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Home , Errol Friedberg, Francis Crick, John Sulston, RNA Tie Club, Sydney Brenner

Sydney

Brenner’s in 1927–2019 A Heroic Voyage: ’s Life in Science

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This companion booklet was originally published in conjunction with the 2015 Sydney Brenner Scientific Symposium and Exhibition, held at Singapore's Biopolis scientific hub.

Agency for Science, Cold Spring Technology and Research, Harbor Laboratory, Singapore New York c A Heroic Voyage: Sydney Brenner's Life in Science ONE OF AN EXCELLENT OUR OWN TRAVEL Message by Lim Chuan Poh COMPANION Former Chairman Agency for Science, Technology and Research Message by Chancellor Emeritus Cold Spring Harbor Laboratory

hirty years ago, when Sydney times to reach over S$29 billion in 2012, ver the course of my career, Then there were the exciting, frenetic Brenner first visited Singapore, contributing to 5% of Singapore’s GDP. I’ve had the privilege of years of the Human Project. We the state of research, especially While Singapore’s success in this area tackling some of the most kept up our exchanges, with him in the UK in biomedical , was certainly cannot be attributed to any one fundamental questions in and me in the US, doing as much science as vastly different from what it is person, few have been as deeply involved , working alongside possible while being responsible for entire Ttoday. Singapore’s economy was structured in raising Singapore’s scientific standing as Osome of the finest minds in science to research institutes. around manufacturing, and there was little Dr Brenner. It is apt then, that Dr Brenner solve them. In this six-decade-long quest, owes a great deal to him research conducted at the universities, if at was the first person in our history to be Sydney Brenner has been an invaluable and his ideas; not just for the worm, all. But Dr Brenner saw the potential in our made an honorary citizen, a distinction colleague and personal friend. which is what his was for, but people and urged Singapore to start its own conferred on him by then President S. R. My first encounter with Sydney was in also technologies like massively parallel research institute dedicated to the exciting Nathan at the Istana in 2003. Dr Brenner April 1953, in the heady days just after our signature sequencing, which allowed new field of . also has an orchid named after him, the discovery of the structure of DNA. Sydney expression to be analysed on a scale few With the enthusiastic support of Singa- Dendrobium Sydney Brenner. The orchid had driven from Oxford to that could have imagined earlier. pore’s founding fathers Mr Lee Kuan Yew can be found at the Singapore Botanic cold, spring morning—just to be among the We both embarked on our careers in and Dr Goh Keng Swee, the Institute of Gardens, which was recently listed as first to look at our model. We went for a an extremely exciting time for molecular Molecular and Biology (IMCB) was a UNESCO world heritage site. long walk that day—six hours as I recall, biology and have enjoyed front row seats. set up within two years, and thus began But Dr Brenner’s greatest legacy is and the first of many over the years— In 1954, Sydney and I actually drove Dr Brenner’s long association with science perhaps the many excellent scientists he because there was so much to talk about. through the eye of a hurricane while on and research in Singapore. Within a decade, has trained, who have gone on to blaze their As important as it was, the structure a road trip across the US to Caltech. IMCB had gained international standing own trails in science and take up leading of DNA was just one part of the puzzle; Then as now, I’m glad to have had such an in the life sciences and by 2000 was roles in academia and industry. In 2009, Dr we still needed to figure out how the excellent travel companion for the journey. recognised as the first major centre for Brenner set up the Molecular Engineering RNA transcribed from DNA could be biomedical sciences in Asia, winning the Laboratory at A*STAR with the aim of ‘read’ into . Twenty of us, led by Nikkei Prize for Technological Innovation. giving young researchers the independence , formed the RNA Tie All this took place before Dr Brenner to explore their ideas. There, researchers Club, to share ideas on molecular biology. himself was recognised with the Nobel continue to explore interactions at the Brenner was , while I was . Prize in or in 2002. boundaries of different disciplines, just And it was Sydney who eventually Internationally respected as one of the as Dr Brenner himself has done all worked out that the was non- great statesmen of science, Dr Brenner through his extraordinary career. overlapping and degenerate, and discovered has for decades been a trusted advisor to It is befitting that this symposium and what messenger RNA and were both the Agency for Science, Technology exhibition in honour of Dr Brenner’s life really doing. As if all that wasn’t enough, and Research (A*STAR) as well as the and work should take place in the same he followed it up by establishing an entirely Biomedical Sciences (BMS) initiative. A year as Singapore’s Golden Jubilee anni- different kind of model system—the relatively short 15 years after it was first versary. Thank you Dr Brenner; we are worm—so wonderfully complex launched, the biomedical sector grew five truly fortunate to call you one of our own. and simple at the same time.

2 A Heroic Voyage: Sydney Brenner's Life in Science 3 f you happened to be in the centre of the small town of Germiston in in 1939, you may have come across a stocky, I12-year-old boy coming out of the public library with a book that he had been allowed to borrow from the adults’ section. »

An Early Start

Sydney Brenner (third from left) with family. (Photo: CSHL Archives)

4 A Heroic Voyage: Sydney Brenner's Life in Science An Early Start 5 “I read everything. As I say, I speak two languages: English and rubbish. I read everything but mostly I read non-fiction.”

Sydney Brenner, interview for SG50 book Singapore’s Scientific Pioneers

Corporal Sydney Brenner (second row from back, far right) at S. H. Military College in 1944, at the completion of a course module. (Photo: CSHL Archives)

You might have also seen him about a mile at a private church school. At age six, he allowed him to stay on after hours to work away down the main street, looking for entered the local primary school two years in the laboratory. Roux was an important frogs in the small stream that ran between ahead of his contemporaries, and completed figure in the long struggle of the African his house and the starch factory; or in his the first three years of primary school in one people in South Africa and this helped garage extracting pigments from flowers. year. Brenner began at the local high school to shape many of Brenner’s subsequent The budding scientist, Sydney Brenner, when he was 11, and graduated just before student activities. In the second year of was no ordinary teenager. As a child, he he turned 14. his course, he moved up the hill to the had not only read The Young Chemist— Throughout school, he continued to read medical school where he was to remain F. Sherwood Taylor’s book for amateur voraciously and perform experiments in his for the next nine years. chemists—but had already performed garage laboratory. One particularly inspiring Two years into the six-year medical many of its experiments using small book was The Science of Life, a nine-chapter degree, Brenner was advised to take an quantities of chemicals purchased from a illustrated science book by H. G. Wells, extra gap year as he was too young to pharmacy. His main interest, however, was Julian Huxley and G. P. Wells. qualify for the practice of medicine. in biology; plants and animals remained a He grasped this eagerly. source of fascination throughout his life. He Brenner at university also discovered early on that his “teachers By the time he finished school, he knew A “heavenly” gap year did not know very much”, and that many he wanted to become a scientist, but his Brenner spent a “heavenly” gap year in things could be learnt by reading and doing. family was too poor to afford a university a medical (BSc) education for him. He won a bursary from course in and physiology. He An avid reader the Town Council to study medicine and was part of a group of about a dozen Sydney Brenner was born on January 13th began a six-year medical course in early medical students, who worked closely 1927 in Germiston to Jewish immigrants 1942 at the University of Witwatersrand— with more advanced researchers in a from Russia. The family lived in a few rooms also known as Wits University. There, the small room in the department of anatomy. at the back of his father’s cobbler shop. 15-year-old studied , , When histologist Joseph Gillman When he was five, one of his father’s botany and , commuting by invited Brenner to stay on for an honours customers—a certain “Miss Walkinshaw”— bicycle and train with packed sandwiches and master’s degree, he accepted and found him reading a newspaper. Impressed, for lunch. He was greatly influenced by supported himself by working part-time A “Proclamation” allowing Sydney Brenner to travel she found him a place, with fees waived, Edward Roux, a lecturer in botany who as a laboratory technician. from South Africa to the UK. (Photo: CSHL Archives)

6 A Heroic Voyage: Sydney Brenner's Life in Science An Early Start 7 A young Sydney Brenner and his team at Sydney Brenner at a scientific meeting in an anthropological site in South Africa. Edinburgh, 1958. (Photo: CSHL Archives) (Photo: CSHL Archives)

During those two years, Brenner learnt around the campfire at night. In 1946, a 1947 paper—of which he was particularly “When I was younger I had another how to produce histological sections, an expedition to the Kalahari Desert led to proud—that showed that the microsomes mount them on glass slides, and stain a publication, “Man and the Great Kalahari”, of the cell were the same as the chromidiac scientific hobby, geology, but it them with various dyes. He reconstructed for which he was the last author. substance of the cytologist. embryos; performed experiments on Brenner once said that he was “the only threatened to become research so neuromuscular junctions; synthesised A clarion call to do science medical student to graduate from Wits I gave it up. I used to go looking for his own dyes; learnt mathematics; and Around this time, Wilfrid Le Gros Clark, a without ever laying hands on a patient until even built ultracentrifuges. professor of anatomy at Oxford University, the actual final examination”. His interest fossils and going on expeditions He also began to publish. Together with visited South Africa and invited Brenner lay in scientific research and, specifically, mentors Joe and Teddy Gillman, the 18- to apply to Oxford. Brenner was advised, molecular biology—“which, of course, did but it’s always been science.” year-old Brenner published his first paper however, to obtain his medical degree first, not exist at the time,” as he later mused. Sydney Brenner, interview for SG50 book Singapore’s Scientific Pioneers in The South African Journal of Medical and so returned to the study of medicine in Upon graduating from medical school, Sciences in 1945. It was on the topic of 1947, completing his medical degree in 1951. Brenner applied to the University of Cam- porphyrins (organic compounds) in the By his own admission, Brenner was not a bridge’s department of , but liver of Africans suffering from pellagra, good medical student. Instead, he continued did not receive a reply. a disease caused by chronic vitamin to spend time in the laboratories in the In 1952, Brenner won a highly competitive B deficiency. A follow-up publication anatomy department, later moving with Joe scholarship from the Royal Commission for the appeared the same year in . Gillman to the physiology department. In Exhibition of 1851, and on the recommendation Anthropology and palaeontology 1946, he taught himself , focusing of the head of Wits University, H. Raikes, became another of Brenner’s favorite particularly on . His MSc went to work in the laboratory of Sir Cyril activities. On weekends, he and other , in fact, was on the of Hinshelwood, a professor of physical students in the science class went on field the South African tree shrew, Elephantulus chemistry at Oxford University. Hinshelwood trips to famous South African sites, where myurus. This marked the beginnings of his set into motion Brenner’s scientific career they sifted through debris in limestone long involvement in genetics. He published by suggesting he work on bacteriophage caves during the day and played poker several papers during this period, including resistance in bacteria. ¦

8 A Heroic Voyage: Sydney Brenner's Life in Science An Early Start 9 Becoming a Molecular

Sydney Brenner (right front, in dark shirt) at the Cold Spring Harbor Laboratory Phage n the 1950s Sydney Brenner’s career progressed rapidly Meeting in 1954. Immediately behind him are (L-R) Al Hershey (chequered shirt), Milislav Demerec and . from the relative isolation of South Africa to Oxford (Photo: CSHL Archives) IUniversity and the top scientific institutions in the US.» 10 A Heroic Voyage: Sydney Brenner's Life in Science Becoming a Molecular Biologist 11 Sydney Brenner was an honorary member of the RNA Tie Club, a “gentleman's club” of scientists founded by Gamow to “solve the riddle of the RNA structure and to understand how it built proteins”. The club’s motto was “Do or die, or don't try”. Each of its 20 members was given a woollen necktie with an embroidered helix, as well as a unique The young Mrs Brenner moniker— (May Covitz). Brenner’s was valine.

Sydney Brenner with Left to right: Francis daughter Belinda (left) Crick, Alex Rich, Leslie and Carla (right) on a Orgel and James Watson beach in La Tranche- in Cambridge wearing sur-Mer, France in 1962. their RNA ties. (Photos: CSHL Archives) (Photos: CSHL Archives)

After some difficulties in getting a passport the importance of the structure. Brenner helped Brenner to be awarded a Carnegie become the . Finally, from the new nationalist government that has often described this visit as a revelatory Corporation Fellowship for a four to five he left for Cape Town to fulfill his had been elected in South Africa in 1948, experience, one that had a definitive month visit to the . In July obligations to the Carnegie Corporation. Brenner sailed to Southampton from Cape bearing on the future of his scientific life. 1954, Brenner, armed with his DPhil, Town in September 1952. In October 1952, went to New York, while the rest of the Return to South Africa post-World War II England was a grim Marriage and family life family—May, Jonathan and Stefan— On his return to Johannesburg, he set up a place. Food was still rationed, and even Brenner had met May Covitz while studying returned to South Africa. laboratory in the department of physiology the colleges of Oxford were not spared medicine at Wits in 1950. May, who was During his visit to America, Brenner met at Wits University’s medical school. He austerity. Brenner—and many of the other completing bachelor’s degrees in psychology and heard of his work on knew exactly what he wanted to do. researchers—were outsiders. As he wrote and English literature, had attended a lecture the fine structure of the gene and spent a Benzer’s work shattered the classical in his Nobel autobiography, “In addition, I given by Brenner on basic statistics. long weekend at Woods Hole where Crick concept of the gene as a unit of and the others were outsiders three times In ’s biography of Brenner, and Watson were also spending part of the and recombination by showing that there over; we were scientists, we were research May spoke fondly of Brenner as “a summer. There he met George Gamow, were many sites of mutation in a gene and students and we were colonials.” combination of a clown and some sort of a Russian-American physicist who had that resolution of recombination was high However, there was an institution called Greek god” and “absolutely different from published a paper on the genetic code enough to separate adjacent base pairs. Halifax House across the road from the anyone I had ever met”. earlier that year. In their second paper, Crick and Watson physical chemistry laboratory where he Shortly after graduating from Wits in Brenner attended the phage course as an had already proposed the essential feature and the other scientists could have lunch, 1951, May moved to London with Jonathan auditor in Cold Spring Harbor and finally of the genetic code: that the sequence of and it was here that he met Jack Dunitz, Balkind, her son from her first marriage, attended the annual phage meeting where bases in DNA specified the sequence of a crystallographer, and through him, Leslie to pursue a PhD in psychology. he presented Benzer’s initial work on the rII amino acids in . Brenner realised that Orgel. Both were to remain lifelong friends When Brenner moved to Oxford in 1952, gene. Benzer had to leave Cold Spring Harbor if he could find the right gene and protein he and colleagues. he contacted May. They married in London early because one of his children was ill, and could begin to analyse the correspondence within two months, in December 1952, and asked Brenner to give the talk in his stead. of the two sequences. In his laboratory in The birth of molecular biology were together until May’s death in January After the meeting, Brenner and Watson Johannesburg, he began to study Dunitz had been to Caltech and knew all 2010. Their children are Stefan, Belinda, went on “an epic road trip” that took them that might affect the protein coat of about the quest to reveal the structure Carla and Jonathan. through Boston, Massachusetts, and New bacteriophage T4. of DNA. In early 1953, he told Brenner Hampshire, and then to Watson’s home Gamow’s theoretical code, known as the that two scientists in Cambridge, James The road to America in Chicago, Illinois. They then continued diamond code, was an overlapping triplet Watson and Francis Crick, had solved the In late 1953, Milislav Demerec, director of the across the US to Caltech in Pasadena, code. Brenner realised that this hypothesis structure of DNA—a where Cold Spring Harbor Laboratory in New York, . Along the way, Brenner might be problematic, as it would impose the two strands are held together by visited Hinshelwood, Brenner’s professor, in met many scientists who would shape a constraint on the number of dipeptide complementary pairing of the four bases: the physical chemistry laboratory in Oxford. molecular biology, such as Max Delbrück, sequences, so he began to collect peptide with and with At that time, there was a controversy about the founder of molecular genetics. Brenner sequences from the literature. By the end of . On a frosty morning in April the development of resistance to drugs ended his trip in Berkeley, California where 1954, he could provide a statistical argument 1953, Dunitz, Brenner and Orgel drove with and antibiotics; most geneticists thought it he worked in the Virus Laboratory with to rule out overlapping codes, and with to Cambridge to see the occurred by mutation and Hinshelwood was Gunther Stent, another eventual lifelong additional data was then able to obtain a model in the Medical Research Council almost alone in pursing work to show that friend and colleague. proof. He circulated his findings in 1956 to Unit in the . it could arise by adaptation. Demerec met Before leaving America, Brenner stopped the other members of the RNA Tie Club (see After a short exposition of the model by Brenner and when he heard that Brenner was in Washington D.C. where he met Gamow photo), in a note called “On the impossibility Crick, the other two left and Brenner spent working on bacteriophage resistance and and Alex Rich and showed them the work of all overlapping triplet codes”. Gamow the rest of the day on a six-hour walk around that he had shown it was due to mutation, he had done on the genetic code. On later communicated the paper to the Cambridge with Watson, talking about he invited Brenner to the Cold Spring Harbor his return to England, he visited Crick in Proceedings of the National Academy of many things but mainly about DNA and Laboratory for the summer of 1954. Demerec Cambridge and discussed what would later Sciences, where it appeared in 1957. ¦

12 A Heroic Voyage: Sydney Brenner's Life in Science Becoming a Molecular Biologist 13 Left to right: Sydney Brenner with , Chris Anfinsen, and at the Cavendish Laboratory, Cambridge in 1957. (Photo: CSHL Archives)

Breaking

lthough DNA was known to contain the instructions for all the Genetic Alife, nobody could quite agree on how it was to be read until 1961, when Brenner and colleagues proved Code that it was a triplet code. » 14 A Heroic Voyage: Sydney Brenner's Life in Science Breaking the Genetic Code 15 On camera: Sydney Brenner, holding a model of a phage, alongside Raymond Baxter, host of “What is Life?”, a BBC tele- vision programme Behind them, from left to right, are models of the , turnip yellow virus, and DNA. (Photo: the BBC)

Jacques Monod and Sydney Brenner in 1960. (Photo: CSHL Archives)

Sydney Brenner and James Watson at the Symposium on Quantitative Biology. (Photo: CSHL Archives)

Francis Crick (centre) and Sydney Brenner (far right).

François Jacob and Sydney Brenner in 1985.

Sydney Brenner with James Watson (centre) and François Jacob (right) at CSHL in 1990. (Photos: CSHL Archives)

Following his adventure in the US, Brenner In Cambridge evidence that the ribosomes are involved in was a long discussion about the Paris spent “a frustrating and lonely” two years Brenner set up a laboratory in a crowded protein synthesis. But there were difficulties experiments when Brenner suddenly leaped in South Africa. Despite his isolation, he space in the basement of the Cavendish with this idea: ribosomal RNA has a constant up, and as described by Crick and Jacob in maintained a lengthy correspondence laboratory. Later, they were able to acquire base composition in many different bacteria their autobiographies, and began to talk at with colleagues such as Francis Crick and more space on the Cavendish site. He whereas the DNA base composition varies an extremely rapid rate. He had seen the Gunther Stent. Eventually, Crick was able continued to search for a gene-protein over an enormous range. Furthermore, in the light, remembering that a minor RNA made to secure a position for him with the system in bacteriophages. He found a new in Paris, , after phage infection had been discovered Medical Research Council (MRC) unit in method of “negative staining” for electron François Jacob and Arthur Pardee working by Elliot Volkin and Lazarus Astrachan and the Cavendish laboratory. In December 1956, microscopy and used it powerfully in his on β-galactosidase “inducibility” showed that was thought by many to be a precursor to Brenner left South Africa for England to join work on the structural components of synthesis of the starts immediately DNA. It had all of the properties required of Crick in building up molecular genetics bacteriophages—all the while continuing after the gene enters the cell and is shut an intermediate and its base composition in what was essentially a laboratory for to work on the genetic code. down immediately after the inducer is was the same as that of the phage DNA. protein . In Gamow’s code, the amino acids are removed. To explain their results, they By that evening, Brenner and Jacob had It was the start of a long fruitful recognised by “cavities” on the DNA, and postulated Factor X, an unstable intermediate formulated the experiment. Because Jacob intellectual collaboration with Crick; they thus polypeptides are assembled directly on between the gene and the enzyme. was going to spend a month in Caltech shared an office in the MRC unit and the gene. Nobody believed in this and indeed One cold Good Friday morning in 1960, in July 1960, it was decided that Brenner continued to do so at its successor, the there was considerable evidence that RNA Jacob, Brenner, Crick and some other visiting would join him there and they would work MRC Laboratory of Molecular Biology. might be involved in the protein synthesis. scientists attended a meeting in Brenner’s with Matt Meselson who had all the heavy The next five years would see explosive Cells contain large amounts of RNA in the room at King’s College in Cambridge isotopes of carbon and nitrogen to prove developments in molecular biology. form of ribosomes and there was clear University where he was a . There the existence of messenger RNA.

16 A Heroic Voyage: Sydney Brenner's Life in Science Breaking the Genetic Code 17 “I learnt very quickly that the only reason that would be accepted for not attending a committee meeting was that one already had a previous commitment to attend a meeting of another organisation on the same day. I therefore invented a society, the Orion Society, a highly secret and very exclusive society that spawned a multitude of committees, sub-committees, working parties, evaluation groups and Triplet codon so on that, regrettably, had a prior claim word games by Sydney Brenner. on my attention. Soon people wanted to (Photo: CSHL Archives) know more about this club and some even decided that they would like to join it. However, it was always made clear to them that applications were never entertained and that if they were deemed to qualify The groundbreaking 1961 paper in Nature—Sydney for membership they would be discreetly Brenner’s second that year. (Photo: Nature approached at the appropriate time.” Publishing Group)

Sydney Brenner, Loose Ends (1997)

But in Pasadena, experiment after to complete the work, Brenner, Jacob Crick decided he would try to study what produce disastrous changes in the protein. experiment failed, as the ribosomes and Meselson authored a paper titled were called intragenic suppressors where Brenner immediately went to do the disintegrated in the density gradient “An unstable intermediate carrying a mutation in one part of the gene could experiments, showing that proflavine generated by centrifuging 8 molar caesium information from to ribosomes for be compensated by a second mutation in mutants could not be obtained in a gene chloride solutions for 24 to 36 hours in a protein synthesis”, which was published another part of the gene. He started with a that specified an essential protein for the high-speed centrifuge. Near the end of their together with a paper by Watson and his set of base analogue mutants but did not phage. His results were published in a paper visit, they went to Malibu Beach with a friend, collaborators in Harvard University, who find very much. However, when he used titled “The theory of mutagenesis” in 1961 and Brenner then realised what was needed. showed a similar unstable RNA revealed the proflavine mutants he found them in the Journal of Molecular Biology. “It’s the magnesium!” he cried. He realised by pulse labelling of E. coli. abundantly in the first part of the rII B gene. Crick and Brenner realised they could that the concentrated caesium salt had It was at first difficult to explain these also use proflavine to decide on the size of displaced the magnesium, which was Frameshift mutants findings but one Saturday morning in 1961, the codon. By constructing triple mutants present only at a thousandth molar. They In 1957, Benzer came to the MRC on a while having lunch with Crick at The Eagle of the same sign, they proved that the quickly returned to the lab and did one year’s sabbatical. He had been working on , Brenner postulated that the proflavine coding unit was a triplet. Their 1961 paper last experiment with added magnesium. chemical mutagens and had constructed mutations are of a completely different (see photo), “General nature of the genetic They had to endure the agony of carrying spectra of occurrences of the induced class. They could be additions and deletions code for proteins”, was heralded as a classic the rotor carefully from a centrifuge that mutations. Proflavine, an acridine dye, of bases and correspond to the plus and in molecular biology. Without the frame had broken down to one in another lab had been found to interfere with phage minus categories that Crick had arbitrarily shift theory it would be difficult to explain but in the end they proved that no new assembly and was known to also produce assigned to the mutants and suppressors. an apparent puzzle: how pairs formed ribosomes are synthesised after phage some mutants. Brenner and Benzer decided A “don’t worry” theory of how they are from the three mutants, A, B and C—e.g. infection and that new RNA becomes to generate a set of rII mutants and map produced could be provided by the known AB or BC—are still mutant; and yet when attached to old ribosomes. them. The rII mutants and mutants induced intercalation of proflavine dyes into the the pairs are crossed to generate a triple, After performing further experiments by other mutagens were not used until DNA structure. Single mutations would function is restored. ¦

18 A Heroic Voyage: Sydney Brenner's Life in Science Breaking the Genetic Code 19 olecular biology’s golden age in the 1950s gave rise to a new era of

Governing board of the developmental genetics in the 1960s. Laboratory of Molecular » Biology (LMB), October M 1967. Left to right: , , Max Perutz, Francis Crick, Fred Sanger, Sydney Brenner. (Photo: MRC Laboratory of Molecular Biology)

Genes, Genes and More Genes

20 A Heroic Voyage: Sydney Brenner's Life in Science Genes, Genes and More Genes 21 C. elegans under the microscope.

In a 1963 letter to C. elegans scientist Ellsworth Dougherty, requesting a culture of the C. elegans Bristol strain, Sydney Brenner asks, “One point that puzzles me at the moment is how one gets males, and if one has them, is it possible to propagate them by crosses with the hermaphrodites?” It turns out that most C. elegans adults are hermaphroditic and self-fertilise; on occasion, a hermaphrodite yields a pure male, allowing conventional genetic analysis. (Photos: CSHL Archives)

complex systems such as nervous systems. “As a more long term possibility, I Although he continued to work in what “I immediately took over the financial management would like to tame a small metazoan would be called classical molecular biology, of the laboratory and spent several years in trying to by 1962 he was focussing on a small to study development nematode worm, . get the finances on a proper basis. These were times

directly. My ideas on this are still C. elegans of hyperinflation in Britain and not enough attention fluid and I cannot specify this in He chose a small nematode with a life had been given to the rising costs of our research. cycle of five days and with a fixed number greater detail at the present time.” of cells. His goal was to find the lineage of I often referred to myself as the ‘epileptic’ director.”

A 1963 letter by Brenner to LMB director Max Perutz every cell and in particular, to determine Sydney Brenner, Nobel Prize autobiography the structure of the nervous system with electron microscopy. He also needed an organism on which he could perform genetic experiments and easily keep in a laboratory. The Medical Research Council (MRC) supported him in this very risky project; among other things, it provided more space for the expansion of the Laboratory of 1961 was marked by the announcement by Molecular Biology (LMB) in Cambridge. new pathogens. A group of scientists in research could proceed more effectively. Sydney Brenner receives the key to the LMB from Marshall Nirenberg and Heinrich Matthaei He started with one technician and was the US made a public call for a moratorium Brenner also began to actively clone departing director Max that they had been able to programme joined by Nichol Thomson who had been on this work. In Cambridge, Fred Sanger genes from the nematode. His C. elegans Perutz in 1979. The letters AUG, which refer ribosomes with a synthetic messenger working in Lord Rothschild’s laboratory. In had begun to develop techniques for research had begun to attract attention to the initiator codon for RNA—polyuridylic acid—and had found the 1970s, his work on C. elegans progressed sequencing DNA and Brenner realised and from the mid 1970s an increasing protein synthesis, were inscribed on the key. that the polypeptide produced is a polymer steadily but a new development in science that this together with DNA cloning could number of young scientists came to of . It became clear that propelled him into a totally different field. create a revolution in biology. Brenner Cambridge to join him. Many were post- Left to right: Leslie Barnett, Francis Crick, the code would soon be found. Brenner In 1974, Stanley Cohen and Herbert accepted ’s invitation in 1975 to doctoral who, upon their return to and Sydney Brenner and Crick both decided that the central Boyer reported that they had been able join the Asilomar conference, which had the US, established their own laboratories at a blackboard in the Laboratory of problems of molecular biology had been to clone DNA by inserting fragments been called to discuss the moratorium. doing research on C. elegans, making it Molecular Biology, solved, and with the entry of many young into plasmid, which they could propagate Brenner was instrumental in getting a a successful global enterprise. circa 1986. (Photos: MRC Laboratory of scientists into the field, they must look for in a bacterial host. There had also been formal motion passed almost unanimously Molecular Biology) new problems. considerable work done on characterising to end the moratorium and to explore The “epileptic” director Brenner had been impressed by the power the DNA of small viruses such new guidelines so that the research could In 1977, the MRC appointed Brenner as of posing the problem correctly and having as SV40. Amidst these developments, proceed. He returned to Cambridge and proleptic (anticipatory) director to succeed the right organism to work on. Therefore, he there were concerns about the escape spent a considerable amount of time on this Max Perutz when he retired in 1979. Three started to look for an experimental system of pathogens from laboratories and an area, first by developing safe strains, which days before his official start date, Brenner that could be used to study the genes that increased concern that recombinant DNA, he tested on himself, and by working to rode his motorcycle to the police station to specified the structure and function of more as it was called, might create completely obtain more rational guidelines so that the deliver a wallet he had found. On his way

22 A Heroic Voyage: Sydney Brenner's Life in Science Genes, Genes and More Genes 23 2002 Nobel Laureates in Physiology or Medicine. “ survive on this planet, because some Left to right: Sydney Brenner, Bob Horvitz and . are able to make the complex using Left to right: Queen elementary sources such as nitrogen, hydrogen and Silvia, May Brenner, King Carl XVI Gustaf and Sydney Brenner. carbon dioxide, and harness the primary source of energy which comes from the Sun. Biological depends on the food chain at each level— organisms survive by eating others lower in the food chain. My research depended on a chain. I NOBEL PRIZE CITATION began my research with E. coli and bacteriophage The Nobel Prize in Physiology or which eats bacteria from the inside. I then moved Medicine 2002 up a level, and using much the same tools began was awarded jointly to Sydney to work on which eat E. coli from the Brenner, H. Robert Horvitz and John outside. I then worked on fish which eat worms E. Sulston “for and finally on humans who eat fish. In the end their discoveries concerning genetic we are eaten by microorganisms and worms to regulation of organ development and start the cycle again.” programmed Sydney Brenner’s Food Chain of Research, for the 2014 re-opening of the Brenner Library in Singapore. cell death”.

Sydney Brenner receiving his Nobel Prize from His Majesty the King at the Stockholm Concert Hall. (Photos: CSHL Archives)

out, a car hit him. A compound fracture in Science”, was an homage to this modest his left knee took more than a year to heal; nematode. Brenner believes choosing the he has had to use a cane ever since. right organism to study is as important During his directorship, the LMB conti- as addressing the right problem. nued to grow as a research institution with While director, he continued his research a unique style and performance. The LMB’s and another project was completed and alumni now include many Nobel Laureates, published. The work on the structure of the including five of Brenner’s former post- nervous system of C. elegans, which had doctoral fellows—John Sulston, Martin been continued by John White and Nichol Chalfie, Bob Horvitz, Sidney Altman and Thomson, was published as a 300-page . paper in the Philosophical Transactions of the In 1983, his scientific “progeny” organised Royal Society. It was the product of 20 years a special symposium for him. Three years of research, and it would take 20 more for later, Brenner retired as director of the LMB. other such projects to be initiated. Brenner likes to call it anatomy; today it has a new C. elegans postscript and Nobel accolades name: connectomics. Few scientists make their mark on In 1998, thanks to a consortium of even one specialised field of research, but researchers in the UK and the US led Brenner has left an indelible mark on many. by Sulston, C. elegans became the first In 2002, Brenner and two of his former multicellular organism to have its post-doctoral fellows, John Sulston and complete genome sequenced. Bob Horvitz, were jointly awarded the Nobel Brenner is nicknamed the “father of the Prize in Physiology or Medicine for their worm”. In recognition of his pioneering role pioneering use of the nematode worm as in spawning a global research community a model for understanding human biology. that works on C. elegans, two researchers in The title of Brenner’s Nobel lecture 2007 gave a closely related nematode the in December 2002, “Nature’s Gift to scientific name Caenorhabditis brenneri. ¦

24 A Heroic Voyage: Sydney Brenner's Life in Science Genes, Genes and More Genes 25 Left to right: Sydney Brenner, Chris Tan, Philip Yeo, Teoh Yong Sea and Tan Chin Nam at a board meeting for Singapore Bioinnovations, a venture capital firm founded by EDB in 1992 to invest in biotechnology companies relevant to Singapore’s economy (Photo: IMCB)

n 1984 Sydney Brenner visited a tiny island in South-east Asia for the first time. Since then, his enduring guidance and influence have indelibly Ishaped the course of Singapore’s biomedical science and industry. » Mentoring a Young Nation 26 A Heroic Voyage: Sydney Brenner's Life in Science Mentoring a Young Nation 27 “I stressed to both Philip [Yeo] and the NSTB that the only way that biomedical research and commercial spin-offs from such research could evolve and prosper in Singapore was by establishing a single agency that oversaw all biomedical research, from molecules to mind— and nothing else.” Sydney Brenner scrutinising a scorpion Sydney Brenner at the 2014 re-opening of the Brenner Library in Singapore. delicacy offered by Deputy Prime Minister Goh Keng Swee (right), during Brenner’s 1984 visit to Singapore. The delicacy came from a recent trip by Goh to China.

The old IMCB building at Medical Drive, renamed the Brenner Centre for Molecular Medicine. (Photo: IMCB)

Sydney Brenner and Deputy Prime Minister Biopolis, a sprawling Teo Chee Hean, thirty scientific hub at years later, at the IMCB Singapore’s One 30th anniversary in North campus. 2015. (Photos: IMCB) (Photo: A*STAR)

It all began in 1981, when Brenner started a nation of technicians and not scientists, middle game, which is tedious, and too few However, Brenner had read extensively consulting for British financier Victor Brenner candidly replied, “Prime Minister, have the chance to play the end game; thus in the library of the Woods Hole Institute Rothschild’s Biotechnology Investments if you don’t do something like this, you will the only alternative is to play the opening where he taught a physiology course in the Limited. It was Rothschild who remain a nation of technicians.” A decision game. Believing that his forte lies in the late 1960s. He found Ralph Hinegardner’s recommended Brenner to the Singapore was made in 1985 to create the Institute opening game, in 1986 Brenner retired early papers reporting the small size of the government, which was eager to diversify of Molecular and Cell Biology (IMCB)—a from his directorship of the Laboratory of genome of the Japanese pufferfish, Takifugu the country’s economy away from low- name Brenner had suggested. That year, he Molecular Biology to pursue a new scientific rubripes (or fugu). He decided that he would cost manufacturing to other industries, also returned to Singapore to give a lecture problem. He left to start a new Medical work on this genome and it became his such as biotechnology. on biology under the aegis of the Lee Kuan Research Council unit of molecular genetics project in his lab in Cambridge and the Brenner came to a meeting in Singapore Yew Distinguished Visitors Programme. in a laboratory in the department of medicine lab he established in the IMCB. Byrappa in 1984. He later discovered that this The IMCB was initially part of the National at Cambridge University’s Clinical School. Venkatesh joined him in this endeavour and invitation had come from Dr Goh Keng University of Singapore, and Brenner became The time was ripe—with technological today is the head of a laboratory in IMCB. Swee, then deputy prime minister. the founding chairman of its scientific advances, the tools were finally available Many of the doctors who Brenner took for During this visit, Brenner met Lee Kuan advisory board, a position he held until 1995. to study the genetics of everything through training in Cambridge also worked with him Yew, then prime minister of Singapore, and He returned several times a year to Singapore the sequencing of DNA. In fact, there had there on the fugu genome. wrote a short proposal to set up a research and started a laboratory in IMCB in 1990. been severals meetings on this topic and in In 1992, Brenner published a paper institute in molecular and cell biology to 1985 there was a meeting in Santa Cruz to showing that the fugu had the same gene train Singaporeans at the PhD level, who Fishy genetics discuss the project of sequencing the human repertoire as humans, but its genome was could then provide the country with the Brenner often recounts J. D. Bernal’s genome. He became a strong supporter of only one-eighth the size. Brenner tried to necessary biotechnology infrastructure. comparison of scientific research to the the project but he also recognised that it get additional support for this work and When Lee remarked that Singapore was game of chess. Most scientists play the was not technically feasible at the time. often called the fugu the “discount genome”

28 A Heroic Voyage: Sydney Brenner's Life in Science Mentoring a Young Nation 29 “My view at the time was that we should treat the human genome like income tax and find every legitimate way of avoiding sequencing it.”

Sydney Brenner’s Nobel lecture, “Nature’s Gift to Science”, 8 December, 2002

Sydney Brenner’s 88th birthday dinner in 2015. Front row, left to right: Sydney Brenner in his Byrappa Venkatesh, IMCB laboratory in 1992, Lim Chuan Poh, Sydney where he is working on Brenner, Philip Yeo, a fugu specimen. Jonathan Balkind. (Photo: IMCB) (Photo: IMCB)

as it offered an almost 90 percent discount and Research (A*STAR), with Yeo as its campus, which will collectively house on the cost of sequencing. chairman. A*STAR’s governing mandate was more than 16,000 scientists and engineers With strong support from Singapore, broadened to encompass all of Singapore’s from the public and private sectors by the a consortium led by Brenner, Venkatesh various scientific research institutes. end of 2015. IMCB’s previous building, and Sam Aparicio of the Joint Genome Brenner not only helped Yeo to recruit affectionately known as the “big fishtank” Institute of the US Department of Energy scientists to work at A*STAR, but he also for its iconic blue glass façade, has since and Celera was formed to sequence worked on developing Yeo’s plans. Yeo been renamed the Brenner Centre for the 400 megabase fugu genome. The set aside S$1bn to train new Singaporean Molecular Medicine. paper was published in Science in 2002. scientists but they had difficulties in their Brenner, Venkatesh and Aparicio received negotiations with the universities. “I think Singapore’s 50th birthday Singapore’s National Science Award for it was a Friday morning,” Brenner recalls. Since 1984, in his capacity as a trusted this work in 2004. “I said, ‘Why don’t we start our own advisor on scientific policy to the Singapore graduate school? We don’t have to give out government, Brenner has been instrumental From the “big fishtank” to the open waters degrees but we will have the best mentors in establishing Singapore as a biomedical In tandem with these research initiatives, in Singapore.’ And on Monday, it was done.” research centre of international repute. Singapore had begun to nurture a The A*STAR Graduate Academy (A*GA) Today, he continues to serve on the biotechnology industry. In 1988, Philip Yeo, was formed. boards of A*STAR and Singapore’s then chairman of Singapore’s Economic Since 2003, A*GA has sent more than 1,400 International Advisory Council for the Development Board (EDB), set up the young Singaporeans overseas to be trained Health and Biomedical Sciences, where National Biotechnology Committee to in the physical, biomedical and engineering his incisive wit and candid remarks never spearhead the venture into biotechnology, sciences. More than half have returned and fail to make meetings memorable. with Brenner as a member. begun work at A*STAR’s research institutes, In 2015, the same year as Singapore’s Brenner and Yeo’s friendship and local universities and other institutions across Golden Jubilee anniversary, A*STAR, professional relationship steadily grew Singapore—a long-term investment that is Cold Spring Harbor Laboratory, Nanyang over the years. Their opportunities for paying off significantly. Technological University and National collaboration were boosted in 2000, when Meanwhile, A*STAR’s biomedical University of Singapore organised the the Singapore government committed research institutes are now housed in Sydney Brenner Symposium and Exhibition a large investment for a major research Biopolis, another name Brenner coined. to celebrate the life and work of Sydney The cover of the instruction manual The Worm Goes and development initiative. According to him, the Singapore accent Brenner. Many of Brenner’s former to School. In 2003, IMCB, in collaboration with the In 2001, the National Science and makes Biopolis sound like a place where colleagues, post-doctoral fellows and National Institute of Education, launched a teaching kit to introduce to Singaporean students the worm ¦ Technology Board (NSTB) was renamed “biology could be policed”. Biopolis is a new students have been invited to attend. as a tool for understanding the relationship between the Agency for Science, Technology scientific hub in Singapore’s One North genes, appearance and behaviour. (Photo: IMCB)

30 A Heroic Voyage: Sydney Brenner's Life in Science Mentoring a Young Nation 31 “I don’t think it’s finished yet”

Sydney Brenner lecturing in 1975. (Photo: CSHL Archives)

ell into his eighties, Sydney Brenner continues to demonstrate the same passion for science Wand commitment to his students as he always has. » 32 A Heroic Voyage: Sydney Brenner's Life in Science "I Don't Think It's Finished Yet" 33 Sydney Brenner received the inaugural Honorary “As was predicted at Singapore Citizen Award from President S. R. Nathan the beginning of the in October 2003. Left to right: May Brenner, Sydney Brenner, President Nathan, , Mrs Nathan and Minister George Yeo, minister for getting the sequence trade and industry (Photo: IMCB) will be the easy part as only technical issues are involved. The hard part will be finding out what it means, because this poses intellectual problems of how to understand the participation of the genes in the functions of living cells.”

Sydney Brenner, Loose Ends (1997)

Brenner has been a part of many molecular a new technique for sequencing large in Japan. He still maintains a research in 2009 with the intent of providing A 1987 group portrait of Sydney Brenner and biology developments around the world. numbers of DNA molecules at the same programme there. an opportunity for young Singaporean colleagues in Japan. In the early 1960s, he helped to found the time. This technique, called “massively In addition to his many scientific scientists to develop their own research (Photo: CSHL Archives) European Molecular Biology Organization parallel signature sequencing”, was the activities, he wrote a monthly column in a broad interdisciplinary field involving Sydney Brenner with (EMBO) and then later worked for many basis of what has become known as from 1994 to 2000 in the journal Current the design, manipulation and synthesis members of MEL. (Photo: MEL) years with John Kendrew in the establishment next-generation sequencing. Illumina later Biology. Initially called “Loose Ends”, it was of molecules for research and industrial of the European Molecular Biology Laboratory acquired Lynx, but Brenner continued later moved to the front of the journal as applications. Shawn Hoon, a young (EMBL) in Heidelberg. From 1985 to 1999 his interest in DNA sequencing. In “False Starts”. In some of these he wrote scientist who worked as a student with he was a visiting fellow and consultant at 2005, Brenner and Eletr, together with as Uncle Syd to his nephew Willie, whom Brenner and Venkatesh on the fugu the Central Research and Development Philip Goelet, founded a new company, he advises throughout his scientific career. genome, leads the laboratory. This has Department of DuPont, a chemical company, Population Genetics, to develop Brenner’s Brenner often complains that he had been successful enough to create a in Delaware. When he retired from the new inventions. become more famous for his columns second laboratory, MEL2, to work in the Laboratory of Molecular Biology, he moved Brenner founded the Molecular Sciences than for his scientific work. field that Brenner calls “human biology”. some of his activities to , California Institute (MSI) in 1996 in La Jolla, with The discovery that human cells could be and became affiliated with the Salk Institute a grant from the Philip Morris Company. Epilogue reprogrammed to become pluripotent stem and also with the Scripps Institute where he His aim was to give young scientists an If you think that Brenner has relaxed with cells, completed the last requirement for initiated research in combinational chemistry. opportunity to develop their own research. age and is no longer involved in research, research into the molecular and cellular Loose Ends, a collection of He also started a fruitful collaboration MSI was moved later to Berkeley. you have only to visit his office or home in bases of the development and function Sydney Brenner’s articles, with Sam Eletr, the founder of Applied Brenner was also for many years asso- La Jolla or Washington D.C. in the US, or Ely of humans. Brenner has long been an was published in 1997 by Current Biology. Biosystems Incorporated (ABI), where ciated with the Basel Institute of Immuno- in England, or in Fusionopolis in Singapore, advocate of this field; and believes that (Photo: Curent Biology) the first instruments were built for protein logy, and he served as an advisor to the where you will find piles of books and the long scientific journey of molecular and sequencing. Brenner Gulbenkian Foundation and as chairman papers covering his many scientific interests. biology has to end in the study of “Homo then realised that new techniques of of the Scientific Committee of the IGC, In Singapore, where he now spends Sapiens: the unique animal”. We are, Bren- nucleic acid sequencing would be needed a successful research institute in Lisbon. most of his time, he continues his work ner says, the only animal that invented and thus he joined Lynx Technologies, In 2004, he became founding president with Venkatesh in comparative genomics. science and has the ability to predict and which had been founded by Eletr when of the Okinawa Institute of Science and His latest endeavour, the Molecular control our future, and we need to know he left ABI. Together they developed Technology, a new graduate university Engineering Laboratory, was founded everything about ourselves. ¦

34 A Heroic Voyage: Sydney Brenner's Life in Science "I Don't Think It's Finished Yet" 35 Comics from Sydney Brenner’s Loose Ends monthly Quotes from Uncle Syd column in Current Biology. (Photos: Current Biology)

Sydney Brenner giving a lecture in 1960. (Photo: CSHL Archives)

“I think it’s the greatest adventure in the world to really know at a given point that you’re the only person in the world that knows something new. That’s a thrill that’s worth it.”

Sydney Brenner, interview for SG50 book Singapore’s Scientific Pioneers

36 A Heroic Voyage: Sydney Brenner's Life in Science "I Don't Think It's Finished Yet" 37 “The best way to prepare for a heroic SYDNEY’S VOYAGE voyage in science is just to start.”

1927 — Born in Germiston, South Africa on 1959 — Elected fellow at King’s College, 2003 — Receives an Honorary Citizen 13 January, 1927. Cambridge University. Award, Singapore’s highest form of — Attends Copenhagen meeting state recognition for non-citizens. 1942— Attends the University of where François Jacob talks about Witwatersrand and completes six factor X. 2004— Receives Singapore’s National years of medical school, interrupted Science Award with Venkatesh by a two-year sojourn into basic 1960— Carries out mRNA experiments with 1986 — Retires as director of the LMB. and Sam Aparicio for their work science. Graduates with a Bachelor François Jacob and Matt Meselson — Sets up the MRC Molecular on the fugu genome. of Medicine and Bachelor of at the California Institute of Genetics Unit at the Adden- — Receives the Surgery degree in 1951. Technology in Pasadena, California. brooke’s Hospital in Cambridge, (Gold), South Africa’s highest UK. The lab closes in 1991. honour. 1945— Publishes first research paper on 1961 — Publishes paper in Nature the topic of porphyrins in The South demonstrating an unstable 1987 — Editor-in-chief of the Journal 2005— Founding president of the Okinawa African Journal of Medical Sciences. intermediate carrying information of Molecular Biology from 1987 Institute of Science and Technology from genes to ribosomes for to 1990. in Japan. 1946— Expedition to the Kalahari Desert protein synthesis. — Senior fellow at the Janelia Farm leads to a publication in the Journal — Publishes paper in Nature describing 1988 — Founding member of the Research campus of the Howard of the Natal University College the general nature of the genetic National Biotechnology Hughes Medical Institute. Scientific Society. code. Committee in Singapore. 2006— Wins National Science and 1949— Publishes first sole authored 1963 — Begins work on the C. elegans 1989 — Scholar-in-residence at the Technology Medal, Singapore’s paper in Nature on the genetics nematode worm. Institute in La highest scientific honour. of the South African tree shrew, Jolla, California from 1989 to 1991. Elephantulus myurus. 1971 — Wins the Albert Lasker Medical Visiting member from 1991 to 1994. 2009— Sets up the Molecular Engineering Research Award. Laboratory at Singapore’s Agency 1952— Wins Royal Commission for the 1990 — Wins Kyoto Prize. for Science, Technology and Exhibition of 1851 scholarship 1974 — Publishes first paper on C. elegans Research (A*STAR). and begins research in the lab of in the journal Genetics. 1993 — Founding scientific advisory board Sir Cyril Hinshelwood at Oxford — Wins the . member of Lynx Technologies 2015 — A*STAR, Cold Spring Harbor University, UK. — During one-year worldwide in California. Laboratory, Nanyang Technological — Marries May Covitz. moratorium on recombinant University and National University DNA work, Brenner is called on 1994 — Writes Loose Ends, a monthly of Singapore launch the 2015 1953— Views model of the DNA double as an expert witness for the UK’s columns for journal Current Biology Sydney Brenner Scientific helix by James Watson and Francis Ashby Working Party and attends from 1994 to 2000. Symposium and Exhibition Crick at the Cavendish Laboratory the Asilomar conference on to celebrate the life and work in Cambridge, UK. recombinant DNA in California. 1996 — Founding president and director of of Sydney Brenner. the Molecular Sciences Institute in 1954— Receives Doctor in Philosophy 1977 — Suffers from a motorcycle accident La Jolla, California; retires in 2001. 2019 — Passes away in Singapore on degree in chemistry from three days before official start 5 April 2019. Oxford University. date as proleptic director of the 2000— The International Fugu Genome — Travels across the US on a Carnegie Laboratory of Molecular Biology Consortium is formed with IMCB’s Corporation Travelling Fellowship. (LMB) in Cambridge, UK. Byrappa Venkatesh and Brenner — Returns to South Africa and at the helm. sets up a lab at the University of 1979 — Appointed director of the LMB. — Wins the Albert Witwatersrand. for Special Achievement in 1981 — Non-resident fellow at the Salk Medical Science. 1956— Sends note “On the impossibility of Institute in La Jolla, California all overlapping triplet codes” to the 2002— The International Fugu Genome RNA Tie Club, which was published 1985 — Visits Singapore on the Lee Kuan Yew Consortium publishes a draft a year later in the Proceedings of the Distinguished Visitors Programme. sequence of the fugu genome Comic from Sydney National Academy of Sciences. — The Institute of Molecular and Cell in Science. Brenner’s monthly column, Loose Ends. — Leaves South Africa and starts Biology (IMCB) is founded with — Receives Nobel Prize in Physiology (Photo: Current work at the Cavendish Laboratory Brenner as chairman of its scientific or Medicine (with Bob Horvitz Biology) in Cambridge, UK. advisory board, a position he holds and John Sulston). until 1995.

38 A Heroic Voyage: Sydney Brenner's Life in Science "I Don't Think It's Finished Yet" 39 REFERENCES

1 Gillman J, Gillman T, Brenner S. (1945) Vitamin A and porphyrin-like fluorescence in the livers of pellagrins, with special reference to the effects of a high carbohydrate diet and . The South African Journal of Medical Sciences 10:67-86.

2 Gillman J, Gillman T, Brenner S. (1945) Porphyrin fluorescence in the livers of pellagrins in relation to ultraviolet light. Nature 156:689-689.

3 Bosazza VL, Adie R, Brenner S. (1946) Man and the Great Kalahari. J Natal Univ Coll Sci Soc 5:1-9.

4 Brenner S. (1949) Multipolar Meiosis in Elephantulus. Nature 164:495-496.

5 Brenner S. (1956) On the impossibility of all overlapping triplet codes. RNA Tie Club note. ACKNOWLEDGEMENTS

6 Brenner S. (1957) On the impossibility of all overlapping The production of this book is triplet codes. Proc Natl Acad Sci 15; 43:687-694. supported by the 2015 Sydney Brenner Scientific Symposium and 7 Brenner S, Jacob F, Meselson M. (1961) An unstable Exhibition steering committee. The intermediate carrying information from genes to committee wishes to acknowledge ribosomes for protein synthesis. Nature 19:576-581. the contributions of the following individuals and organisations: 8 Brenner S, Barnett L Crick FHC, Orgel A. (1961) The theory of mutagenesis (editorial letter). A*STAR J Mol Biol 3:121-124. Lim Chuan Poh Ng Choon Peng 9 Crick FHC, Barnett L, Brenner S, Watts-Tobin RJ. Seow Shih Wee (1961) General nature of the genetic code for proteins. Tay-Png Hong Lan Nature 192:1227-1232. Hong Wanjin Byrappa Venkatesh 10 Barnett L, Brenner S, Crick FHC, Shulman RG, Shawn Hoon Watts-Tobin RJ. (1967) Phase shift and other mutants Choong Ket Che in the first part of the rIIB cistron of bacteriophage Tracy Loo T7. Phil Trans R Soc Lond B 252:487-560. CSHL 11 White JG, Southgate E, Thomson JN, Brenner S. (1986) James Watson The structure of the nervous system of the nematode Caenorhabditis elegans: The mind of a worm. Richard Roberts Phil Trans R Soc Lond 314:1-340. Ludmila Pollock Judith Cuddihy 12 Brenner S, Elgar G, Sandford R, Macrae A, Venkatesh Stephanie Satalino B, Aparicio S. (1993) Characterization of the pufferfish (Fugu) genome as a compact model vertebrate genome. Organisations Nature 366:263-268. Institute of Molecular and Cell Biology, A*STAR 13 Aparicio S, Chapman J, Stupka E, Putnam N, Chia J, CSHL Archives Dehal P, Christoffels A, et al. (2002) Whole-genome Current Biology shotgun assembly and analysis of the genome of Nature Publishing Group Fugu rubripes. Science 297:1301-1310. Advisor 14 Brenner S. (1997) Loose Ends. Current Biology. Benjamin Seet

15 Brenner S. (2001) My Life in Science: Sydney Brenner, Editorial consultants A Life in Science. BioMed Central Ltd. Wildtype Media Group Pte Ltd

16 Friedberg E. (2010) Sydney Brenner: A Biography. Designed by Cold Spring Harbor Laboratory Press. Epigram Design

"I Don't Think It's Finished Yet" 41