to the US side of the operations. Run as an independent subsidiary, the Burroughs Wellcome company remained profitable during and after the War and could prop up its UK parent. And it was the US side that drove the growth of the company over the next few decades. A whole new generation of drugs emerged from a programme developed by two chemists, George Hitchings and Gertrude Elion, who worked steadily from the 1940s through to the 1980s, and earned Nobel honours in 1988 for their discoveries. Along the way, they produced a stunning array of landmark therapies. They included products effective against agents that medicine had previously been helpless to combat: viruses. In the 1980s and 1990s, two of those antivirals took the company into the billion-dollar league.

So valuable did the company become that when the Wellcome Trust floated the shares on the stock market in 1986 and sold them over the next 15 years, diversifying its assets, it became the world’s largest medical research charity at the time.

Starting out

If you had to pick a moment that was important for improving the Trust’s future prospects, a good choice would be the day in 1942 when George Hitchings reported for work at Tuckahoe, New York. Burroughs Wellcome & Co. had opened its offices in New York in 1906, and moved to new premises for manufacture, packaging and research in Tuckahoe in 1925. From 1945 it was led by William Creasy, largely credited with saving the Wellcome Foundation financially after the War.

Hitchings, fresh from a fellowship at Harvard, was the newly recruited head of the biochemistry department – and also its sole member. But, he recalled, the job had a crucial ingredient: “Support was limited, but I was free to develop my own programme of research.” Hitchings had a clear vision of how this programme might develop. He believed in a new approach to pharmaceutical research: rational drug design.

The classic method of drug development was to make many compounds, and screen them for biological activity, using a fast-reproducing organism such as a bacterium. That was what pioneer drug researchers did, generally working doggedly on one disease at a time. Today’s rational drug design entails pinpointing a particular protein as the target. When the precise three-dimensional structure of the enzyme is known, the drug can be designed to dovetail with the shape the structure reveals.

Hitchings had no enzyme structures, but picked up on one of the earliest formulations of rational drug design, the ‘antimetabolite’ strategy. Investigation of the first class of antibiotics, the sulfonamides, showed that they blocked bacterial use of an essential metabolic chemical, para-amino-benzoic acid. By 1940, this finding was cited by Paul Fildes of the UK’s Medical Research Council, among others, as inspiration for “a rational approach to chemotherapy”. Focusing on antibiotics, he suggested that “an antibacterial substance should be capable either of combining with an essential metabolite to form a product devoid of the essential metabolic function, or of blocking an enzyme specifically associated with the metabolite”.

On that basis, the kind of substance to look for followed logically. Fildes again: “It is to be expected that the antibacterial substance should have a chemical similarity to the essential metabolite.”

Hitchings chose to investigate the nucleic acids, RNA and DNA, and their components. The precise role of these two vital cellular constituents was not yet known – the structure of DNA, revealing the way its chemical code allows the storage and copying of genetic information, was not uncovered until 1953. But Hitchings did know that cells could not reproduce without DNA and RNA, and that they were large molecules made up from simpler chemical units. It was those simpler chemicals – purines and pyrimidines – he turned his lab’s attention to.

Purines and pyrimidines, both of which feature ring structures, are not only subunits of DNA: they also furnish ‘high-energy’ intermediates that allow the cell to move energy from where it is liberated in chemical reactions to where it is needed. Both types of base feature ring structures, and many different variants of these bases are used by cells – some variants with different atoms in the rings, others with chemical groups added onto the rings.

Hitchings’s idea was that certain variants would interfere with cells’ normal systems and stop them reproducing. For normal human cells, this could be toxic. But rapidly reproducing cells, such as bacteria, might be more seriously affected. And cancer cells also reproduce faster than most body cells, so exploring the chemical variants of the bases might generate potential anticancer agents as well. It all hinged, as Hitchings and Gertrude Elion later put it, on finding compounds that would fool the cells’ machinery – they were looking for a “rubber doughnut”.

New recruit

Gertrude Elion, who joined the lab in 1944 on $50 a week, brought in more chemistry expertise. Her career had a faltering start after she graduated, but the War made employers overcome some of their reluctance about hiring women scientists. Even so, she had been getting by doing food safety analyses. She lacked a PhD, and never got round to completing one, but joining Burroughs Wellcome was her chance to do real research.

The rational search strategy for new drugs still turned into a long slog at the bench. “At the beginning,” she recalled, “it was my job to find out how to make compounds. So I’d go to the library, look up the old literature to see if I could figure out how to do it…I would just go ahead and make the compounds, and then the question was, well what do we do with these compounds? How do we find out if they really do anything?”

To test whether the new compounds were active was the next problem. The team settled on a microbial system as a screening aid. Lactobacillis casei, a harmless bacterium used for making cheddar cheese, can grow on defined mixtures of purines and on some of their metabolic precursors. New compounds added to the growth medium in culture sometimes enhanced growth, sometimes inhibited it.

Elion explained that “you could throw it in a defined medium and you could tell when you added something that was a real growth antagonist, then analyze why it was an antagonist. We knew that this organism would grow and from that it could make DNA and folic acid…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 antagonizing folic acid or it might be antagonizing the purine. [We] didn’t know the structure of DNA, because nobody did at the time, but [we] knew what the building blocks were, and so we were starting really at the very basic portion of the DNA and saying we don’t know how it gets to be DNA…but let’s find out how we can deal with it…”

The work meant trying out new syntheses, and screening the compounds for activity. But restricting growth of the bacteria was only the first hurdle a new chemical had to clear. It had to pass much more exacting tests to be any use for therapy. First, it had to act on cells that were a problem for patients. And it had to act on those cells without damaging others too much.

The second requirement can be difficult for any drug, but has been a particular problem for substances affecting DNA replication. The first compound that Elion and Hitchings selected for further testing because it inhibited growth of L. casei – 2,6-diaminopurine – also showed promise in restricting growth of mouse tumours, and tumour cells in tissue culture. It was tried in people with leukaemia, and produced some remissions, but its wider toxicity also produced nausea, vomiting and depression of bone marrow in some cases.

The new syntheses had to go on. By 1951, they had made and tested over 100 purines. The lab grew slowly. As a colleague recalled, “the budgets were really small, and the labs were pretty antiquated”. Then, a purine with a sulphur substitution in the ring, 6-mercaptopurine (6-MP), finally hit the spot. By now, the Burroughs lab was working with the Sloan-Kettering Institute on cancer research, and the team there found that the new compound showed promise against a range of tumours and leukaemias in rats and mice. It was then tried in children with acute leukaemia, whose life expectancy was only a few months, and produced some complete remissions. It was not a permanent cure, but was far superior to the drugs then in use. Mercaptopurine (Purinethol) was approved by the authorities in 1953. As Elion put it, “this convinced us that antimetabolites of nucleic acid bases were fruitful leads to follow”.

Intensive work continued on other possible anticancer compounds, informed by more and more detailed knowledge of the enzymes involved in purine synthesis and processing in the body. But it was 6-MP again that triggered a new round of research in 1958, when it was found to inhibit the immune system. Rabbits given the drug at the same time as they were exposed to an antigen failed to make antibodies to the foreign substance as they normally would. Afterwards, the creatures would tolerate the antigen in question, while still having an immune system that reacted normally to other things.

This intriguing finding led to a lengthy collaboration with the British surgeon Roy Calne, who was experimenting with kidney transplantation. Within a few years he and others were using another drug from Elion and Hitchings, azathioprine, to suppress immune reactions in patients who received kidney transplants from unrelated donors.

This was clearly a productive research programme, and that was confirmed when efforts to find compounds that would boost the effects of 6-MP helped to reveal that another purine they had on the books, allopurinol, inhibited production of uric acid, the compound whose excess causes the pains of gout. It is still used to treat chronic gout, preventing build-up of the uric acid crystals that cause joints to seize up. Another important 1950s finding was the activity of inhibitors of the key enzyme dihydrofolate reductase, with pyrimethamine especially active against the malarial enzyme and trimethoprim against bacterial versions. Trimethoprim was even more effective as an antibiotic when put together with a sulphonamide, and the combination antibiotic was marketed as Septrin or Septra.

Gertrude Elion and colleagues

Gertrude Elion and George Hitchings with colleagues (including then Wellcome Trust Chairman David Steel, front centre) after receiving the Novel Prize in 1988. Credit: Wellcome Library

A new home

These laboratory offerings were quickly taken up in the clinic, and became lucrative products. The US company (and its research arm) was still doing rather better than its UK counterpart. The main British research lab, in the south London suburbs, was known in the USA as the ‘University of Beckenham’. There was strong science there, but not so much successful application. The US company was, in effect, carrying the business. That strengthened Hitchings’s hand in his disputes with the head of the Tuckahoe labs, William Creasy. They clashed over Creasy’s hands-on management style. According to Tom Krewitsky, who worked with Hitchings and later became Burroughs Wellcome vice-president for research, Creasy tried to tell the chemist what to work on, but when his suggestions were resisted, “he backed off”, knowing that the lab’s commercial successes made it unwise to hamper Hitchings’s work.

Creasy also clashed with the UK-based board of the Wellcome Foundation, led between 1948 and 1970 by Sir Michael Perrin. Before World War II, Perrin worked for ICI and developed their first plastic products, while during the War he was responsible for British monitoring of nuclear matters. He had been on the Manhattan Project, and ordered the bombing of heavy water plants in Norway. Sir Henry Dale, Chairman of the Wellcome Trust between 1938 and 1960, recruited Perrin personally to be Chairman of the Foundation, and Perrin in turn recruited a Yorkshireman called Fred Wrigley as Managing Director of the Foundation outside of North America. Perrin and Wrigley set up a global distribution network that could market the new products emerging from the US labs, adding about 55 new overseas subsidiaries. They also strengthened the Foundation’s veterinary business – in the 1950s and 60s, it was as important to have good veterinary products such as vaccines, anthelminthics and antibiotics as it was to have good medical lines – through the purchase in 1959 of Cooper, McDougall and Robertson Ltd, an animal health company based at Berkhamsted, Hertfordshire.

Back in the USA, in 1969 the decision was taken to move from the outdated labs at Tuckahoe to a new site, with state-of-the-art facilities, at Research Triangle Park in North Carolina. Creasy refused to make the move, and was replaced, but Hutchings and Elion’s team transferred to the new labs, and enjoyed better support. Although their work so far had produced new products, profits were still modest. But the company, and the Trust, saw increased investment in research in the USA as the best way to safeguard future prospects.

This investment paid off in the 1970s. Turnover grew, driven largely by allopurinol and Septrin. By 1980, sales had grown to £400m per year, having been just £10m per year in 1950. And in the 1980s, two drugs were introduced that transformed the company’s finances and that tackled a previously unheralded area: viruses.

Tackling viruses

Developing drugs that might be effective against viruses had been long-cherished ambition of the Elion-Hitchings lab. It was widely believed that viruses were unpromising targets for drugs and that vaccination was the only effective way to tackle viral diseases. Elion and Hitchings disagreed, remembering that in 1948 Elion had made a base that showed some inhibition of viral growth. It was also toxic, so had to be set aside.

Twenty years later, they decided to get back to it. Now armed with a much larger array of purine and pyrimidine derivatives, they had the most likely candidates screened for antiviral activity at the Wellcome Research Laboratories in the UK, and relatively swiftly found compounds that showed promise against herpes and vaccinia viruses. Several years of further tweaking led to development of acyclovir (Zovirax), which found wide use in treatment of genital herpes infections, shingles and more serious herpes infections in people with weakened immune systems. It became the world’s first billion-dollar drug.

Emboldened by this antiviral success, the Burroughs Wellcome lab joined the search for treatment for a new disease, HIV, in the 1980s. This also faced numerous obstacles. There was a widespread belief that RNA viruses would be especially difficult to treat. Few pharmaceutical labs were equipped to study viruses, and their parent companies saw HIV at that time as a problem affecting too few patients to be commercially attractive.

Elion had officially retired by this time, but her group continued, and signed up to collaborate with Dr Samuel Broder of the US National Cancer Institute to look for potential anti-HIV drugs. As Broder recalled, unlike the other companies, Burroughs Wellcome “were willing to do things, to develop products, and not just to talk. They were willing to exchange information and provide drugs that could be tested. And they were pretty clear that they would make a commitment to try to develop and commercialize a product that looked good.”

They quickly found that the compound they needed was already on the shelf. An existing purine analogue, AZT, inhibited virus growth in cultured human cells, without harming the cells. Animal tests followed and then, in 1985, human trials began after fast-track approval from the US Food and Drugs Administration. AZT does also affect the normal DNA polymerase that copies DNA in human cells, and has stronger effects on the enzyme that does the same job in the energy-generating stations inside the cell, the mitochondria. The side-effects this produces need careful management, but the slowing of HIV growth is much more powerful. AZT went on to become part of the standard cocktail of drugs that turned HIV infection from a usually fatal condition to one that is survivable with medication.

AZT continues to be in widespread use, and remains perhaps the most important long-term result of the programme George Hitchings began in 1942. His and Elion’s achievements were recognised in 1988 with the award of the Nobel Prize in Physiology or Medicine, shared with Sir James Black. Both Hitchings and Elion looked back with satisfaction on the proof that opportunistic investigation of a likely-looking family of compounds can generate drugs that find a wide variety of uses.

Which of their discoveries was most important to them?Impossible to say, according to Elion. As she told one interviewer: “It’s like being asked to discriminate amongst your children. It’s very difficult to say that mercaptopurine was more important than Imuran, was more important than allopurinol. Or that acyclovir was more important than all of them. Because they came at different times. They were for different uses. And each one in its own time was kind of a revolutionary drug.” The Nobel Committee agreed.

Jon Turney

Find out more about activities marking the Wellcome Trust’s 75th anniversary, including links to other features as they are published.

Jon Turney has been a science writer, editor and reviewer since the early 1980s, with spells as a journalist, academic and publisher. He has authored a number of books, including ‘The Rough Guide to Genes and Cloning’ (2007) and ‘The Rough Guide to the Future’ (2010). He has also lectured widely and created and taught science communication courses in several universities. 

Further reading

  • Avery ME. Elion. Hunter Department of Physics and Astronomy.
  • Colvin M. Gertrude Belle Elion (1918-1999). Science 1999;284(5419):1480.
  • Elion GB. The purine path to chemotherapy. Science 1989;244(4900):41-7.
  • Fildes P. A rational approach to research in chemotherapy. Lancet 1940;235(6091):955-7.
  • Koenig R. The legacy of great science: the work of Nobel Laureate Gertrude Elion lives on. Oncologist 2006;11:961-5.
  • Marx JL. The 1988 Nobel Prize for Physiology or Medicine. Science 1988;242(4878):516-7.
  • Nobel Prize in Physiology or Medicine 1988. Autobiographies of Elion and Hitchings and acceptance speech from Hitchings.
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