South Africa

Sydney Brenner grew up in a Yiddish-speaking Jewish community that included many aunts, uncles, and cousins. He lived with his parents, sister Phyllis (b. 1929), and brother Isaac (Joe) (b. 1937), in two rooms at the back of his father’s cobbler’s shop. While Morris was barely literate, he had learned to speak English well and could also converse in Russian, Afrikaans, and Zulu. According to his daughter, ‘he was always laughing and joking and loved parties and dancing’ (Friedberg, Sydney Brenner, 5).

Taught by an elderly neighbour from newspapers, Brenner was reading fluently by the age of four. Noticing his precocity, one of his father’s customers then arranged for him to go to kindergarten. By the time he started Germiston junior school at the age of six he was advanced enough to skip the first three years. He read voraciously in the local library: a favourite book was The Young Chemist by F. Sherwood Taylor, which inspired him to buy chemicals and start doing his own experiments. ‘I made the (to me) astounding discovery that the pigments I extracted [from flowers] changed their colours when I changed the pH of the solution’ (Brenner, 'Sydney Brenner'). A second book, The Science of Life by H. G. Wells and Julian Huxley, fascinated him so much that he never returned it to the library and paid a fine for having ‘lost’ it. The book introduced him to topics such as natural selection, embryonic development, and photosynthesis, discussed at a far higher level than anything in his school textbooks.

Starting Germiston high school at the age of nine, Brenner graduated with first-class results before his fifteenth birthday. He succeeded largely as a result of his enthusiasm for self-education rather than inspiration from his teachers, whose bullying gave him a lifelong resistance to authority. A bursary from the local council enabled him to go to university, which would have been beyond his parents’ means. Acceding to their desire for him to gain a professional qualification, he entered the University of the Witwatersrand (Wits) in Johannesburg to study medicine. The medical school was led by the professor of anatomy and palaeontologist, Raymond Dart, world renowned for his fossil discoveries of early hominins.

Dart introduced intercalated one-year bachelor’s and honours courses in anatomical sciences and physiology as options for medical students after their second year. Brenner was among the first to take these; had he not done so, he would have been too young to practise by the time he qualified in medicine. He was far more engaged by the palaeontological fieldwork, exposure to evolutionary thinking, and laboratory experiments included in the two ‘science years’ than by the routine dissections and dry lectures of the medical course. Other influential teachers at Wits included the botanist Eddie Roux, whose classes incorporated recent findings in plant biochemistry.

Roux was also politically active as a former member of the South African Communist Party. While Brenner never joined a political party, he was heavily engaged in progressive student politics. He became director of research for the National Union of South African Students and chaired the Student Representative Council at Wits. These organizations campaigned against racial segregation on university campuses, though with little success. His wicked sense of humour and talent for impersonation made him a popular figure among his peers.

By the end of his two years of science studies Brenner had published several articles (including two in the influential British journal Nature). He taught himself cytogenetics, making his own dyes to stain subcellular compartments, and in the following year wrote a master’s thesis on the chromosomal content of the South African tree shrew Elephantulus myurus. Having already decided that his future lay in scientific research, on his return to medical school he cut most of the lectures, ward rounds, and clinical responsibilities. As a result he faced his final clinical examination having barely laid eyes on a patient, and was failed for his inability to recognize the smell of acetone on the breath of a diabetic. Six months of further unwelcome clinical studies followed before he managed to scrape through at a second attempt.

By the time he qualified in 1951, Brenner had begun to build up an impressive network of international correspondents interested in the boundaries between chemistry and biology, and particularly in the relationship between nucleic acids and proteins. The principal of his university, Humphrey Raikes, introduced him to the Oxford chemist Sir Cyril Hinshelwood (later to win a Nobel prize), who offered him a place in his laboratory to study for a doctorate. Brenner successfully applied for a scholarship for postgraduate study abroad from the Royal Commission for the Exhibition of 1851.

Oxford

Brenner arrived in Oxford in October 1952. ‘As the boat docked in Southampton on a very cold winter morning I looked out and everything was much smaller than I had imagined’, he recalled (Brenner, My Life, 20). Joining Hinshelwood’s physical chemistry laboratory, he began to work on phage. Phage are viruses that infect bacteria by inserting their genetic material into their hosts. They were of great interest to geneticists looking at the physical basis of inheritance. Brenner immediately made himself familiar with excellent work then under way at Oxford in other departments, such as pathology, biochemistry, and organic chemistry. In two years he successfully demonstrated that bacterial resistance to phage came about as a result of mutation and not adaptation (contrary to the view of his supervisor), and obtained his DPhil in 1954 for a thesis on ‘The physical chemistry of cell processes’.

Brenner claimed to find the wider Oxford unwelcoming: ‘Being (a) a scientist and (b) a colonial I never really participated in the Oxford scene’ (Brenner, My Life, 23). Devastated on his arrival to hear of the sudden death of a South African friend, Harold Daitz, with whom he had hoped to be reunited in Oxford, he instead looked up another Wits contemporary, May Woolf Balkind, née Maise Covitz (1921–2010), daughter of Isaac Covitz, tea and coffee merchant, and his wife, Marie. Recently divorced and with a young son, Jonathan (1946–2018), from her marriage to Gabriel Balkind, a South African businessman, she was studying in London for a PhD in psychology. In very short order Brenner proposed to her. Once she had confirmed that she could continue with her own work, she accepted, and they married at Chelsea Old Town Hall on 6 December 1952. They commuted between London and Oxford until she became pregnant with their first child, Stefan, who was born in October 1953. They later had two further children, Belinda (b. 1954/5) and Carla (b. 1960). May pursued her own career as an educational psychologist, mostly remaining at their home in Ely as Brenner took up an increasingly international lifestyle: she felt particularly at odds with the political atmosphere in the USA. Brenner recognized the difficulties of a marriage in which one partner lived in ‘a world created mostly in one’s head’ (Brenner, 'Sydney Brenner').

Brenner may have overstated his social isolation. He made good friends among the Oxford scientists, especially young visiting researchers like himself. These included Jack Dunitz, a Scottish crystallographer who was working with Dorothy Crowfoot Hodgkin. In April 1953, Dunitz told Brenner that James Watson and Francis Crick in the Cavendish Laboratory at Cambridge had solved the structure of DNA. With Hodgkin, Dunitz, the chemist Leslie Orgel, and another member of Hodgkin’s laboratory, Beryl Oughton, he drove over to Cambridge to see the DNA model Watson and Crick had built, a week or two before their ground-breaking paper in Nature was published. He subsequently described the moment he saw the model as a watershed in his life. ‘I felt as if a curtain had been lifted in my mind, in the sense that I knew this was a fundamental breakthrough in biology and we could now find out how genes worked’ (Friedberg, Sydney Brenner, 68). He took the chance to have a long discussion with Watson about the nature of the gene, and was also inspired by his first encounter with the voluble and energetic Crick.

What struck Brenner immediately was that the DNA structure allowed one to think of the information in the genetic material as one-dimensional—a single string of ‘letters’ encoding everything needed to make a living body. For him, this focus on information content was a radical perspective in biology, one that he recognized immediately thanks to his reading of early papers in computing science. When he heard the Cambridge biochemist Fred Sanger reveal that the protein insulin consisted of two chains of amino acids, each with a unique and specific order, he became even more convinced that this was the new frontier.

Brenner wanted nothing so much as to join Crick at Cambridge, working as part of the Medical Research Council (MRC)'s Unit for Research on the Molecular Structure of Biological Systems, located in the Cavendish Laboratory and headed by the protein crystallographer Max Perutz. Brenner’s aim was to crack the DNA code: how the sequence of nucleotide bases became translated into chains of amino acids in proteins. Discussions within the RNA Tie Club—a talking shop convened by the eccentric Russian physicist George Gamow, which also included Crick and Watson—had already concluded that one amino acid (of which there are twenty) must be specified by three nucleotides (of which there are four). Brenner wrote a paper for the club, later published in the Proceedings of the National Academy of Sciences, proving theoretically that such a triplet code could not be ‘overlapping’: no nucleotide could participate in encoding more than one amino acid.

However, Brenner’s fellowship ran out at the end of June 1954 and he had a lectureship back in South Africa lined up: it was a condition of his Exhibition of 1851 fellowship that he return to teach there. That summer May took the children back to Johannesburg while he put off the moment by spending a few months at the Cold Spring Harbor Laboratory on Long Island, New York, and at the Woods Hole Oceanographic Laboratory in Massachusetts—both highly regarded for their research summer programmes. The trip, funded by the Carnegie Corporation of New York, also took in a few weeks on the west coast of the USA at the California Institute of Technology (Caltech) and the University of California at Berkeley. Brenner made a somewhat hair-raising journey from east to west coasts in a convertible driven by Watson.

During the months he spent in the USA, Brenner met and worked with all the great and good of molecular biology, and in his turn made a strong impression on them. For the next two years, reunited with his family in South Africa, he worked diligently on the coding problem and others, but though he kept up a vigorous correspondence he keenly felt the lack of daily contact with minds such as Crick’s. He had offers from several American universities, but eventually Crick managed to secure him a three-year contract in the MRC unit in Cambridge. He returned there with his family and started work on 1 January 1957.

Cambridge

Brenner initially moved into The Hut, a temporary building adjacent to the Cavendish Laboratory that housed the MRC unit. He and Crick spent hours bouncing ideas between them and laughing uproariously. But Brenner was also hands-on in the laboratory, ably assisted by the technicians Leslie Barnett and Muriel Wigby.

In 1962 Perutz’s unit moved into the purpose-built Laboratory of Molecular Biology (LMB) adjacent to Addenbrooke’s Hospital in the south of Cambridge. With one Nobel prize-winner (Sanger) among its founders and three more (Perutz, Crick, and John Kendrew) added before the year was out, the LMB quickly became a mecca for able researchers. By 2018 the tally of Nobel prize-winners who did their critical work at the LMB had reached sixteen (Sanger having won the prize twice). Brenner accepted a permanent appointment at the unit and in due course became co-head, with Crick, of the molecular genetics division. They continued to share an office until Crick left for California in 1976. In 1959 Brenner was elected a fellow of King’s College and participated fully in college life, enjoying conversations over dinner and the opportunity to expand his knowledge of fine wines.

A major question at the end of the 1950s was how the DNA sequence in the nucleus of a cell became translated into protein manufactured in the cytoplasm on organelles called ribosomes. One momentous evening in 1960, when a group including Crick and the French geneticist François Jacob were gathered in Brenner’s rooms at King’s, discussion turned to the possibility of an unstable intermediate or ‘messenger’ that carried information from the nucleus to the ribosome for transcription. Brenner and Crick simultaneously started shouting—they realized that this intermediate, later known as messenger RNA or mRNA, had been discovered by others a few years previously, but no one had recognized its significance. That summer Jacob and Brenner went to Caltech to work with Matthew Meselson on a technique that would definitively reveal the messenger. Credit for the discovery was shared with another group that included Jacob’s colleague from the Pasteur Institute in Paris, François Gros, who used different methods to obtain the same result.

That still left the question of the code itself. Crick, Brenner, and their colleagues carried out a painstaking series of experiments using mutations in phage to show that, as previously thought, the code for each amino acid is a triplet of three bases; that the code is degenerate—that is, more than one triplet can code for the same amino acid; that the sequence is read from a fixed starting point, so that if one or two bases are missing the sequence cannot be read correctly; and that there are no ‘commas’ or other forms of punctuation to show where the triplets begin and end. The paper they published in Nature in 1961, ‘General nature of the genetic code for proteins’, was a landmark. The deciphering of the triplets themselves was the fruit of an international effort by chemists that took place over the next few years.

Worms

With the cracking of the code, Brenner’s restless imagination led him to move on to a larger challenge: to choose a whole organism and try to define how its genes encoded its development and the function of its nervous system. The organism he chose in 1964 was the nematode worm, Caenorhabditis elegans. This creature lives in the soil, senses, eats, moves, and reproduces, and has only around 1000 cells. Most individuals are self-fertilizing hermaphrodites. Brenner planned to trace its entire nervous system using electron microscopy, follow its development cell by cell from egg to adult, and study the behaviour and development of mutants.

Brenner successfully obtained funding from the MRC to buy a computer and set up a new research group. Wigby was the first member of the team. Nichol Thomson, who had been Lord Rothschild’s electron microscopist, took on the task of making electron micrographs of fixed sections of embedded worm. John White programmed the computer to reconstruct the slices. John Sulston joined in 1969 to work on the worm genome and cell lineage. As time went on, Brenner’s enthusiasm attracted a continuous stream of mostly American post-doctoral researchers who went on to spread studies of the worm worldwide.

Having set up the team, who needed little or no direction, Brenner became absorbed first in working with the computer, a novel tool that fascinated him, and in attempting to clone mutant worm genes. The output of papers from the group was slow at first, but when they came they broke new ground. Work on the nervous system produced ‘The structure of the nervous system of the nematode Caenorhabditis elegans: the mind of the worm’, published in the Philosophical Transactions of the Royal Society of London B in 1986, which described all 302 of the creature’s neurons and the connections between them. Jonathan Hodgkin studied how the worm’s genes controlled whether it developed into a hermaphrodite or a male, and curated the genetic map as it slowly emerged from studies of mutants.

Sulston, assisted by a visitor from Harvard, Robert Horvitz, sat in front of a microscope for days on end until he had traced the lineage of all the nematode’s cells from larva to adult. In the course of this work they noticed that some cells routinely died in the course of development, a phenomenon that became known as ‘programmed cell death’. The genetic control of this phenomenon turned out to be critical to understanding development and medical conditions including cancer. This work would earn a Nobel prize for Brenner, Sulston, and Horvitz in 2002. Sulston went on to complete the cell lineage by studying the much more difficult embryonic stage, from egg to larva, and then, with his colleague Robert Waterston at Washington University in St Louis, Missouri, to sequence the entire worm genome. Their success at this endeavour won them leading roles in the Human Genome Project, launched in 1990, with Sulston being appointed director of the Wellcome Trust’s new Sanger Centre (later the Wellcome Sanger Institute) near Cambridge in 1992.

Brenner himself was captivated by the possibilities offered by gene cloning—isolating specific genes and growing them in bacteria so that their functions could be studied. As a result he became involved in international efforts to conduct such recombinant DNA experiments safely. However, after 1979 his time in the laboratory was limited by his surprising decision to step into Perutz’s shoes as head of the LMB.

Director of the LMB

The MRC agreed to postpone the retirement of Perutz as chairman from 1974 until 1979, having been stumped by the difficult job of replacing him. During that period the easy-going relationship between MRC head office and the LMB came to an end. A report by the crystallographer Sir David Phillips had been highly critical of the laboratory’s management, especially in relation to its budget. It recommended a 25 per cent cut in funding and a much tighter management structure. It was in these circumstances that Brenner, rather against his better judgement (he later said it was the worst mistake of his career) agreed to become director-elect in 1977 with control of the budget, and take over as director in 1979.

Brenner began his tenure from a hospital bed, having been badly injured in a collision between a car and his motorcycle. The injury plagued him thereafter, and he needed to use a walking stick. The problems at the lab were serious: it was £1 million in the red, and the country was entering a period of high inflation. The election of a Conservative government in 1979 brought in further cuts in research funding. Assisted by a senior administrator from MRC head office, Bronwen Loder, Brenner instituted much closer oversight of spending by the three divisions, tried to bring in a stronger focus on recombinant technology, and negotiated unsuccessfully with the MRC to establish a new neurobiology division.

Brenner found himself both unpopular with his colleagues for an approach they found dictatorial, and at odds with MRC head office over his efforts to fund the laboratory adequately. Soon after the secretary of the MRC, Sir James Gowans, recalled Loder without explanation, Brenner gave up the directorship on reaching his sixtieth birthday in 1986. The MRC set him up in his own small Molecular Genetics Unit, which he ran at first from unused space within the LMB, before moving to laboratories provided by Cambridge University’s department of medicine at Addenbrooke’s Hospital. There he established a programme to map and sequence the genes of the puffer fish, Fugu, which had an unusually compact genome. He remained a staunch advocate of the use of comparative genomics to improve the understanding of the human genome. He finally left his long-standing post as an MRC staff scientist in 1992. There was no retirement party.

Global influencer

In a book based on a series of interviews on his life, Brenner told the geneticist Lewis Wolpert that ‘I think my real skills are getting things started’ (Brenner, My Life, 179). In 1964 he helped to found the European Molecular Biology Organization, cornering Perutz to become its first chairman. The organization’s aim was to act as a pan-European virtual academy, offering fellowships to allow young scientists to move between laboratories in member countries, and organizing meetings to share expertise in the rapidly growing field. Brenner’s was also a critical voice in winning support for a separate but connected European Laboratory of Molecular Biology in Heidelberg, for which he recommended his LMB colleague Kendrew as founding director.

At a meeting at Cold Spring Harbor in 1988, Brenner instigated the establishment of the Human Genome Organization (HUGO), a ‘UN for the human genome’ (Nature Genetics, 34, 2003, 115) that ensured that the job of mapping and sequencing the twenty-three pairs of human chromosomes was coordinated internationally. He was less enthusiastic about the Human Genome Project, funded by the USA's National Institutes of Health, the Wellcome Trust, and others, which sought to sequence all 3 billion ‘letters’ of the human genome. Brenner believed a faster route to finding genes was to use short sequences of DNA, reverse engineered from proteins, to fish out the genes from the vast lengths of non-coding DNA in the genome.

Decades as a heavy smoker took their toll on Brenner’s health, and he sought to find a more congenial climate during the grey and damp winters around his fenland home. Beginning with a fellowship at the Scripps Research Institute in La Jolla, California, he made California a second home, later joining Crick as a distinguished professor at the Salk Institute, also in La Jolla. In 1996 he obtained a large grant from the Philip Morris tobacco company to set up the non-profit Molecular Sciences Institute in Berkeley, with the aim that ‘young people could pursue science in an atmosphere of harmonious purpose and high intellectual challenge’. He advised Singapore’s Agency for Science, Technology, and Research, and was a founder faculty member of the country’s Institute of Molecular and Cell Biology. He was also instrumental in establishing the Okinawa Institute of Science and Technology Graduate University, becoming its president from 2005.

Brenner never had the patience (or perhaps the self-regard) to write a book, but he was a witty and engaging writer and for seven years contributed a monthly column, ‘Uncle Syd’, to the journal Current Biology. He relished the opportunity this gave him to air his opinions to a wide and informed readership. His lectures were legendary, pervaded with his characteristic wit, but also full of insight into the future directions that science might take. He was kind to young scientists, committed to the idea that they should look for new directions, and not fall into the trap of grinding out publications for the sake of it at the behest of unimaginative laboratory heads. But he could be acerbic in his relations with others, landing sharp barbs to puncture pomposity or expose sloppy thinking.

While Brenner never became a household name, his profound influence on his field was widely recognized, and he received many honours in addition to the Nobel prize. He was appointed Companion of Honour in 1987, became the first person to be an honorary citizen of Singapore in 2003, and received the grand cordon of the order of the Rising Sun from the government of Japan. Eventually his breathing difficulties meant that he needed constant access to an oxygen tank, making any form of travel a challenge. During his final years he lived in a hotel in Singapore, but with a driver to take him to and fro he continued to work in his office at the Institute of Molecular and Cell Biology. He died in Singapore on 5 April 2019. He was survived by his son, Stefan, and daughters, Belinda and Carla.