In the spring of 1973, the inhabitants of the Imperial Cancer Research Fund Lincoln’s Inn Fields laboratories heaved a universal sigh of relief, probably the first time they had been able to breathe out collectively in a while. For the last few years, they had been squashed like scientific sardines into half of a building, and to make matters worse, had had to endure 40 months of heavy construction work going on next door as the extension of their existing laboratory space took shape. Now, however, all was finished, and the new had been seamlessly merged with the old, but for a slight bump in the floor at the join itself. Although the assertion of the architects, Messrs Cusdin, Burden and Howett, that the brick and granite façade provided “a quiet and dignified completion to the South West corner of the square” was definitely wishful thinking (the laboratory stood out from its elegant neighbours like a sore thumb), the interiors were actually rather well designed. The laboratories were and are large and well lit, with moveable internal partition walls to allow rapid remodeling of internal space, and the wood-paneled public areas give an impression of solidity and competence, without being too showy.

After a year in Berkeley, the Crawfords upped sticks and moved down to Pasadena, to Caltech and Renato Dulbecco. After their initial meeting in Cambridge, Dulbecco and Michael Stoker had greatly taken to each other, and Dulbecco, still confined to the subbasement, was more than happy to do his friend a favour by teaching Lionel and Elizabeth the intricacies of animal virus work. Caltech at that time was still a major site of pilgrimage for molecular biologists, so the Crawfords met Boris Ephrussi, the legendarily bad-tempered Russian who had had a hand in virtually every major molecular biology advance before the discovery of the structure of DNA. Ephrussi was determined to maintain some semblance of European civilisation in the wastes of Pasadena; he insisted on afternoon tea accompanied by civilised discourse, although after a while, tea morphed into visits to the local ice cream parlour, and the discourse frequently descended into energetically loud arguments with Howard Temin.

Working at Caltech also meant an opportunity to witness the Max Delbrück phenomenon at first hand. After an initial disappointing start, when Delbrück discovered that neither Lionel nor Elizabeth played an instrument and were not going to be able to join in his musical soirees, they became regulars on his famous camping weekends in the desert, together with an ill-assorted straggle of other international fellows. Delbrück’s camping technique fell at the lower end of the comfort and amenities spectrum; all were expected to sleep on the ground, although Manny, Max’s wife, did permit those who were pregnant, over 60, or both, to use air mattresses. Nevertheless, after the damp grayness of Cambridge, the desert was magical, and Lionel’s love affair with it continues to this day.

In the desert, 1960s. (Left to right) Renato Dulbecco, Howard Temin, Guy Echalier, Marguerite Vogt. (Photograph courtesy of Lionel Crawford.)

Coming out of the lifts at one end of the floor and turning left, one passed through a set of double doors, over the bump in the floor signaling the start of the new building, and turned right into the large, open-plan Crawford lab. In there, Lionel had amassed a remarkable set of young scientists, all attracted by Lionel’s international reputation as the man to go to for polyoma virus research. Three, in particular—Bob Kamen, Alan Smith, and Beverly Griffin—would end up running their own independent labs and would be major catalysts of the research that transformed the Fifth Floor of the ICRF into one of the world’s best DNA tumour virus research environments.

Bob Kamen, 1979.

(Photograph courtesy of Cold Spring Harbor Laboratory Archives.)

Alan Smith, who’d arrived at much the same time as Bob, was cast in a very different mould. Very English, educated at Christ’s College Cambridge, he had started off wanting to be an astronomer but switched over to molecular biology, infected by the excitement of what was going on in the MRC Laboratory of Molecular Biology, the new home of Francis Crick, Sydney Brenner, Max Perutz, and numerous other luminaries, and at that time the best place in the world for the structural approach to working out the nuts and bolts of life. During his PhD there with Kjeld Marcker, Alan developed a way of translating messenger RNA (mRNA) into proteins in a test tube, and using his new technique, discovered one of the fundamentals of how proteins are made; all of them begin with the amino acid methionine, coded for by the triplet DNA sequence ATG. After moving with Marcker for a short while to Copenhagen, he arrived at the ICRF, because he’d realised that it would be possible to use his very biochemical approach to study translation of the proteins being made by polyoma and other tumour viruses.

Beverly Griffin, 1979.

(Photograph courtesy of Cold Spring Harbor Laboratory Archives.)

There were two other notable inhabitants of the Fifth Floor front corridor—Guido Pontecorvo, one of the founders of the field of human genetics, semi-retired, but still an important part of the intellectual life of the ICRF, and Mike Fried. In terms of personality, Ponte and Fried were polar opposites, but together, they laid down a standard of excellence for the ICRF that kept everyone on their scientific toes. Mike, in his own words a brash New Yorker who always liked to have the last word in an argument, was an invaluable sounding board for ideas and experiments, because he was an unrelenting perfectionist when it came to science. He was another molecular biology aristocrat, having been one of Renato Dulbecco’s graduate students at Caltech. Lionel, who met him during his own year with Dulbecco, remembers him as “a brilliant student—Renato had a very high opinion of him. He had a very good academic record [and] was pretty good in the lab—very careful.” Mike’s reputation as a major figure in the field was made during his PhD, when he worked out how to make and detect a temperature-sensitive mutant of polyoma virus; using techniques similar to those of the phage biologists working upstairs, Mike isolated the first example of a defective virus that could only transform cells at lower temperatures and showed that his mutation had to be in a polyoma protein essential for viral replication. Thanks to this pioneering work, such conditional mutants, equipped with an on/off switch operated by changing the growth conditions, became powerful tools in early studies of cell transformation by tumour viruses and also opened up tumour virus molecular genetics; using conditional mutation, individual genes could be disabled, their functions deduced, and their positions in the viral genome mapped. The relevance of Mike’s work persists: conditional mutation remains an important weapon in the molecular biologist’s armoury to this day.

Lionel Crawford, Mike Fried, Beverly Griffin, Bob Kamen, and Alan Smith: the lab heads of the Fifth Floor. The personal chemistry between some of them rivaled that found in the toxic mix of developer chemicals, dropped samples, cigarette smoke, caffeine, and stale sandwiches enjoyed by users of the coffee room. Tales of shouting matches; battles over equipment, status, and territory; the mysterious overnight repartitioning of labs; political shenanigans—all abound, but above all, the abiding memory seems to be that the Fifth Floor was a family—a large, unruly, somewhat dysfunctional family, whose members fought, made up, and fought again, but a family nevertheless, remembered with surprising fondness. And the family had one abiding obsession: to do the best science it could. Whatever the personal differences, they were put aside when it came to experiments, because science came first for everyone who worked there. As a result, extraordinary things were accomplished in a very short time.

Kit Osborn was a prime example of another of the ICRF’s invaluable assets—its technical staff. Far in advance of the times, Bill House had had the vision to put in place a proper training programme for technicians, who could come in as school leavers and, if they had the aptitude, work their way up. Starting in the central media kitchen, technicians could earn a place in a lab, and in many cases, progress to doing a PhD and beyond, all on a paid work-study scheme. This enlightened strategy resulted in a large cohort of extremely competent people, and on the Fifth Floor at least, most labs ran at almost a 1:1 ratio of technical to scientific staff. Experiments performed by two well-trained people take an awful lot less time, and the presence of technicians who knew their way round the lab techniques and protocols ensured that even the most cack-handed student had a strong chance of succeeding.

Good staff and a great setup are solid foundations on which to build, but what made the labs buzz was the constant flow of communication. The labs were cross-fertilised by the many interactions between their occupants; new techniques, being invented almost daily at that time, spread rapidly because there was a general willingness to collaborate and cooperate. If somebody needed help with a protocol, rather than struggling along with a printed recipe, they could go and ask the person who had developed it, or at least find somebody who would know the parts of the recipe that hadn’t made it into the written instructions. In this respect, molecular biology is a lot like cooking, although the results are not generally edible.

New ideas spread just as quickly. People talked science all of the time; there were coffee breaks, tea breaks, lunches, seminars, journal clubs to discuss exciting papers, and the evening ritual of going to The George, the pub round the back of the lab, which functioned as an alcoholically endowed extramural meeting room. The George was where you went for a quick pint and a sausage before going back to start your evening’s work (the sausages were so horrible that one postdoc started making his own, left science, and founded a best-selling sausage company, Aidell’s, in California), or where you spent long inebriated nights discussing data, theories, and gossip, or drowning your experimental sorrows in the presence of sympathetic cosufferers.

Life on the Fifth Floor was made yet more exciting by the presence of migratory flocks of Americans, often from Cold Spring Harbor, come to London to check in with their colleagues, have some fun, and do the experiments that they were unable to do back home because of a cloning moratorium (in a brief fit of overzealous caution, the United States stopped work with recombinant animal DNA for 18 months in the mid-1970s). Postdocs and graduate students were not only able to hang out with the finest minds in molecular biology, but were also treated to the spectacle of some of the eminent American visitors oversampling the wares of The George, scrounging for dates to enliven their out-of-hours existence, and generally spicing the place up. The sabbatical visitors got visits from their friends too, and in some weeks, the choice of top-quality seminars was so great as to start to cut seriously into time at the bench.

Harold Varmus, future Nobel Prize winner, head of the NIH, presidential advisor, and all-round viral superstar, was one of the (more abstemious!) sabbatical visitors, arriving for a year’s break from his lab in San Francisco to explore London with his wife Connie and their two small children. Harold’s account of his time in Mike Fried’s lab is a perfect demonstration of why he and many others enjoyed themselves so much:

Here is another view, this time from an insider, Adrian Hayday. Adrian is now Professor of Immunology at King’s College and a lab head at the London Research Institute, but in the 1970s he was Mike Fried’s PhD student, fresh from Cambridge:

It was flamboyant and incendiary, but I thought it was a pretty good place to train. There was a certain generation represented by people like Bob Kamen who had cut their teeth on phage, and had a certain rigour and appreciation of what very rigorous science was about. We felt similarly working on these DNA tumour viruses, because the genetics, transcription and protein analysis were so exquisitely interdigitated that you felt really good in that environment, despite the fact that some people’s behaviour was not ideal!

It is hardly surprising that in this supercharged atmosphere, passions ran high. Although the hormonally driven interactions between floor members should remain in decent obscurity, the scientific arguments are exemplified by this story from one Fifth Floor inhabitant: “[My boss] and I had this big disagreement about something relatively trivial and it was really a big disagreement, so it got kind of loud in the corridor between the lab and his office. He marched off in a huff into the lab, and I marched off into the other door of the lab. But the lab was a rectangle, so we stormed round and kept passing each other, to the immense amusement of the other people in there. We managed three times round I think!”

In the early 1970s, knowledge regarding SV40 and polyoma was still fairly limited, and there was a lot of scope for discovery. The size and shape of the viral capsid, the protein coat that enclosed the infectious viral genome, was known, and the double-stranded DNA genome had been shown to be circular. There was some understanding of what happened during a productive viral infection, in which a virus enters a cell, replicates, and then bursts (lyses) the cell, releasing hundreds of progeny. There were two stages, early and late, classified as happening before or after the viral DNA was replicated, and different mRNAs and proteins were made at each time. Late-stage proteins were to do with making the structural bits of the virus, fitting out the newly replicated DNA genomes with capsid coats before their release by lysis. In contrast, in the early stage of infection, the viruses’ main concern was to persuade their host cells to fire up DNA synthesis. This they did by trickery; because the viral genomes were limited in size by the rigid capsids in which they were contained, they had evolved to carry a cargo of genes able to activate the host’s own replication machinery, which could be fooled into copying the viral DNA in addition to its own.

The early stage of infection was most interesting to those concerned with how DNA tumour viruses caused cancer, because the early genes were the only things the virus switched on during transformation, the lab-induced state roughly analogous to tumour growth in animals. Viral infections leading to transformation were always nonproductive—there were multiple cellular changes leading to uncontrolled growth, but there was no lysis and no production of more virus—indeed, the virus disappeared.

In transformation, as early but not late events happened, an early protein was the obvious culprit for corrupting the cell. The likely villain had a name, T (for “tumour”) antigen, but only a nebulous identity because of the method of detection. When its xenophobic immune system finds a developing tumour, an animal with a virally induced cancer makes antibodies directed against tumour antigens, the foreign-looking bits of the tumour cells. The tumour antigens are likely to derive from the viral proteins because these are the most alien component of the tumour and will elicit the biggest immune response. Antibodies circulate in the bloodstream, and thus extracting blood from tumour-bearing animals produces a tumour-specific antiserum, which can be used for experiments.

Quite early on, in the 1960s, it was realised that when used to label cells in tissue culture, tumour antisera went straight for the tumour cells, ignoring the normal control cells. Used at such low resolution, the antisera were like burglar alarms, able to detect the presence of T antigen on the tumours, but unable to tell what it was; T antigen could have been a posse of tiny tap-dancing penguins, for all the antisera could tell, although admittedly this was unlikely. Whatever the true nature of T antigen, its ubiquitous presence on tumours meant that it was the obvious suspect as the inducer of the cancer; how it might do this was, however, unknown. In line with the virus’s need to subvert cellular DNA synthesis, there was speculation that T antigen’s normal function might be to switch on the cell’s replication machinery, perhaps by suppressing a vital negative regulator—a bit like taking the handbrake off in a car—and in cancer, this function was never switched off, leading to tumours.

With such a comprehensive to-do list, it was very good that as the 1970s progressed, the molecular biology methods repertoire underwent an exponential expansion, from a small number of low-resolution, highly radioactive, potentially toxic techniques to a much larger number of higher-resolution, highly radioactive, potentially toxic techniques (advances in safety had to wait until well into the 1980s). The turning point was Hamilton Smith’s purification in 1970 of a restriction enzyme, one of a large group of bacterial enzymes capable of cutting up DNA by recognising and snipping open a specific DNA sequence. The following year, Dan Nathans and Kathleen Danna showed that SV40 viral DNA could be cleaved by Smith’s enzyme preparation into defined fragments. With the purification of more and more restriction enzymes, each with a specific cutting sequence, DNA could now be chopped up into small pieces, and the pieces ordered relative to one another by doing single or double enzyme digests. (It turned out that Smith’s original prep actually contained two enzymes, so Danna and Nathans’s paper inadvertently showed the fragments generated after a double, not a single digest of SV40.)

With the availability of restriction enzymes, mapping viral genomes became possible, and after Herb Boyer and Stan Cohen’s demonstration in 1972 that a piece of restriction enzyme–digested DNA could be introduced into a plasmid, a small circular DNA parasite able to replicate in bacteria, cloning was born. Once put back into bacterial cultures, plasmids carrying cloned inserts could replicate their DNA very efficiently, meaning that a small amount of DNA could be amplified into the large amounts needed for the experimental techniques of the day.

In 1974, gel electrophoresis became even more useful when Ed Southern worked out that gels could be blotted wholesale onto special membranes made from nitrocellulose, which could then be probed with radiolabeled (“hot”) DNA or RNA. Southern blots revolutionised mapping; because it was now possible to pinpoint exactly which restriction fragment a probe recognised, the location of specific DNAs and RNAs within genomes, whether viral or otherwise, could now be established. Southern blotting was followed in 1977 by a method for transferring RNA rather than DNA from gels, inevitably dubbed “northern blotting,” and in 1979, by “western blotting,” using antibodies to probe protein blots (“eastern blotting” doesn’t exist, but not from want of trying; many researchers have tried to appropriate the name for a multitude of new techniques, but none have succeeded in making it stick).

Richard Treisman, now Director of the London Research Institute, started as a graduate student with Bob Kamen in 1977. His recollections of a couple of the techniques he had to do during his four years at the coalface give some idea of just what was involved. Firstly, preparation of RNA:

To make an RNA prep, you would do a viral infection which would involve infecting a hundred 9 cm dishes of cells. Then you’d have to scrape them all with rubber policemen [an exotic name for a prosaic tool for getting cells off tissue culture plates] and lyse them. Everyone was using buckets of stuff because everything was low specific activity—there weren’t pinpoint methods for analysing RNA. You’d have to make polyA+ RNA [a.k.a., mRNA] and because that was only two percent of the total cellular RNA if you wanted to quantify it accurately you’d have to make a lot of it. It was a very blunt instrument.

Richard Treisman, ca. 1975.

(Photograph courtesy of author.)

And for making radioactive DNA probes:

And all this was repeated day after day, week after week, with astonishing persistence on the part of the investigators.

What exactly was achieved by the Fifth Floor labs? The short answer is that they helped build the foundations of modern biological science, in a series of contributions that were intricately tangled up with contemporaneous work performed in the powerhouse labs of the United States. They then went on to populate the world’s labs with their trainees, many of whom have risen very high. They were, to paraphrase Michael Stoker in his valedictory Director’s Report, riding a bandwagon, but playing at the front. The field moved fast, and they had helped establish it and continued to drive it.

Early on, an informal arrangement on how to carve up the work was agreed, with each person playing to his or her strengths: Lionel would continue with his work on viral DNA, its structure and how it replicated, with a bit of protein work on the side. Mike would do the molecular genetics, making mutants and using them to locate viral genes and determine which were important. Beverly (who had moved shortly after her arrival into Mike’s lab space on the other side of the double doors) would map and sequence the polyoma viral genome, working out where genes were located and what they encoded. Alan would work on viral proteins, and Bob would work on viral RNA. The overarching issue of how the viruses caused cancer would be tackled by determining which bits of their genomes mattered for transformation and by studying T antigen. There was complete sharing of information. Beverly and Mike’s genetic and sequencing data were fed hot off the presses into Bob, Alan, and Lionel’s work on RNA and protein, and vice versa. And if, as was sometimes the case, the lab heads were currently fighting about something, the information flow still continued through their postdocs and PhD students. The result was phenomenally rapid progress on all fronts.

DNA tumour virus investigators were handed the blueprints of their viruses with the polyoma and SV40 sequences, twin Rosetta stones allowing the mysteries of the viral genomes to be resolved. Regions occupied by genes could be identified, and the sequences of the proteins encoded by the genes could be deduced, by translating the triplet codons specified by the DNA into the run of amino acids making up the protein. The sequences of the mutant genes mapped in Mike’s genetic screens could be compared with their normal counterparts, and the amino acid changes causing the mutation identified; sequence could be correlated with functionality, and guesses made regarding what the proteins did, and what was going wrong.

The two virus sequences were also the start of something much bigger: they were the first demonstration that it was possible to assemble a complete genome sequence and that the information gained from the sequence was valuable. This led to the sequencing of much larger viruses, which, in turn, produced the exponential explosion in DNA sequencing technology and analysis culminating in the unveiling of the draft sequence of the human genome in 2001. Today, sequencing DNA is a triviality, performed by robots that can easily sequence millions of bases in a single day.

Mike’s mastery of cloning resulted in a very significant Nature paper in 1979, which resolved a key safety issue in the cloning of eukaryotic DNA. As mentioned above, several of the ICRF’s transient American scientists were there in part to get around the cloning ban that the U.S. biological science community had voluntarily put in place in the mid-1970s. Cohen and Boyer’s demonstration of cloning, with its potential to move genes from one organism into another, had provoked extreme alarm in some of their fellow scientists, with inevitable fears of spreading dangerous genes through the human and animal populations. Even when cloning resumed, the suggested restraints mean that any cloning experiment involving eukaryotic genes had to be performed under extraordinarily stringent containment, which, being expensive, meant many experiments could not be performed at all. Although this, as pointed out by John Cairns, by now head of the ICRF’s North London outstation at Mill Hill, meant that the less competent had a perfect excuse for not doing hard experiments, it was a real nuisance, especially as it became increasingly clear that the regulation was excessive. Mike and his collaborators put the lid on the controversy by cloning the complete polyoma genome into a bacterial plasmid, introducing it into mouse cells, and showing that in this form it was not infectious and could not spread.

Joe Sambrook and Mike Fried, 1974.

(Photograph courtesy of Cold Spring Harbor Laboratory Archives.)

On either side of Lionel, despite their differences in lab hygiene, Bob and Alan got along well and collaborated extensively, Bob contributing his expertise in making RNA, which Alan could then plug into his cell-free systems and translate into protein. Bob’s literary style also benefited: “[Alan] was much more organised than I was—he could actually write papers. I couldn’t do first drafts and he did first drafts very easily. Alan would look at all my adjectives and take them down one level of superlative!”

Alan Smith, 2002.

(Photograph courtesy of CRUK London Research Institute Archives.)

The Smith lab, with its connections to Cambridge and the Laboratory of Molecular Biology, attracted some high-calibre trainees, amongst them a young Tony Pawson, whose PhD project there was to look at cell-free translation in Rous sarcoma virus. Tony, erstwhile Director of the Sam Lunenfeld lab in Toronto, Companion of Honour, and winner of multiple prizes and medals, including the Kyoto Prize, the “Japanese Nobel,” thought the ICRF was “... a daunting challenge for a young 21-year old. On the other hand, it was the most stimulating and thought-provoking environment that one could possibly imagine. The cloning of recombinant DNA was just starting, as was the tentative identification of genes and proteins that might be causally involved in the development of cancers. I shared a bench with Ed Ziff [one of the pioneers of the transcription field] who had just developed an early approach to DNA sequencing, and he was unfailingly generous with his time and advice.”

The puzzle was finally solved by the ICRF–Cold Spring Harbor connection, in the person of Joe Sambrook, who showed up in Bob’s office one day in 1977 with some advance notice of a major scientific breakthrough by Phil Sharp at MIT and Rich Roberts at Cold Spring Harbor—the discovery of splicing. Both Sharp and Roberts were working on adenovirus, a larger DNA tumour virus that can cause human cancer, and both had now shown that adenovirus late mRNA molecules were made in an entirely novel way. As in bacteria, the RNA was transcribed as one long molecule, but then there was a new, eukaryotics-only twist to the story: the long RNA was then spliced. Exactly as one edits out an unwanted scene in an old-fashioned film reel, the cell chopped loops out of the precursor RNA to produce the final, smaller molecule. Therefore, as Bob had been seeing back in London, mapping of the final product would make it look as though the RNA was being made from bits of unconnected DNA.

After splicing was discovered, eukaryotic mRNA studies were a lot easier to decipher, but also became a lot less simple. Once it was proven that splicing was not just a viral peculiarity, but happened in all eukaryotes, it was clear that transcription of a eukaryotic genome was incredibly complex, with multiple mRNAs being made from the same stretch of DNA, mRNAs starting and stopping in different places, and differential splicing galore. The study of the DNA sequences controlling transcription and the proteins that bound to those sequences to direct the process, became and remains a field in its own right, and transcription research continues to produce unexpected explanations for mystifying data.

For SV40 and polyoma, splicing was the key to understanding why the viruses were so powerful. In getting around the constraints of being packed into a small capsid, both viruses had come up with an ingenious way of maximising their impact on a cell. Like tiny tardises, their genomes had the potential to encode far more than had been thought possible, because multiple differentially spliced mRNAs could be transcribed from the viral DNA.

The belief that T antigen was just the one 100-kDa protein was abandoned in 1977, in the same year as splicing was discovered, when both SV40 and polyoma were shown to have two T antigens. The original 100-kDa protein was renamed large T, with its new smaller companion unsurprisingly christened small T. SV40 and polyoma small Ts were both ICRF finds, one discovered by Lionel, off on sabbatical on the West Coast in future ICRF group leader George Stark’s lab, and the other by Yoshi Ito, a postdoc in Renato Dulbecco’s fourth-floor lab. (Ito was to become another star of the cancer field and was also a major force behind Singapore’s transformation into a world-class centre for biomedical research.) In the case of SV40, Lionel and his Stanford colleagues also scored a first regarding small T’s origins, when they proposed that it shared the same front end (“amino terminus”) as SV40 large T but had a different back end (“carboxyl terminus”); in all but name, they had shown that splicing could occur, and their data slightly preceded Sharp’s and Roberts’s. The relationship between large and small T was rapidly confirmed, at the protein level by Alan Smith’s lab at ICRF and Carol Prives and her colleagues at the Weizmann Institute in Israel, and at the mRNA level by Phil Sharp and Arnie Berk at the Massachusetts Institute of Technology (MIT). The two proteins are made from the same genomic sequence but are splice variants: SV40 small T mRNA is unspliced and only encodes 174 amino acids before a stop codon is reached, and translation, and hence small T protein, terminates. Large T mRNA also starts off at the same place but is spliced to remove the sequences unique to small T, including the stop codon; it therefore makes a far larger final product 708 amino acids long. The discovery was important not just to the SV40 field; Sharp and Roberts’s adenovirus splices were in an untranslated part of the RNA, so the large T/small T result was the first example of splicing in a coding region. It illustrated just how exquisitely precise the process had to be; an exact base-to-base join always had to be made at the splice junction, because otherwise the proteins translated from the mRNA would be gibberish.

To finish the middle T story, c-Src was the first of many proteins with which middle T was shown to interact, and all these multiple interactions mean that middle T sits at the centre of a web of signaling pathways and turns them all on, driving cells into uncontrolled replication and thus causing cancer. Using middle T as a probe for derangement of cellular function proved to be hugely important for cancer research, more than fulfilling the DNA tumour virologists’ hunch that their viruses were a simple way into a complex system. Middle T strikes right at the heart of a cell’s regulatory pathways, and all of the proteins and interacting pathways first found using middle T are universally important in controlling normal and cancerous growth.

With all the kerfuffle on the Fifth Floor surrounding polyoma, it was inevitable that the SV40 camp started to wonder whether their virus had a middle T antigen too. SV40 large T did some suspiciously oncogenic things, like stimulating cellular DNA synthesis, but perhaps there was more to it than that; perhaps it was just a decoy, or perhaps it was only part of the story. It would be great to find an SV40 middle T, but the problem was that the immunoprecipitation technique, the method of cellular fishing described above, was, to be frank, pretty rubbish. There was certainly a slew of other bands that were pulled down in immunoprecipitates at the same time as SV40 large T, but most of them were probably chopped up bits of large T or background contaminants, there because the anti-tumour antisera could sometimes be alarmingly nonspecific. Yoshi Ito had succeeded in finding polyoma middle T by spending a lot of time tinkering with his immunoprecipitation conditions, and something similar was needed for SV40. Lionel, especially, was aware of this, and started to think very hard about how to proceed, talking at length to the hard-core immunologist Av Mitchison at the ICRF Tumour Immunology Unit just down the road at University College. Av, although sympathetic, was not very helpful. Fortunately, help was at hand in the person of Av’s PhD student, a promising young chap with a knack for immunochemical troubleshooting. To cut to the chase, Lionel and his new recruit would find that there was no SV40 middle T. What there was instead, for all of the marvellous doings of the rest of the Fifth Floor, would in the end eclipse them completely.