Chapter 1: Beginnings

The Dawn of Molecular Biology: What Is Life?

In 1944, the theoretical physicist and Nobel Laureate Erwin Schrödinger published What Is Life?, based on a series of public lectures he had given in Dublin, where he had settled after fleeing Austria following the arrival of the Nazis in 1938. The little book, less than 100 pages long, is a unique mixture of quantum physics, the biology of heredity, and an unexpected dose of mysticism, and became a bestseller, with eventual sales topping 100,000 copies. In it, Schrödinger publicised to an English-speaking audience a paper written in an obscure German journal in 1935 by the theoretical physicist Max Delbrück and his colleagues Nikolay Timoféeff-Ressovsky and Karl Zimmer. The “Three Man Paper,” as it came to be known, suggested that, just as for inorganic matter, life itself had to be governed by the laws of physics. From this it followed that genes, rather than being just the geneticists’ theoretical units of inheritance, might actually be real things that could be studied at the molecular level. In addition to enthusiastically espousing this hitherto esoteric view, Schrödinger dangled in front of his readers the tantalising possibility that exploring biology might reveal new laws of physics: “it emerges that living matter, while not eluding the ‘laws of physics’ as established up to date, is likely to involve ‘other laws of physics,’ hitherto unknown, which, however, once they are revealed, will form just as integral a part of this science as the former” (Schrödinger 1944).

Schrödinger’s book, combined with a surprising romanticism in his readership, was responsible for recruiting an outstanding cohort of physicists to populate the new field of molecular biology; it should be noted, however, that he misconstrued some of the 1935 paper’s ideas, and much later on, the crystallographer Max Perutz, whose own conversion had preceded Schrödinger’s, observed that “what was true in his book was not original, and most of what was original was known not to be true even when it was written” (Perutz 1987).

Looking back with a modern eye on the rumpus that What Is Life? caused in the physics world in the 1940s, it is hard to understand how the simple statements that biology and physics had things in common and that there were experimental techniques that could be applied to finding out exactly what genes were could have been such novel concepts. Probably, much of the secret of the book’s success lay in its timeliness. In François Jacob’s words:

After the war, many young physicists were disgusted by the military use that had been made of atomic energy. Moreover, some of them had wearied of the turn experimental physics had taken … of the complexity imposed by the use of big machines. They saw in it the end of a science and looked around for other activities. Some looked to biology with a mixture of diffidence and hope. Diffidence because they had about living beings only the vague notions of the zoology and botany they remembered from school. Hope, because the most famous of their elders had painted biology as full of promise. To hear one of the fathers of quantum mechanics ask himself: “What Is Life?” and to describe heredity in terms of molecular structure, of interatomic bonds, of thermodynamic stability, sufficed to draw towards biology the enthusiasm of young physicists and to confer on them a certain legitimacy (Jacob 1970).

Fortunately for Schrödinger’s readers, the new field he had described so persuasively was already up and running; the source of the book’s inspiration, Max Delbrück, had been rather busy in the decade since the “Three Man Paper” had appeared. Delbrück had been awarded a fellowship in 1937 from the Rockefeller Foundation to leave Germany and learn some fruit fly genetics at the California Institute of Technology (Caltech) in Pasadena. Luckely for molecular biology, the Drosophila genetics literature was by that time so convoluted and stuffed with jargon that Delbrück had difficulty making head or tail of it, and instead fell in with Emory Ellis, a physical chemist at Caltech. Ellis was interested in cancer and had reasoned that because it was known that viruses sometimes cause cancer, he should try to work out how. He decided that the best way to do this was to study the simplest possible viruses, those that infect and kill bacteria. To this end, he had taught himself some basic microbiology, built some equipment, and learned how to grow cultures of Escherichia coli bacteria on the surface of agar plates, creating a smooth opaque lawn of bacteria atop the jelly-like clear agar after overnight incubation at 37°C. Next, he had collected a bucket of Los Angeles sewage and found in it a bacteriophage, a bacterial virus able to kill E. coli; when he overlaid his opaque bacterial lawn with a solution of minute particles purified from the sewage, in the morning he could see clear holes or plaques in the lawn, each showing where a virus particle had infected and killed the surrounding bacteria. By counting the number of holes, one could precisely quantitate the number of infecting viruses.

This plaque assay completely blew Delbrück away: “I was absolutely overwhelmed that there were such very simple procedures with which you could visualize individual virus particles; …you could put them on a plate with a lawn of bacteria, and the next morning every virus particle would have eaten a 1 mm hole in the lawn. You could hold up the plate and count the plaques. This seemed to me just beyond my wildest dreams of doing simple experiments on something like atoms in biology” (Delbrück interview, Caltech Oral History Archive, with permission from the California Institute of Technology © 1979).

Delbrück took to phage work with a vengeance, although sadly, Ellis dropped out shortly afterwards (his funders, not recognising his prescience, were unable to understand what relevance his work had to cancer research and forced him back into dull mainstream studies transplanting tumours between mice). After the outbreak of war, Delbrück remained in the United States, moving to Vanderbilt University, and in late 1940, he met Salvador Luria, an Italian microbiologist, and Al Hershey, a bacteriologist. The three men applied a combination of genetics, bacteriology, and the rigorous experimental methodology of physics to the task of understanding how phages transmitted their genetic information down the generations and how the information remained stable.

Quite early on, Delbrück realised that to succeed, the phage field needed to accrue disciples as rapidly as possible, and to this end, he and Luria started a summer school in 1945 at the dilapidated but beautiful Cold Spring Harbor Laboratories on Long Island. Aspiring phage researchers could learn the techniques necessary to study phage, have a whale of a time at the multitude of social events, and fall under Delbrück’s spell; a charismatic and brilliant man, he inspired great affection and loyalty, despite being alarmingly difficult to please when it came to matters of science. The summer school’s aim, that participants would leave as fully indoctrinated phage group members, or at least phage-literate converts, was extremely successful; the phage group’s ethos (with respect to both experimental methodology and how to have a good time) was widely disseminated, to the extent that virtually all molecular biology bloodlines in the United States can ultimately be traced back to Delbrück, Luria, or Hershey. For their own valuable discoveries, and also for their achievement in laying the philosophical foundations of modern molecular biology, the three men were awarded the 1969 Nobel Prize in Physiology or Medicine.

Max Delbrück “on trial” at the 1950 Phage Meeting.

(Photograph courtesy of Cold Spring Harbor Laboratory Archives.)

The new molecular biology field was transformed from an intriguing minority discipline into a major scientific force by the arrival in 1951 at the Cavendish Laboratories in Cambridge of a 23-year-old American, Jim Watson. Watson, who had grown up in the phage group as a student with Salvador Luria, had come to Europe to try to learn some biochemistry in Copenhagen but had become so bored that he decamped to England, where he annoyed, entertained, and stimulated his bemused new hosts in approximately equal measure. Watson, true to his phage roots, was obsessed with how hereditary information was transmitted down the generations. DNA had been known for some time to be the hereditary material, thanks to an experiment performed in 1944 by Oswald Avery, Colin MacLeod, and Maclyn McCarty, but nobody knew how it replicated itself or how its information was decoded. Watson realised that the key to understanding how DNA worked was to determine its structure, and this he and Francis Crick did, building their famous double-helical model in a brilliant extrapolation from Rosalind Franklin’s beautiful X-ray data.

Watson and Crick’s paper “Molecular Structure of Nucleic Acids; A Structure for Deoxyribose Nucleic Acid,” published in Nature in April 1953, opened up an enormous landscape of biological possibility. In the years that followed, a small and extraordinarily talented band of pioneers showed how DNA was replicated, that DNA made RNA, that messenger RNA (mRNA) made protein, and that the linear sequence of the amino acids comprising a protein was determined by the triplet genetic code that was carried in the DNA, copied (transcribed) into mRNA, and translated into protein on ribosomes. Much to the annoyance of some classical biologists, whose belief in the complexity of nature was almost mystical, and some of the phage group physicists, who were still hoping to fulfil Schrödinger’s prediction that they would find new laws of physics by studying biology, the basis of life really was as simple as Francis Crick’s central dogma of “DNA makes RNA makes protein” suggested. Molecular biology, with its triumphantly vindicated reductionist outlook, was on a high.

Although Gunther Stent, one of Delbrück’s original phage group at Caltech, dismissed the era following the remarkable conceptual leaps leading to the central dogma as “what remained now was to iron out the details” (Stent 1968), to those working in the steadily expanding field it was anything but mundane. Building on the central dogma, molecular biologists turned their attention to filling in the vast information voids that still existed in their new submicroscopic landscape, particularly in terms of how processes were regulated. How did a cell know when to replicate its DNA, to make RNA, and to make protein? How did proteins know where to go in a cell? There were so many truly important questions to be answered, and advances in methodology and technology meant that quite often, the only limit on what could be achieved was the intellectual capacity of the researcher involved.

From Phage to Papovaviruses: Tackling Cancer

Even before the mechanisms governing the prokaryotic bacterial and phage world were partially understood, or Jim Watson had set foot in Cambridge, attention had turned towards the universe of the eukaryota. Eukaryotes, defined as organisms whose cells contain a nucleus, as opposed to the nonnucleated prokaryotes, range from the simple, such as the unicellular yeasts, to complex multicellular organisms such as ourselves. Understanding the molecular engineering involved in building and maintaining a eukaryote, and importantly, the molecular failures that lead to defects and disease, began to appear possible. Prospective pioneers started to look for ways in which to attack the problem but first had to figure out how to do the kind of experiments that had been the key to the work in prokaryotes. They were stumped by two big problems: the difficulty of getting live cells out of an animal and growing them in the lab and the lack of a tool akin to a bacteriophage with which to probe cell function.

In 1950, a fortuitous collision between extreme wealth and extreme discomfort jump-started the field of eukaryotic molecular biology by fixing both these issues. Max Delbrück, who was back once more in Pasadena as head of a small but flourishing phage lab, received an interesting proposition from Lee DuBridge, President of Caltech. The richest cotton baron in California, Colonel James G. Boswell, had been hospitalised with a serious case of shingles, and finding out from his doctor that almost nothing was known regarding the shingles virus, Varicella zoster, which was causing him so much pain, had decided to throw some money at the problem; he was offering Caltech, with its world-famous expertise in virology, $225,000 to spend on research into animal viruses. Boswell’s hoped-for cure did not arrive in time to fix his shingles (in the end, his doctor prescribed a daily dose of bourbon, which the formerly teetotal Boswell took to with gusto), but his money was well spent. Delbrück was happy to take on the challenge and decided that because he knew nothing about animal viruses, the most sensible way to proceed would be to spend the first chunk of money from the James G. Boswell Foundation on a conference, getting together the leading lights in the virus world. A motley assembly of 35 plant, animal, and bacterial virologists showed up at Caltech in March 1950, but the conference was not particularly successful; a camping trip to Death Valley immediately afterwards seems to have been the highlight of the meeting, and some useful scientific collaborations were forged in the dust and heat of the desert. The problem was that as far as molecular biology was concerned, plant and animal virology was very much in the Dark Ages; apart from the structural biologists, who were starting to explore how the viruses looked and what they were made of, nobody had even managed to develop a simple way of counting their viruses, let alone doing anything else to determine how they replicated.

After seeing off his new colleagues, Delbrück returned to his lab and decided that if anything was to be done about dragging eukaryotic virology into the modern age, he would have to do it himself. He summoned two of his laboratory members, Renato Dulbecco and Seymour Benzer, and asked whether either of them would be interested in taking on the Boswell Foundation project. Benzer was quite happy with what he was doing and said no. Dulbecco, however, was interested. Originally trained as a medic and therefore with an interest in human disease, he was a bit fed up with his current phage work and agreed to have a look at what could be done in the new system. After a three-month road trip to look in detail at what was going on in the existing animal virus laboratories, he returned to Caltech, where he was promptly banished to a small room in the second basement for his decision to work on the human pathogen Western equine encephalitis virus, which scared the pants off the rest of the department.

Dulbecco realised that to do any meaningful work with animal viruses, he first had to sort out the issue of how to quantitate them, just as bacteriophages could be quantitated in a plaque assay. To set up an animal-cell version of the plaque assay, he needed to find a way of growing viruses on flat lawns of animal cells in tissue culture, rather than in the animals themselves, as was currently done. Fortunately, back in his native Italy, Dulbecco had worked with Giuseppe Levi (mentor of three future Nobel laureates—Salvador Luria, Dulbecco himself, and Rita Levi-Montalcini) and had learnt some tissue culture, then in its extreme infancy. In his dingy subbasement at Caltech, he managed, after much trial and error, to hit upon a way of growing a monolayer of chick embryo cells that he could infect with virus and then stain in order to see the viral plaques. When Dulbecco achieved this tour de force for the first time and showed Delbrück, the latter was so impressed that he told Dulbecco to take particular note of the day and date; unfortunately for science historians, neither of them did. What is very clear, however, is that from the date of publication of Dulbecco’s 1952 paper, “Production of Plaques in Monolayer Tissue Cultures by Single Particles of an Animal Virus,” animal virus research entered the age of molecular biology, and simultaneously, molecular biology finally had a foothold in a eukaryotic system.

Cancer biology was soon to get in on the act too. Shortly after Dulbecco’s development of the animal virus plaque assay, he acquired a new postdoc, a former vet named Harry Rubin. Rubin wanted to extend Dulbecco’s plaque assay to viruses that did not kill their host cells, but instead caused the cells to overgrow and develop into tumours. Using the same tissue culture techniques as Dulbecco, Rubin, subsequently joined by Howard Temin, discovered that instead of plaques, tumour viruses caused the normal tissue culture cells to “transform.” Virally infected cells could be seen as little foci of odd-looking rounded cells, all heaped up on each other, growing out of the otherwise flat cell monolayers. Such transformed cells could grow in culture for far longer than normal cells, and when injected into animals, caused tumours.

Temin and Rubin’s focus-forming assay, published in 1958, was a gift to the cancer research community, who were in dire need of the fresh approach offered by tumour viruses. There was a growing acceptance that current research methods in cancer were not likely to yield any significant molecular information. Jim Watson, in his influential textbook Molecular Biology of the Gene, laid out the problem very clearly. The issue facing the biochemists and geneticists studying cancer was that because nobody was anywhere near understanding how a healthy animal cell worked, how on earth were diseased cells to be understood? In the case of cancer, a disease of uncontrolled cell growth, trying to understand how the trillions of cells in a normal body do not divide, and how that control can be overcome, was not even approachable using current methodology. Of the many thousands of genes in the human genome, the functions of only a few were known, so the chances of stumbling upon a crucial control gene were very small.

The solution, just as it had been for Delbrück 30 years earlier, was the reductionist approach offered by viruses. Watson pointed out that just as phages were so simply constructed that they had been used as efficient probes of basic prokaryotic biology, tumour viruses held the same promise for cancer: Their genomes were tiny but were nevertheless so powerful that an entire eukaryotic cell could be effortlessly bent to their will. To have such an effect, the tumour viruses had to be attacking the central command system of the cells, and if an intrepid explorer could follow in their tracks, they would be led to the same destination. In other words, finding what the viral proteins did would lead to the cellular mechanisms they were subverting. It was not known whether the ways in which tumour viruses caused cancer were similar to the mode of action of other carcinogens, but they were a way in to previously unknown territory that virologists, cancer biologists, and basic molecular biologists were willing and able to colonise.

By the 1960s, animal virus work had really taken off. Dulbecco’s laboratory, and an increasing band of collaborators around the world, had developed methods for large-scale tissue culture. They could infect cells in sufficient numbers to purify large amounts of virus for physical and chemical analysis and could also examine what was going on in the virally infected cells. In the cancer world, it had also been discovered that tumour viruses fell into two types—those with DNA as the infectious material, and those with RNA. Of the DNA tumour viruses, two, SV40 and polyoma, were particularly prominent.

Mouse polyoma virus was discovered in 1953 by Ludwig Gross but did not acquire its current name until 1958, when Sarah Stewart and Bernice Eddy showed that it could cause multiple different tumour types in newborn hamsters, mice, and rats. SV40, purified by Ben Sweet and Maurice Hilleman in 1960 as a contaminant of the monkey kidney cell lines used to produce polio vaccines, was also shown by Bernice Eddy to cause tumours in hamsters, and could transform human cell lines in culture, although it has never been shown to directly cause human cancer. Both viruses are a similar size and shape, and their DNAs appeared to have similar properties, so they were classified as members of the same family, the papovaviruses. Their labeling as DNA tumour viruses is a gross libel: In their native hosts in the wild, they persist as endemic, harmless infections that rarely cause tumours because their hosts’ immune systems keep them well under control. Only when forced by scientists to infect the wrong species at the wrong time (such as at birth, when the immune system is poorly developed), do they reveal their more sinister sides.

Polyoma and SV40 were hugely attractive to the molecular biologists studying cancer: They were small, with double-stranded genomes of just over 5000 base pairs (bp) of DNA (by comparison, the human genome contains ∼3 billion bp), and they could transform cells. The existence of polyoma- and SV40-transformed cell lines, which could be grown for long periods in tissue culture, meant that not only could the changes wrought by the viruses on the cells be studied, but also large quantities of viral protein and DNA could be made; this latter was particularly important, because bucket loads of cells were required to produce enough material for the techniques available to researchers at the time.

With the tools and equipment now to hand, the molecular study of cancer began in earnest. As the new field took off, a few places in the world became centres of expertise in tumour virus research, and by extension, eukaryotic molecular biology. By the 1970s, there were two undisputed leaders in the field: the original home of the phage group courses, the Cold Spring Harbor Laboratory, and a new European interloper, the Imperial Cancer Research Fund (ICRF) in London.

ICRF Reborn: Michael Stoker and Tumour Viruses

In 1968, Cold Spring Harbor and the ICRF, after periods in the doldrums (financial in the case of Cold Spring Harbor and scientifically at the ICRF) had each just appointed new Directors. At Cold Spring Harbor, Jim Watson had taken over from John Cairns, who had heroically rescued the laboratory from fiscal disaster and put it back on its feet again, and in London, Michael Stoker had been brought in following the retirement of Guy Marrian. Stoker and Watson were good friends—they had first met in Cambridge in the 1950s—and this friendship was of great significance for the development of both the ICRF and Cold Spring Harbor. Like Watson, Stoker had realised early on the importance of DNA tumour viruses, and both men wanted to shape their laboratories around a research programme in the molecular biology of cancer. The result was a close transatlantic scientific alliance driven by a white-hot intensity of purpose on both sides, and featuring a galaxy of present and future scientific stars making fundamentally important discoveries. In this period, Cold Spring Harbor and the ICRF, nowadays renamed the Cancer Research UK London Research Institute, became the powerhouses of science that they are today. However, although the names of Watson and Cold Spring Harbor remain inextricably linked, Stoker, perhaps because he was a fundamentally nice man with a normal-sized ego, occupies a more obscure place in the pantheon of eukaryotic molecular biology.

Michael Stoker.

(Photograph courtesy of the CRUK London Research Institute Archives.)

Michael Stoker originally trained as a medic at St Thomas’s Hospital in London. After war service in the Royal Army Medical Corps, he became a research Fellow of Clare College, Cambridge in 1948, and remained there for the next 10 years. His early research interests, on Q fever, a bacterial infection with flu-like symptoms, morphed in the 1950s into some of the earliest work, contemporary with Temin and Rubin’s, on growing animal cells in tissue culture and virally infecting them. His research went well, and by 1957, when Renato Dulbecco came through Cambridge on a visit, Stoker was one of the people he was very keen to see. Working upstairs in a sort of hut on the roof of the Pathology Department building (for some reason, much of the really exciting work performed at Cambridge in the 1950s appears to have emanated from huts, aerial or otherwise), Stoker was very much a part of the Cambridge molecular biology scene until 1958, when he moved to Glasgow, to take up the first Chair in Virology ever created in the United Kingdom, and to direct a new virology institute. In Glasgow, Stoker further expanded his studies on cell growth in culture and moved into working with tumour viruses, doing some of the earliest research into transformation by polyoma. Today his contributions to the field have unaccountably been almost forgotten, but they were substantial and important, leading to his election as a Fellow of the Royal Society in 1968.

The brand-new, well-funded Glasgow Institute of Virology became a 1960s magnet for talented, ambitious scientists, so much so that at one point, the majority of the United Kingdom’s best molecular biologists had trained in the rain and gloom of Glasgow. The influx of talent was in large part due to Stoker’s qualities as its Director. Modest, unassuming, courteous as only a well-brought up Englishman can be, Stoker was an astute star spotter, and a brilliant manager of the often fractious stable of scientific thoroughbreds he accumulated. One of these, Mike Fried, summarises Stoker’s talents thus: “He was so likeable that nobody bore a grudge. He could get on with everybody and get them to do what he wanted, so he was a great organiser. Nobody spoke badly of him and he was always able to work things out.” In other words, under Stoker, if you had the potential to do great science, you were given the best possible chance of succeeding, however much your difficult temperament or tendencies to misanthropy tried to intervene. He was therefore an inspired choice when the Trustees of the ICRF recruited him as the new Director of the ICRF in 1968; the laboratory was in deep trouble, and it would take a scientist and administrator of Stoker’s calibre to sort it out.

Stoker knew that his task in reforming the ICRF was going to be difficult. Upon accepting the Directorship, he had written to Jim Watson that “My job will be rather formidable, but I should like to see all this cancer money well spent” (letter dated 4 May 1967). The problem was that the ICRF that Stoker inherited had gone from being a central player in cancer research after its foundation in the early part of the 20th century to a rather peripheral concern, riven by arguments between the Director, Guy Marrian, and its trustees. Marrian, to his great credit, had overseen the building of new laboratories in Lincoln’s Inn Fields and was in the midst of negotiating their further expansion, but his research priorities were considered outmoded, with their emphasis on traditional biochemistry, endocrinology, and chemical carcinogenesis, and the trustees were consequently unhappy with him. His health was also a cause for concern, because the stresses of the job had precipitated a heart condition. His retirement in 1968, at the age of 64, was a matter of some relief to all.

Stoker had a simple brief; to turn the ICRF into a modern research operation, and this he did, with spectacular results. However, he had some help; a good leader knows that success lies in assembling a team of able lieutenants, and Stoker had a corps of close colleagues, some from Glasgow, others hired from the world’s top molecular biology labs, to form the nucleus of the reborn ICRF.

Two of Stoker’s valued team would play especially important roles in the remoulding of the ICRF. The first of these was the Laboratory Manager, Bill House, an archetypically canny Glaswegian brought down from Scotland by Stoker to turn the ICRF into a place where it was as easy as possible to do world-class science. Adjutant, administrator, fixer, and general trouble-shooter, Bill completely reorganised the Central Services Department, turning it into a well-oiled machine providing reagents, solutions, tissue culture media, and sundry other services to the ever-increasing numbers of labs. He was a great believer in problem solving by example; after being told the washing up ladies were on the verge of quitting because they couldn’t cope with the new regime, for three months at the beginning of his tenure he spent every morning collecting and washing glassware with them, until the system ran smoothly. Bill was the person you had to convince if you wanted new equipment or complicated media, although his efficient system of secretarial barricades meant that most often, ambushing him in the corridor was the best way of ensuring success.

Stoker had a scientific lieutenant too: Lionel Crawford, then in his late 30s, was a meticulous and green-fingered experimentalist, who, as much as Stoker, helped to forge the links with Cold Spring Harbor that were so useful to both places. Crawford’s importance is evident in a letter from Stoker to Jim Watson, written in summer 1968: “I am very glad Lionel is coming to you for a few months, and hope that, perhaps through him, we can keep in touch and even set up some joint or complementary programmes. Don’t keep him too long however. He is badly needed in London, particularly at the beginning, to set the proper standards. He is going to be head of a new division but will also be chairman of the group of new divisions” (letter dated 10 July 1968).

The necessity of setting the proper standards was clear from Crawford’s very first view of his new London lab space; somebody had managed to set fire to it, and it was a charred wreck. It transpired that some time previously, a technician euthanising animals with ether had finished work in a bit of a hurry, and instead of disposing of the corpses properly, had shoved them into the laboratory fridge to sort out the next day. Unfortunately, the fridge was so old and decrepit that when the compressor kicked in, it sparked and ignited the ether vapour drifting from the animals. In the subsequent explosion, the door of the fridge blew off, all the now burning flammables stored in the fridge fell on the floor, and the lab had been comprehensively trashed.

The existing denizens of the Lincoln’s Inn Fields laboratories may have come to view the exploding fridge incident as a worrying omen of Michael Stoker’s plans for the future, because it rapidly became clear that research in an analogous state to the fridge was destined for the rubbish heap too. In 1968, shortly after Stoker’s arrival, Crawford’s Cell and Molecular Biology Division, comprising five laboratories, had 17 people working in it, whereas the “old” ICRF, comprising the Endocrinology and General Studies groups, had 57 scientists and technical staff. In 1972, with the ICRF building now doubled in size after the completion of the last tranche of laboratory space, Cell and Molecular Biology contained 68 staff, and Endocrinology and General Studies had shrunk to 47. The ICRF had been well and truly propelled into the new age and was starting to accumulate the group of scientists that would make its name as a major centre of molecular biology.

In addition to the DNA tumour virologists working on polyoma and SV40, who are featured in the next chapter, Stoker invested heavily in RNA tumour virus research, a field that exploded once Howard Temin and David Baltimore independently discovered the enzyme reverse transcriptase in 1971, thereby solving the mystery of how RNA tumour viruses managed to turn their RNA genomes back into DNA so they could replicate. At the ICRF, the RNA tumour virologists, under Robin Weiss, John Wyke, and Steve Martin, worked extensively on the mechanisms by which RNA viruses were able to infect cells, but their major contributions were probably in the study of how retroviruses, a particular subtype of RNA viruses, cause cancer.

Perhaps Stoker’s most spectacular hiring coup was to persuade Renato Dulbecco to come to the ICRF as its Deputy Director in 1971. Dulbecco and his wife Maureen had recently had a daughter, Fiona, and both were dubious regarding the U.S. education system, to say nothing of the political climate; the Vietnam War was still raging, Richard Nixon was President, and for left-leaning Europeans, it was all getting a bit much. Dulbecco moved to Chislehurst and stayed at the ICRF for six years, during which time he won the 1975 Nobel Prize, together with his old student Howard Temin and David Baltimore, for his fundamental work on animal viruses and tumour genetics.

Renato Dulbecco.

(Photograph courtesy of the CRUK London Research Institute Archives.)

Dulbecco’s account of the day he found out he’d won the prize is worth relating (Dulbecco Web of Stories):

One morning I arrived [at work], I took off my coat in my office and then I went to the laboratory. When I came back from the laboratory, I noticed that my secretary had a piece of paper in her hand. She shook it and said, “What does this mean?” I went to have a look at what she had and it was a telegram from Stockholm, from someone that I knew well, which said, “Congratulations, we’ll see you in Stockholm in December,” but it was mysterious, there was nothing specific—he couldn’t say, as the official announcement would take place a few hours later. So, then, she said to me, “What does it mean?” so I said, “The only thing I think it can mean is the Nobel Prize.” The poor woman stood as if struck by lightning. And so I said, “Before anything, I must call Maureen.” I said to her, “Something has happened,” and she said “Stay calm, don’t say anything until we know some more.” And she told me that in the meantime, she had organised a small lunch with some of her friends, they were women whose children were in the same class as Fiona. And then I spoke with my friend who was the Director of the Institute and he also said, “Well, let’s wait, let’s see how things go.” And two or three hours passed by, the time came to have lunch, I went down to the cafeteria, sat there with my friend and started to eat. At a certain point, from the door, I saw, I must say, the enormous stomach of my secretary—she was pregnant and close to the birth. And I said, “It must be something serious for you to have come down here!” And she said “There’s a journalist from Stockholm who wants to talk to you on the phone.” So it was true, I said this to my friend, and then things progressed from there, the telegram arrived, then the celebrations, all there in the laboratory. I phoned Maureen to tell her, and when I got home, she told me that when she received this call, she returned to her friends and her friends said to her “What’s wrong, you seem worried. What’s happened? Has something happened?” She said, “Yes, my husband has won the Nobel Prize!” And the reaction to the news was interesting; [her friends thought it was wonderful], but because I was living in Chislehurst, which was a somewhat privileged area, I remember speaking to people about it and they would say to me, “How is it possible for someone from here to win the Nobel Prize?” Because they thought that they were all rich and rich people don’t work. How strange.

Not surprisingly, Chislehurst and the daily commute from Kent eventually proved too much for Dulbecco, who went back to San Diego to be Director of the Salk Institute in 1977.

After Michael Stoker, the ICRF went through two further Directors, Walter Bodmer and Paul Nurse, until, at the venerable age of 100, the charity that funded the laboratories was dissolved and merged with the other major cancer charity in Britain, the Cancer Research Campaign, to become a new entity, Cancer Research UK, in 2002. The ICRF laboratories, with Richard Treisman as Director, entered their final incarnation as the Cancer Research UK London Research Institute (CRUK LRI). Over the years, the changes of laboratory director have inevitably led to changes in focus and management style, but the essential character of the place is unchanged. The laboratories are still full of creative, smart people living on the edge of the known scientific world, and the spirit of adventure that motivated their predecessors is alive and well.

The Cancer Research UK London Research Institute in Lincoln’s Inn Fields.

(Photograph courtesy of David Bacon.)

Web Resources

http://library.cshl.edu/archives/genentech.html   The online archives of the Cold Spring Harbor Laboratory are not only informative but entertaining.

http://oralhistories.library.caltech.edu/view/person-az/index.C-G.html   Delbrück and Dulbecco’s reminiscences—well worth a look.

www.london-research-institute.org.uk/about-lri/history/milestones   A larger selection of scientific milestones at the ICRF and the LRI.

www.webofstories.com/play/14689?o=S&srId=237034   Dulbecco’s account of his Nobel Prize day comes from the Web of Stories, an online collection of reminiscences by scientists and others, which is a terrible trap for the curious—one could easily spend a whole day there in the company of its erudite, funny, and moving subjects.

Further Reading

Austoker J. 1988. A history of the Imperial Cancer Research Fund, 1902–1986. Oxford University Press, Oxford. A good history of the foundation and early days of the ICRF.

Cairns J, Stent GS, Watson JD, eds. 2007. Phage and the origins of molecular biology, the Centennial edition. Cold Spring Harbor Laboratory Press, New York.

The classic book on the history of molecular biology, written by the people who did the work.

Quotation Sources

Schrödinger E. 1944. What is life? The physical aspect of the living cell. Cambridge University Press, Cambridge, UK.

Jacob F. 1970. La Logique du vivant. Gallimard, Paris (translated by Spillman BE. 1973. The logic of living systems: A history of heredity. MW Books).

Perutz MF. 1987. Physics and the riddle of life. Nature 326: 555–558.

http://oralhistories.library.caltech.edu/ Interview with Delbrüuck. © 1979 California Institute of Technology.

Stent GS. 1968. That was the molecular biology that was. Science 160: 390–395.

Letter dated 4 May 1967, from M.J. Stoker to J.D. Watson. Cold Spring Harbor Laboratory Archives.

Letter dated 10 July 1968, from M.J. Stoker to J.D. Watson. Cold Spring Harbor Laboratory Archives.

Dulbecco, Renato. Web of Stories; www.webofstories.com/play/14689?o=MS.

Blue Skies and Bench Space: Adventures in Cancer Research. Electronic edition © 2014 Cancer Research UK, London Research Institute. Website published by Cold Spring Harbor Laboratory Press