oger Kornberg, one of Arthur's boys, has a Sydney Brenner story. We all do, but his is more telling than most. Roger spent four years in the 1970s as a postdoc with Francis Crick and Sydney Brenner at the Medical Research Council Laboratory of Molecular Biology, in Cambridge, UK. Francis and Sydney shared an office with a blackboard toward the east end of the second floor; as we know from Jim Watson's The Double Helix. Francis does science in large part by talking, and Sydney is a talker. Sydney was also arduous at the bench. Typically, he arrived around noon and worked through until past midnight. The building had a library, quite good and comfortable, up the stairs at the west end. But the stretch of the second floor where Crick and Brenner worked had a room also called a library, with a few books and back issues of journals, a table, and the makings of tea. As Roger told the story, late one night he, Sydney, and several other postdocs who followed Sydney's work habits were drinking tea and talking, mostly science. One of the postdocs left. Sydney immediately said of him something true, funny, and cruel. Ten minutes later, another left. Sydney said of him something true, funny, and cruel. So it went. "Finally, Sydney and I were sitting alone," Roger said. "And I was afraid to leave."
Savage intelligence and wit characterize Brenner's science, too. He is the son of a Lithuanian cobbler who emigrated to South Africa at the turn of the old century. At 15, he entered the University of the Witwatersrand, then won a fellowship to Oxford to take a D.Phil. There he heard a talk by Fred Sanger, over from Cambridge, about the amino-acid sequences of insulin. "I had never understood proteins before!" In the spring of 1953, in his last term, he crossed to Cambridge to see the model of DNA. Watson and Crick liked his nimble mind. The fellowship required him to return to South Africa, but first he had a summer in the United States, coast to coast. Eager, intelligent, mordantly funny, he made friends with all the biologists he met, notably Gunther Stent, at Berkeley. And he learned. On the way back to South Africa, he stopped again in Cambridge for a few days, staying with the Cricks. They talked about coding and about an idea Crick was postulating, on purely theoretical grounds, that cells must contain small molecules specific to individual amino acids to grab and carry them to be correctly assembled in the growing polypeptide. Brenner suggested calling them "adaptors."
At the medical school of the University of the Witwatersrand, he began to do phage experiments. Desperate to get out of apartheid South Africa and into the scientific world he had toured, he wrote letters, scores of them, and his friends wrote back. His are dispersed; their replies make wonderful reading.
Sydney's letters from Francis are stacked with science hot from the griddle. They are quietly encouraging. Crick is not one for gushing sympathy. No, but when it's someone he likes and respects he helps, directly and practically. He campaigned unflaggingly to get Brenner to the Medical Research Council unit, then still in the Cavendish Laboratory and still small, though crammed with visitors. Money was tight, space tighter. On Oct. 20, 1955, he wrote among much else, "I was delighted to hear that that you were prepared, if necessary, to work in a cupboard!" On Dec. 30, he wrote that he was authorized to make Brenner a definite offer, although the details of bureaucracy, housing, moving, schools for Brenner's two step-children, took months more, Crick ever deft and sensible with arrangements and suggestions.
The coding problem was central to those years: how the 64 possible triplets of DNA sequences related to the 20 amino acids of polypeptide chains. George Gamow the physicist, who among much else promoted the Big Bang, had pressed the coding problem on Crick and Watson in the summer of 1953, and had organized the RNA Tie Club, with loopy enthusiasm, to promote discussion and to circulate papers that were too speculative to risk formal publication. Half a dozen got written. Crick sent out one, "On Degenerate Templates and the Adaptor Hypothesis," suggesting that several different sequences of nucleotides in DNA might code for a given amino acid, and crediting Brenner. The adaptor hypothesis predicted the discovery of what we now call transfer RNAs. Employing the increasing number of polypeptide sequences that became available, in September of 1956 Brenner circulated "On the Im-possibility of All Overlapping Triplet Codes," demolishing with a dazzling piece of analysis the possibility, springing from an early notion of Gamow's, that DNA was read 123, 234, 345, and so on.
Later, after the code was cracked and almost completely worked out, he coined the term "codon" for a coding triplet. Three of the 64 triplets did not code for any amino acid. With elegant bacteriophage experiments, Brenner got two of them. Alan Garen, at Yale, got the other: they are nonsense codons, which signal the end of the polypeptide chain. Brenner described that work. "Finding out about the machinery without touching the biochemistry," he said. "There was a culture, well, a cult, almost, that became typical of molecular biology. What became prized was ingenuity. You know?" He added, "Of course, the simpler the methods used, the more highly prized." Brenner was the acknowledged master of experimental minimalism.
The most arresting discovery, though, began with a meeting in Brenner's rooms in King's College, Cambridge, the afternoon of Good Friday, 1960. Crick and Brenner were there, François Jacob from the Institut Pasteur, in Paris, Alan Garen and his wife, others of the international inner circle. Crick, Brenner, and Jacob put together what separately they knew, and realized in a classic explosive "Aha!" that between the DNA and the assembly of protein chains, a short-lived RNA intermediate carried the genetic instructions. Until then they had assumed that ribosomes, tiny bits of cellular anatomy where polypeptides are assembled, themselves were specific to particular genes. Now they saw that the ribosome was what Crick called "a reading head." In June, Brenner and Jacob went to Pasadena, to the Caltech laboratory of Matthew Meselson, to apply Meselson's method of density-gradient centrifugation to demonstrate the existence of the RNA intermediate. The Brenner, Jacob, and Meselson paper1 is one of the canonical papers of the golden age of molecular biology. The intermediate, of course, was later termed messenger RNA.
A science can be an exclusive club. Most scientists draw a circle, and others are either within it or not. Max Delbrück was like that, but once you were accepted he was open, interested, generous. Brenner has, perhaps, drawn that circle tighter. All around him, though, colleagues were winning Nobel Prizes. His work was always in the penumbra of the prize, and of greater quality and importance than that of some laureates. Messenger RNA might well have turned the trick. Though he has never given a hint of disappointment, one has sensed over the years a certain bitterness.
In the mid-1960s, Brenner began to abandon elegance for brute force and Caenorhabditis elegans. Such a total change in intellectual style is extremely rare in the sciences. This tiny worm of disgusting habits and hardly more than a thousand cells, a slightly different number for males and females, he chose as a model organism, as simple as could be found, for studying embryological development, rather as Delbrück in 1938 had chosen bacteriophage as the simplest for genetics. The plan was, first, "to get the wiring diagram" of the nervous system, and to trace the lineage of each cell in the adult back through the development to the fertilized egg. Also the genetics; later, when technology permitted, the genome. Today, a thousand or more investigators are working on C. elegans, and the problem is to complete the analysis of the functions of the genes.
In 1976, Crick left Cambridge and molecular biology for La Jolla, the Salk Institute, and neurobiology. In 1979, Max Perutz retired as chairman of the lab. The Medical Research Council, as is their wont, reorganized it, and in September Brenner became director. On his motorcycle the evening two days before he started, he spotted a wallet in the road, and took it to the police station. Riding sedately home, he was struck by a taxicab emerging from a side street. Both legs were broken, badly. To this day, he is in discomfort and requires walking sticks. He was temperamentally ill-suited to the director's job, not a natural administrator, not a politician, and not adept at working with the great variety of scientific interests and talents. Aaron Klug replaced him.
Brenner went to the Scripps Research Institute in La Jolla, California. Later he founded the Molecular Sciences Institute, in Berkeley, Calif. Today, he lives much of the year in La Jolla, with a connection with the Salk, and sometimes in the warmer weather lives in Ely, the cathedral town north of Cambridge. He has, perhaps, mellowed—but you'd better not leave the room.
Matthew Meselson has a Sydney Brenner story, more telling than most. On Harvard Square stands a branch of the American nationwide sandwich-soup-and-coffee chain Au Bon Pain, with outdoor chairs, tables, even chess-players in warm weather. Brenner was visiting. They walked through the square. Brenner looked at the cafe's sign and growled, "Bone pain." Matt has avoided the place since.
Student Years at Wits
Those were heady days at Wits (the University of the Witwatersrand, Johannesburg) in the 1940s when a wide-eyed and tousle-haired Syd Brenner began to lay the foundations of an extraordinary career. Having matriculated from high school in Germiston, close to Johannesburg, at the young age of 15, he entered the Health Sciences Faculty as a medical student in 1942. His background was humble and he, like myself, was the first member of his family to enroll for a university education.
Had he gone through his medical course without interruption, he would have been too young, on qualifying, to be placed on the Register of Medical Practitioners. Happily there was a mechanism whereby scientifically minded students could branch off from the medical course in midstream to take what was called a Medical BSc. Syd chose this direction. It was during this 'science year' that he fell under the spell of such people as Raymond Dart, the head of the anatomy department, Joseph Gillman, Michael Wright, and Harold Daitz—or should that be, they fell under Syd's spell?
Joe Gillman was a powerful, if eccentric, personality; students found him difficult to get on with, yet he inspired them with his scientific zeal and, especially, with his constant air of divine discontent, of kicking against the pricks, of rowing against the current. These traits in his make-up found a ready echo in Syd Brenner as they, in an as-yet half-formed way, mirrored features of his own personality. For Syd was never one to follow the common herd, to tolerate the trite or to run headlong with the Gadarenes. These features were already manifest during seminars, class presentations, and everyday discussions.
Although not yet out of his teens, Syd's BSc and BSc Honours degrees gave him scope for his first ventures in research. He could argue knowledgeably and persuasively about chromosomes and genes, DNA and Caspersson's ultraviolet absorption spectromicrophotometry, Bernal and his X-ray diffraction, heterochromatin, Soviet genetics and where Lysenko had got it wrong. The power of his memory was gargantuan, and Syd would cite not merely references but the very pages on which key points were made.
Most people, after an absence of one or two years from their medical studies, would return to the humdrum of pathology, pharmacology, and bacteriology, in the medical course. Syd decided to spend a further full year in the anatomy department as an MSc student. His master's dissertation was devoted to the chromosomes of the little insectivore, Elephantulus, so named because of its trunk-like proboscis.
Remember, this was still several years before Francis Crick and Jim Watson produced their model of the structure of DNA, before the genetic code was cracked and before, even, it became known that Homo sapiens had 46 and not 48 chromosomes. Yet Syd was toying with the nature, biochemistry, and genetics of heterochromatin, as Prokofyeva-Belgovskaya had been doing in the Soviet Union, and demonstrating multipolar mitotic spindles in neoplastic cells, even as P.C. Koller at the Cancer Hospital in London was struggling to understand the effects of irradiation—discouraging cancer cells and encouraging surrounding 'normal' cells, fearful of the delicately poised boundary between the two processes.
It was not surprising that, with these interests, Syd was soon to be drawn to England and new pastures, where he was to become involved with frontline researches on DNA, molecular biology, and developmental genetics. But let me return to his time at Wits, where he completed his MSc at frenzied tempo and his medical degree between 1947 and 1951.
It should not be thought that the microscope, test tube, and centrifuge were the only things occupying Syd's roving mind as he entered young manhood. The department in which he and I were working fell under the headship (for 36 years) of Raymond Arthur Dart. He was who had first revealed to the world the Taung child of Australopithecus africanus—who had lived in the department ever since.
With this aura permeating the corridors (on the floor above the cadavera), and with physical anthropologists like Sandy Galloway and Lawrie Wells among our teachers, it was not surprising that we in the Medical BSc class received a healthy dose of palaeoanthropology on the side. Syd plunged in with verve. On our student expeditions to one of the apeman sites, Makapansgat, 300 kilometers north of Johannesburg, Syd made a valiant attempt to clear up the jumble of strata comprising the cave filling. The sequence of layers he clarified provided some leads on cave morphology and was followed, a couple of years later, by studies of cave formation by C.K. Brain and of the stratigraphic sequence by T.C. Partridge.
One of the challenges in the study of cave fillings in South Africa was provided by the "Kalahari sand," looming on South Africa's west flank. In 1946, Syd joined forces with V.L. Bosazza and R.J. Adie and together they made a gallant assay at understanding the repeated advances and retreats of the Kalahari sand eastward from Botswana across South Africa during the time that hominids were playing out some of their early evolutionary stages in this part of the world. They recognized that there had been a series of major expansions of the Kalahari Desert over the caves of the central Transvaal, an interpretation that I, in my 1947 'dig' at Mwulu's Cave, and Lester King, at three apeman caves in 1951, were able to corroborate.
So life was replete with fieldwork, expeditions, excavations, and fossil collecting at such famous sites as Sterkfontein, Kromdraai, and Makapansgat, as well as with probing of the morphogenesis of cave earths. There were also veld frolics to catch elephant shrews at Bronkhorstspruit and the lizard, Agama, northwest of Johannesburg so that studies could be made of the placentation, chromosomes, and embryogeny of the former, and the brain morphology of the latter. All conspired to whip up a froth of what we liked to think of as constructive and mind-expanding activities, not only in the laboratory, but in what American geneticist L.C. Dunn called "that ultimate laboratory of biology, free nature itself."
Syd's love of fun was ever present. At class parties his recitals, imitations, bawdy songs, buffoonery and inimitably zany behavior reduced us to uncontrollable laughter. Imagine it—in the lab (out of hours) or around the campfire at Sterkfontein, or imitating the lusty sex-cries of baboons on the roof of Medical School, where Dart had set up the first primate colony in Africa.
The parties were, I suppose, escapism from the pressures of thesis writing and project deadlines, but also from the new set of stresses—O tempora! O mores!—imposed by the apartheid government from 1948 onward. Syd threw himself energetically into the anti-apartheid movement that some of us had started on the Wits campus and in the National Union of South African Students (NUSAS). Soon Syd was president of the Students' Representative Council (SRC) of Wits University, giving a strong lead to the campaign against racial exclusions that the government was threatening to inflict on our Universities.
Every time a student of color was refused an inter-provincial permit or a visa to attend Wits, Syd and I set in train protest meetings and démarches against the government's unacceptable policies—he as president of the Wits SRC and I as president of NUSAS. One of our most memorable meetings was an open-air gathering in the amphitheatre near the Wits swimming bath. A Mozambiquan—Eduardo Mondlane—a few months before he was due to complete his degree at Wits, was refused renewal of his visa, so he had to return to Maputo. An isolated incident? No, we showed that it was part of a tissue of measures to whittle away the number of black African students at Wits as part of a softening up before apartheid was legislated into the universities. Syd presided over the meeting; I moved the motion of protest. It was carried, according to the Rand Daily Mail, by 700 votes to four. That was, I believe, the first occasion on which Syd and I had an encounter with the Special Branch. This was the same Mondlane who later led the Frelimo movement for the liberation of Mozambique and who still later was assassinated by a parcel bomb.
Sydney became the director of Research of NUSAS. One of the fruits of that was a multidisciplinary and multiracial expedition to the Ndabakazi 'Location' in what was then called the Transkei. Syd and I toured the various universities that belonged to NUSAS, promoting its image (as we say these days) and trying to head off disaffiliation movements when some student leaders thought that NUSAS was becoming "too political" in its opposition to apartheid and racism. That was another dimension of life, often depressing, sometimes exciting, not without danger.
One other little image of Sydney, the many-sided genius: there hangs on a wall in my Johannesburg apartment a Brenner water color, painted on a warm February day in mid-century. Yes, Syd took up painting and the "Two Cultures" met and merged for a while in his person. Was it the influence of Conrad Waddington, the geneticist, who tried so hard to be a whole rounded person ("It is time the different kinds of scientific cobbler stopped sticking to their last") and whom we brought to Wits from Edinburgh when we set up the Visiting Lecturers' Trust Fund? Or was it Syd's own private rejection of C.P. Snow? Perhaps it was a simple therapy from life's fitful fever.
Bliss was it in that dawn to be alive, But to be young was very heaven!
I always think of Sydney as young Brenner partly because he was born one day after me and partly because he has successfully maintained his youthful exuberance right up to the present. I first met the then literally young Brenner more than 50 years ago, when we were both working toward our PhDs at the Physical Chemistry Laboratory, a part of the Oxford University chemistry department.
At that time, I was a theoretical chemist beginning to use the methods of quantum mechanics to calculate the properties of inorganic molecules, and Sydney was supposed to be carrying out experiments designed by Sir Cyril Hinshelwood to show that the workings of a bacterial cell were readily understood as a network of chemical reactions. Sir Cyril did not have much time for genetics.
Jack Dunitz, a crystallographer now working at the ETH in Zurich, Sydney, and I became close friends. We spent much time discussing science and gossiping about our colleagues. If it was not for those conversations, I might well have remained a theoretical inorganic chemist for the remainder of my career. In those early days, Sydney was already pre-occupied with viruses, DNA, mutation, and the other topics that were central to the molecular biology of the 1950s. No hearing person around Sydney could remain unaffected by his enthusiasm, so I was inducted into subjects that were still unknown territory to almost everyone else studying chemistry.
Sir Cyril, an English eccentric in the best tradition and a formidable scholar, was certain that chemical kinetics would suffice to explain the behavior of bacterial cells while Sydney knew that this was impossible. Sydney did experiments that proved the importance of mutation and Sir Cyril was convinced, but only temporarily. Soon, Sydney was back at work proving the importance of mutation even more conclusively, and Sir Cyril would reluctantly accept the evidence and then slowly retreat to his old position. As far as I could tell, the whole cycle was repeated many times, always with the greatest civility. Sydney has told me that he did finally convince Hinshelwood. But I wonder whether, deep down, Hinshelwood could ever have abandoned his beloved kinetic theory.
Even in those days, Sydney was already a wonderful mimic and storyteller. His descriptions of the members of Hinshelwood's research team were early classics of the Brenner genre. I particularly liked his account of an obsessive colleague who had a different pencil for each day of the week and would only sharpen his pencils according to an immutable schedule. Sydney was interested in everything scientific, and was as inventive then as he is now. It has always been enormous fun to be around him, but you do need adequate intellectual stamina.
DNA was very much on Sydney's mind at that time. He believed, for reasons that I cannot recall, that by adsorbing dyestuffs onto DNA he could somehow simplify the process of structure determination. I believe that he and Jack Dunitz were still thinking about this approach when we first heard that an interesting structure was on view in Cambridge. I will not retell the story of the visit that Sydney, Jack, and I made to Cambridge in the spring of 1953 to inspect the Watson-Crick double helix. We were all impressed by the beauty of the structure and were convinced that it was correct. The following morning we sent a telegram that read: "Congratulations-Gene." I am sure that Sydney saw more clearly than Jack or I that biology had entered a new era.
Cambridge and the Code
Sydney and I shared an office in Cambridge for 20 years, starting in 1956. I first met him in 1953 when he came over from Oxford, with Leslie Orgel and Jack Dunitz, to see the model of the double helix that Jim Watson and I had just made, but I only got to know him in the summer of 1954, while we were both visiting the Marine Biology Laboratory in Woods Hole, Mass., and, briefly, again at the Cold Spring Harbor Laboratory, in New York.
Sydney became for a time 'Our Representative at Cold Spring Harbor,' explaining to Milislav Demerec (the laboratory's director) what DNA was all about. After Sydney's return to South Africa, we corresponded at some length about the latest results, and our plans for future research. Max Perutz and I were able to persuade the UK Medical Research Council to give Sydney a job in our unit. He arrived with his family in 1956, and as there was then no accommodation available for them in the town, they all lived in our attic for a while. Not the ideal introduction to Cambridge.
Sydney had said that, if necessary, he was prepared to work in a cupboard, but fortunately the Cavendish (the physics lab at Cambridge) had by then allocated us some space for experimental work in biochemistry and genetics, and over the next few years we managed to accrete a little more, here and there, by colonizing small vacant rooms in adjacent buildings.
Even before Sydney arrived, he had devised an ingenious proof that the genetic code (assuming it was universal) could not be overlapping. But his great strength was in experiments, and in particular the choice and execution of ones that were both important and ingenious.
Our main target was to study protein synthesis and in particular to discover the genetic code, using microorganisms, and especially bacteriophage. Our hope was to combine genetics and biochemistry, firstly to show that a gene and the protein it coded for were co-linear (we had no suspicion of introns) and then to discover which group of bases (triplets, as we always suspected) coded which amino acid. A prolonged attempt was made to purify the rII protein of phage T4, but it was handicapped by the rather primitive biochemical techniques available, though, thanks to Seymour Benzer, we could do fine genetic mapping of the two rII genes.
Eventually we were able to show by purely genetic methods (using phase-shift mutants and a neat cross devised by Sydney), that the code was almost certainly a triplet code and that most, but not all, of the triplets probably stood for one amino acid or another. Most of the details of the code were worked out by others, but Sydney, with great ingenuity, worked out the three STOP codons by genetic methods. He also discovered suppressors of them.
Sydney and Anand Sarabhai finally showed that, at least for the head protein of phage T4, the gene was co-linear with its protein, not, as Charlie Yanofsky did, by actually sequencing the protein, but merely by comparing the size of the polypeptide chains made by STOP (amber) mutations at a series of mapped sites on the gene.
Sydney has given a much fuller account of all the work we did then in his recent book, My Life in Science (BioMed Central London; 2001). It was a blissful period, because the problems were important, only a few people (most of them friends) were working on them and, thanks to the Medical Research Council's support, we didn't have to write grant requests and could study whatever we liked. Sydney and I had discussions almost every working day—using several large blackboards—but he also spent long hours in the lab and considerable time reading the literature. He was much better than I at thinking up novel experiments. My role was more that of a critic and clarifier.
Collaborating with Sydney not only made all the difference to my ideas and my few experiments but it was all such fun. It says much for his tolerance and good temper that there was never an angry word between us. Happy days!
Asilomar and Recombinant DNA
In 1974, the scientific community was stunned by a letter in Science from a group of eminent biologists, of which I was one. It called for a moratorium on the conduct of certain kinds of experiments using the newly developed recombinant DNA technology. Its purpose was to call attention to the possibility that recombinant DNA experiments posed potential risks to those carrying out such experiments, to the general public, and to the environment. Many molecular biologists were already aware of, and appreciated, the promise of the new methodology and its potential to advance molecular biological research, particularly on gene structure and function.
Unsurprisingly, there were articulate critics and defenders of the call for a pause in the research and debates flared among scientists in the United States and abroad to assess the wisdom of that recommendation. Somewhat unexpectedly, the UK Medical Research Council declared all the experiments described in the moratorium letter virtually illegal until the risks could be evaluated. The worldwide press had a field day conjuring up 'what ifs' that matched the scariest science fiction scenarios.
Nevertheless, although shaken, the general public appeared to be comforted by the fact that the very scientists who had played a role in that technology's development, and who were most likely to adopt it in their own research, were those who proposed the moratorium. In spite of some grousing about having to forego planned experiments, there was little if any contravention of the moratorium in academia or industry, in the United States or abroad.
The moratorium proposal was accompanied by a call for an early international conference at which scientists from around the world would help evaluate the scientific opportunities and potential risks of the new technology. With encouragement and financial support from the US National Institutes of Health, the National Academy of Sciences, and the National Science Foundation, the conference on recombinant DNA was planned for the Asilomar Conference Center, a rustic and secluded setting on the shore of Monterey Bay in Pacific Grove, Calif., during February 1975.
The United Kingdom, however, had been even quicker to address the potential benefits and risks of recombinant DNA by convening a 'working party' under the chairmanship of Cambridge University's Lord Ashby. Sydney Brenner was a key participant in Ashby's team and played a critical role in persuading the group to recommend lifting the moratorium, while requiring stringent controls on how recombinant DNA experiments were to be conducted.
The responsibility for organizing the Asilomar Conference's proceedings was vested in a small group that had been active in raising the issue. To ensure coordination and consistency between the Ashby working party's deliberations and the Asilomar conference's discussions, Sydney was invited to join the organizing committee's planning efforts. It was perhaps the committee's wisest decision.
Throughout the conference, Sydney's vision of the new technology's opportunities energized the discussions and helped lay the foundation for the conclusion that a way had to be found to proceed with the research, safely. One of the conference's fundamental decisions, in part driven by his vision, was to assign a best estimate of potential risk to kinds of contemplated experiments and to devise guidelines for increasingly stringent requirements for minimizing those risks.
Two ways were conceived that could achieve that end. One, physical containment, pertained to the nature of the facilities to be employed for particular experiments; laminar-flow hoods and laboratories under negative pressure were recommended to minimize the release of engineered organisms. The other proposed barrier to inadvertent release of engineered organisms reflected Sydney's ingenious suggestion of biological containment: experiments that were judged to present the greatest possible risks were required to use, as their hosts for cloning experiments, genetically modified bacteria that could not survive an escape from the laboratory.
Sydney's forceful personality and prodigious skill in microbial genetics helped convince the assembled scientists that 'safe' plasmids, phages, and cells could be developed. He joked that perhaps scientists contemplating recombinant DNA experiments should use Pasteurella pestis as the host for cloning experiments.
There were times during the conference when the sentiment for doing nothing that might impede research conflicted with a realization that a workable solution for dealing with presumptive safety concerns was essential. On such occasions, the conferees needed to be reminded of the consequences of doing nothing: public condemnation of seemingly self-serving behavior with consequent government interference and possibly legislated prohibition. Scariest of all, there was the possibility of legal action with financial penalties.
At one of these turning points, Sydney rose and admonished the "die-hards" to "reject the attitude that I'll go along and pretend there is no biohazard and hope we can arrive at a compromise that won't affect my own small area", so that "I can get my tenure and grants and be appointed to the National Academy and all the other things scientists seem to be interested in."
The final day was set aside to hammer out the conference's assessment of the technology and of the potential biohazards of lifting the moratorium and, most importantly, to produce recommendations about how to proceed. Once again, Sydney's adroit use of humor and pressure helped keep the discussion on track when it seemed to be veering into chaos.
Finally the conference accepted the organizing committee's draft recommendations for instituting rather stringent regulations governing how recombinant DNA research could be conducted. In the ensuing eight months, Sydney continued to advise the National Institutes of Health in drafting The Guidelines, which were subsequently adopted virtually unmodified by those nations where recombinant DNA research was conducted.
Working with Sydney throughout the recombinant DNA debate, especially during the Asilomar Conference, was one of the more rewarding aspects of the experience. His unique brand of humor kept us going; his creative way of attacking scientific issues inspired us all. And his deeply felt ethical responsibility motivated many to forego some of their more selfish instincts.
The signatories of the moratorium letter (Science 185: 3034, 1974) were Paul Berg, David Baltimore, Dan Nathans, James Watson, Norton Zinder, Sherman Weissman, Richard Roblin, David Hogness, Stanley Cohen, Herbert Boyer and Ronald Davis. The Asilomar Conference Organizing Committee comprised Paul Berg (chairman), Maxine Singer, David Baltimore, Sydney Brenner and Richard Goblin; Nils Jerne was invited but declined to participate.
The JMB years
When I first started working with Sydney Brenner as a young postdoc in the late 1970s, he was, in addition to being the director of the Medical Research Council's Laboratory of Molecular Biology, the editor in chief of the prestigious Journal of Molecular Biology.
Once or twice a week, Gillian Harris, the editorial assistant for JMB, as it is universally known, would come to up to the laboratory laden with a stack of 15 or 20 manila folders containing the manuscripts requiring his attention. Whenever Sydney would see her walking down the corridor, he would shout, "Not that bloody woman again!" But he would immediately drop whatever else he was doing and rush off to attend to JMB matters. Gillian, who was long accustomed to this curious salutation, would usually smile and say, "Not too much this week," although, as far as I could tell, the piles of manuscripts were constant and never ending.
Sydney took his editing responsibilities seriously, and he was very adept at filtering out the mediocre papers from the more interesting ones by exercising a form of triage. "Bumph" and "More bumph" became in Gillian's translation, "Your paper was considered at a meeting of the Cambridge editors. I regret to inform you that the board felt that it falls outside the scope of the journal's editorial policy and would therefore be better suited to a more specialist journal." Sydney's: "Oh no, not again!" became "We regret that owing to the limitations of space we are unable to reconsider your manuscript."
On the other hand, if Sydney felt that a paper had merit that was unappreciated by the referees, he would lean over backward to accept it, occasionally over-ruling highly negative reports. This was particularly true for papers reporting innovative techniques, which were often harshly criticized by referees because their applications appeared very limited. As a result of Sydney's active endorsement, JMB assembled an enviable record in the early 1970s for publishing seminal new methods in the emerging field of recombinant DNA.
Anyone who has ever read one of Sydney's columns, erstwhile in Current Biology but now appearing in this magazine, or one of his scientific papers, quickly realizes that as well as being a thoughtful editor, he is a brilliant writer, who has a rare gift for being simultaneously insightful and funny. But only those of us who have written papers with him realize that he can also be a terrible procrastinator when it comes to completing scientific manuscripts. However, in keeping with everything that he does, Sydney procrastinates with élan. My first experience of this came during the writing of our paper on 'phasmids.'
Phasmids were an early type of cloning vector, created as a hybrid between plasmids and bacteriophage lambda. They were particularly useful because the plasmids could either be picked up or released from the bacteriophage automatically by site-specific recombination and then manipulated genetically using phage crosses. The assembly of the lambda phages needed to accommodate the plasmids had been done by Sydney himself using an extremely complicated set of genetic crosses, while Gianni Cesareni and I contributed to the project by cloning attachment sites into the plasmids and using the vectors in various cloning projects. The work had mostly been completed in 1979, but by the time 1981 rolled around, and Gianni had long-since departed for the European Molecular Biology Laboratory, the work still hadn't been written up. It fell to me to try to assemble a manuscript.
Unfortunately, I needed to extract details about the phage crosses from Sydney, who considered this to be an extremely boring task and would quickly change the subject whenever I brought it up at work. I finally resorted to visiting him at his home in Grantchester on the weekends. Things proceeded quickly for about two visits, but on the third visit, soon after I arrived Sydney said: "Oh, I forgot to tell you, Victor Rothschild is coming to lunch, so you'll have to go!" A few minutes later, Lord Rothschild arrived, I was duly introduced, and then quickly ushered out by Sydney's wife, May. The next weekend Paul Berg came to visit, then Francois Jaçob's son, and there followed a host of other luminaries.
Despite the delays, the manuscript was eventually completed and we sent it off to Max Gottesman to edit for JMB. It came back with alarming rapidity and a polite note from Max suggesting that it was "too applied" for the Journal—proof, indeed, that no special favors were granted to the editor in chief when it came to publishing in JMB. Finally, the paper was sent to Gene (and published in 1982, 17, 27-44), where it received such glowing reviews that Waclaw Szybalski, who was then the editor in chief, was prompted to invite Sydney to join the journal's editorial board.
As time went on, Sydney started giving me more and more papers to referee, including a large number on arcane issues far away from my main areas of interest. Whenever I protested about not knowing anything about a particular field, Sydney would say: "Don't worry, I have already consulted a real expert and just want the opinion of someone who doesn't know anything about the subject!" Eventually I resorted to complaining that I was getting too many papers to review, so Sydney said with a broad smile: "Well, I guess you'll have to join the editorial board," with the advice that I should "get rid of the junk quickly, so you can concentrate on the interesting papers."
Years later, I learned from Aaron Klug that the same thing had happened to him: when he started complaining to John Kendrew about the volume of JMB papers given to him to review, he was promptly appointed to the board. So, all my illusions that people are elected to the editorial boards of learned journals after long and solemn deliberation were shattered: the simple truth is that no journal ever wants to lose a co-operative referee.
The last word about JMB belongs to Sydney himself. Reminiscing on the 30th anniversary of the journal, he said: "The Journal of Molecular Biology (JMB) was founded by John Kendrew just over 30 years ago and the first issue, a modest one of less than a hundred pages, appeared in April 1959. Few present-day readers can appreciate how daring this venture seemed at the time; after all, the subject had only just begun, and the number of people willing to call themselves molecular biologists in public was still quite small. But as we now all know, the subject and, for that matter, the Journal, were doomed to success from the start. Molecular biology became pervasive and now dominates areas of biological research, and, today, nearly everybody is a molecular biologist."
As the prototypical molecular biologist, Sydney, too, was doomed to success.
Some important techniques published in JMB during Brenner's reign.
The Worm - C. elegans
In the dozen years from 1965 onward, Sydney Brenner laid the groundwork for making Caenorhabditis elegans a major system for genetics, neurobiology, and developmental biology research. As a direct result of his original vision, this tiny nematode worm became the first, and still so far only, animal for which the complete cell lineage and the entire neuronal wiring diagram are known. And as a further consequence of Sydney's foresight, in 1998 C. elegans provided the first complete genome sequence (98 million base pairs) to be determined for any multicellular organism. Today, more than 400 laboratories actively pursue research on C. elegans, studying problems across the entire spectrum of biology. All of them owe a profound debt to Sydney.
The project started small: just Sydney, his former bacteriophage technician, Muriel Wigby, to help with genetics, and Nichol Thomson, an electron microscopist. Nichol played a crucial role in the decision to focus on Caenorhabditis elegans, rather than one of many other small nematode species, because he found it was especially suitable for electron microscopy. It was easy to fix and gave excellent thin sections. The latter quality was essential for the detailed analysis that Sydney had planned and which eventually culminated in the monumental description of the C. elegans nervous system, published in 1986 in Philosophical Transactions of the Royal Society of London1 under the grandiose but justified running title, "The Mind of a Worm."
The intricate and laborious electron microscopy studies inspired a dream of automated analysis of thin sections and reconstruction of the worm's neuroanatomy from them. This led to the acquisition of a powerful (for its day) but unwieldy computer, and to the recruitment of John White, an electrical engineer who metamorphosed under Sydney's influence into a neurobiologist, cell biologist, and microscopist. Another key early arrival was John Sulston, who initiated work on the genome of C. elegans, and also worked out how to freeze worms for their permanent storage in liquid nitrogen.
From about 1970, Sydney began to accept postdocs and graduate students specifically to work on C. elegans, but several of the early converts were almost accidental: postdocs such as David Hirsh, Dick Russell, and Don Riddle, who had come to the Medical Research Council's Laboratory of Molecular Biology (LMB) to work on tRNA but became entranced by the opportunities and promise of the worm project.
Word began to spread, not least from Sydney's own lectures on the subject. As an undergraduate, I heard him give a wonderfully exciting talk on C. elegans, which persuaded me that this was what I wanted to study in graduate research. Fortunately Sydney agreed and I began my studies in 1971, not long after the arrival of Sam Ward and Henry Epstein, who were among the first overseas visitors to LMB to work specifically on C. elegans projects (Sam on chemotaxis, Henry on muscle proteins). Later years brought many others, notably the "Bobs" - Edgar, Herman, Horvitz and Waterston - as well as Donna Albertson, Jim Lewis, Marty Chalfie, and Phil Anderson.
In those years, the nematode research labs in Cambridge had a unique atmosphere. At all hours of the day and night, Sydney could be found in his genetics lab, at the electron microscope or at a computer terminal, concentrating on one of the many different facets of his research. Periodically he would retreat to his office, shared with Francis Crick, or descend on the adjacent coffee room. Here he would hold forth for hours at a time, to a transfixed audience of whoever happened to stray in seeking coffee or enlightenment.
These sessions were mesmerizing to all who experienced them, and for many of us were a major learning experience. Occasionally one could manage to get a word in edgeways, to report a novel or pleasing observation on the worm. Usually it would then turn out that Sydney had long before made the same observation, but he would reward one with expositions of its possible implications and ramifications, together with further thoughts, jokes, and unpublished findings in whatever field was involved.
In retrospect, those were extraordinary times. Ignorance of the genetic underpinnings of development and neurobiology was almost complete, but it became obvious that C. elegans had a huge amount to contribute. The revelations were not as rapid in arrival as in phage research (perhaps one reason why Sydney moved on from the worm), but they came in the end.
In particular, Sydney identified and focused on an initial set of 70 genes that affect the movement of C. elegans. He called them unc genes, for the uncoordinated movement of mutants. The unc set has proved to be a cornucopia, for almost every member has ultimately turned out to play a major and conserved role in developmental or functional neurobiology.2 To a remarkable degree, the investigation and understanding of the unc genes has provided answers to the questions that Sydney so boldly set out to explore in the 1960s.
1. J.G. White et al, "The structure of the nervous system of the nematode C. elegans," Philosophical Transactions of the Royal Society of London, 314B:1-340, 1986.
2. S. Brenner, "The genetics of Caenorhabditis elegans" Genetics, 77: 71-94, 1974.
Singapore and Fugu
I met Sydney Brenner for the second time in Singapore at a biotech conference in 1983. I had first met him 10 years earlier when he reviewed my proposal for an Interferon Institute that I had been invited to set up in the Memorial Sloan-Kettering Cancer Institute. After the conference, I took Sydney for an evening walk in the Singapore Botanical Gardens. He said that he thought that China had made a good decision to start in biotech by making restriction enzymes, and it was clear that he was thinking about how Singapore could make its own start. An hour before Sydney left for Changi Airport, Singapore's prime minister, Lee Kuan Yew, asked him for his views on this.
A month later, in Canada on Christmas Eve, I received a phone call from the deputy prime minister of Singapore, Goh Keng Swee. He asked: "Christopher, would you come to Singapore and build us an institute?" Singapore must have accepted Sydney's view that a research institute, eventually christened the Institute of Molecular and Cell Biology (IMCB), was the entrance fee for Singapore into the world of biotech. I jumped at the opportunity.
Sydney returned to Singapore the following year as the first Lee Kuan Yew Distinguished Visitor and agreed to chair IMCB's scientific board. Soon the bureaucrats were looking for tangibles from IMCB. We had very little self-generated revenue, so I offered them the number of PhDs and postdoctoral fellows we had trained, the number of discoveries made, and so forth. It was a mismatch of expectations between the civil servants and the scientists.
This is where Sydney played his critical role on behalf of science in Singapore. On nearly every visit he made, I would get him and Alice Huang, a member and now chair of the board, to meet with a member of the cabinet. They would, in their own ways, reassure the decision makers that things were on track, and that outstanding recruitment and excellent science at IMCB were the tickets to Singapore's eventual participation in the biotechnology and pharmaceutical industries. Their efforts were helped by several deals we made with industry. One was a $60 million deal to screen for lead compounds by high-throughput automation: Sydney helped persuade Sir Richard Sykes that IMCB was a natural partner for GlaxoWellcome.
One dry July afternoon in 1992, Sydney and I went to a remote part of Singapore looking for fighting fish. Sydney had been talking for a while about Fugu (the Japanese pufferfish) as a model genome. I persuaded him to form a small Fugu group in IMCB with Byrappa Venkatesh, who had trained as a postdoc with him in Cambridge. In 1993, they reported in Nature that the genome of Fugu rubripes was the most compact vertebrate genome known.
Sydney was convinced that this genome would be the key to interpreting much of the human genome and that it should therefore be sequenced. It was not easy to obtain funding, but in October 2000, he persuaded Trevor Hawkins of the US Department of Energy's Joint Genome Institute to collaborate with IMCB in sequencing the Fugu genome. This was jointly completed a year later, enabling tiny Singapore to become a player in the analysis of the human genome.
Sydney helped Singapore to choose biomedical research for its future. He continues to surprise us all with new achievements, especially in computational biology. Only recently he devised techniques to compare global gene expression down to two copies of messenger RNA in a single test tube. As for me, I feel as if I have just completed a 15-year-long postdoc with Sydney, studying human behavior.
The MSI years
I first met Sydney in the 1970s, when the Earth was still young, and the number of molecular biologists small, but our paths only crossed decisively in the mid-1990s. At the time, I was trying to think through where biology, functional genomics, and my own work should go, and in that process had begun corresponding with 'Uncle Syd.' His take and my take on What Was To Be Done were almost congruent: Real progress required quantitative models that made testable and nontrivial predictions, and new experimental methods to gain the input for those models. Sydney also realized, and eventually convinced me, that nucleating the needed research effort could not happen easily in a university.
Sydney had a little startup money from Philip Morris Inc. and had created a nonprofit organization that could receive research grants and philanthropic money. The Philip Morris connection also supplied a gifted lawyer who had come to believe in Sydney and in the project. The idea was that we could get government and philanthropic support for the lab by the time the startup money ran out.
Thus it was that Sydney, the lawyer, and I scoured the United States for sites for a lab. We knew we had found our spot when a couple of somewhat disreputable landlords pointed us toward second-floor space in downtown Berkeley just vacated by a Web search engine company. Zoning was not a problem, and after, for example, swearing to keep less than one pound of explosives and 800 gallons of acetone on site at all times, we built the lab. Sydney moved his people from San Diego, I moved my lab from Boston, and the Molecular Sciences Institute (MSI) opened its doors in 1998.
Sydney was seldom at the institute—once a month, possibly—but his involvement was decisive in a number of ways. First, he continued to direct his own Fugu (pufferfish) sequencing and sequence-analysis group. Second, he recruited or helped recruit a number of the most gifted scientists here. Third, in conversations he, as always, spread ideas around with profligacy. Some ideas were diamonds, some seemingly not, but all were products of high-level and highly original intellectual connections. Fourth, and most importantly, Sydney provided a direct link to the foundations of molecular biology.
Why was such a link important? Well, the days of the 'RNA Tie Club' may seem, in retrospect, to have been a little self-conscious, even a little precious, but these were days in which intellect mattered, creativity mattered, honest criticism mattered, identification of the right problem mattered, and individual achievement mattered. Now, when the creation of a quantitative biology of function seems possible, perhaps inevitable, but it also seems dreadfully difficult. In the early days, molecular biology must have seemed necessary and inevitable, but it must also have seemed dreadfully hard to achieve. In 2000, it was easy to foresee an age of sequencing factories, protein interaction factories, and SNP factories—brilliant but sometimes unsatisfying technical collective efforts. The factories are wonderful, but their existence does not negate the fact that scientific knowledge will continue to come from original, creative thought and insight. At MSI, Sydney reminded the researchers, consistently, by story and simply by being Sydney, that original achievement by individuals and small groups is as possible, and is as needed, now as it was then.
In part because of the rising interest in Fugu by larger sequencing operations, Sydney recently wound down his activities at MSI. In addition to his multifarious commercial interests and activities, Sydney fell back on one of his numerous strong suits, his ability to use his unparalleled knowledge of the diversity of living things to identify an organism that might answer a problem. There are, he says, species of newts that are just as greedy, gluttonous, lustful and anxious as any mammalian organism, but which are blessed with a hypothalamus controlling these drives that comprises only a few hundred, gigantic, mircoelectrode-friendly neurons. Perhaps Sydney's next step will be the electrophysiological deconstruction of emotions and drives.
As it has for so many others, interaction with Sydney has helped me articulate a scientific vocation, but even more importantly, it reminded me—already a risk taker—of the true meaning, and true potential, of cold-eyed, thinking, hardworking, adult, scientific risk-taking. The 21st century will not get the biological understanding and capabilities that it needs unless numbers of talented young people take risks. We can only try to pass this on.