Sydney Brenner’s scientific endeavors began early. At the age of nine, after devouring F. Sherwood Taylor’s book “The Young Chemist” he carried out the experiments it described and then branched out on his own, extracting pigments from leaves and grasses. As a young boy, he already exhibited the experimental skills that would define his career as a Nobel Prize-winning geneticist.
Brenner’s college years were equally precocious. A native of South Africa, he entered medical school at the University of the Witwatersrand at age 15 with a scholarship, an important aid for a family with little money. He realized he would be too young to practice medicine when he graduated and took some time off to do research, publishing 10 papers before graduating in 1951. Despite a flair for delivering babies — Brenner graduated top of his class in obstetrics — he decided he was better suited to the rigors of science.
“There has been only one quest, the quest to find out how organisms are encoded by their genes, to study that unique property of biological systems that distinguishes them from all other complex natural systems, of containing an internal description of themselves,” Brenner noted in his autobiography, “My Life in Science.”
Brenner discovered his life’s work during a now-legendary trip to Cambridge University to view James Watson and Francis Crick’s new model of DNA in the Cavendish Laboratory. Brenner, then a graduate student at Oxford University, had an epiphany. It was as though a “curtain had been lifted and everything was now clear what to do. … I just knew that … this was really the beginning of molecular biology,” Brenner wrote. During that visit, he spent hours talking with Watson and met Crick, who would become a long-term collaborator.
The meeting with Crick was the start of one of science’s great partnerships. Crick arranged a position for Brenner at the Cavendish, in what was then the Medical Research Council Unit for Research on the Molecular Structure of Biological Systems, better known by its later title, the Laboratory of Molecular Biology (LMB). The two shared an office for the first 20 years of Brenner’s 30-year tenure there, the result of an inspired decision by Max Perutz, director of the unit, to bring together two inveterate talkers. As Crick wrote later of their time together:
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.
The hot topic of the time was deciphering the genetic code, that is determining the relationship between the sequence of nucleotides in DNA, and the sequence of amino acids in a protein. Brenner’s first publication from the Cavendish was a theoretical paper that he had begun in South Africa. It was clear that there had to be a minimum of three nucleotides (triplets) coding for each amino acid, and both the physicist George Gamow (better known, perhaps, for his “Mr. Tompkins” series of science books for children) and the chemist Leslie Orgel had proposed overlapping triplet codes. The title of Brenner’s paper succinctly refutes that idea: “On the Impossibility of All Overlapping Triplet Codes in Information Transfer from Nucleic Acid to Proteins.” This is a classic paper of molecular genetics — elegant, simple, concise. It was clear that a major new player was in town.
Over the next 10 years, Brenner, Crick, Orgel and colleagues carried out a wonderful series of experiments directed at understanding genes and the genetic code. One set proved unequivocally that the code was made up of triplets of nucleotides. Brenner described these experiments in his autobiography as “one of the most beautiful … aesthetically elegant experiences of my life.”
Brenner’s major contributions to science lie not just in his genetic insights, but also in the new methodologies he pioneered. One of his most highly cited papers, with more than 1,300 citations, describes a new method of staining the fine structure of the bacteriophage, a virus that infects bacteria. This advance reflects Brenner’s lifelong fascination with experimentation, from his childhood chemistry experiments to his mature achievements, which include building an air turbine centrifuge and developing methods for cloning genes.
Brenner’s most famous experiment, carried out in 1960 with French biologist François Jacob in Matthew Meselson’s laboratory at the California Institute of Technology, demonstrated the existence of messenger RNA, which carries genetic information from nucleus to cytoplasm.
Creating a New Field
By 1966, the genetic code was essentially cracked. Looking for new challenges, Crick and others moved to established fields, but Brenner decided to create a new one. Intrigued by the nervous system, Brenner wrote to Perutz that he would “like to tame a small metazoan organism to study development directly.” After reading extensively on zoology and botany and considering several organisms, he settled on the nematode Caenorhabditis elegans, now known familiarly as “the worm.”
Brenner induced mutations in worms, observed the abnormal behavior that resulted, and mapped the responsible genes. In 1974, 10 years after beginning work on the worm, Brenner published a paper describing some 300 mutants. This proved to be his most influential paper, having garnered more than 6,000 citations to date.
An accompanying paper he co-authored with John Sulston, a postdoctoral fellow in Brenner’s lab, reported that the worm genome was only 20 times larger than that of E. coli, a fact that became important years later in discussions about sequencing the worm genome. Brenner’s lab also began mapping the wiring of the worm’s nervous system using electron microscopy, an epic endeavor that led to a 340-page monograph in 1986 — his second most cited paper — and the only complete neural map to date. Sulston and Robert Horvitz, another postdoctoral fellow in the lab, also traced the lineage of all 959 cells of the adult worm as well as those of embryo cells. The work won Brenner, Sulston and Horvitz the Nobel Prize for Physiology or Medicine in 2002.
Brenner has rightly called the C. elegans initiative “a monumental achievement,” rivaling the role played by the fruit fly, Drosophila melanogaster, in the development of classical genetics. By 2013, the worm had become the subject of more than 20,000 papers.
By the late 1970s, Brenner had moved on. As he readily acknowledges in his autobiography, “…my skills are in getting things started … once it gets past that point I get rather bored with it and want to do other things.” He also considers himself adept at “convincing people to join the crusade,” an essential skill in establishing a new field, as well as “brainwashing, which is to persuade people to do things that their upbringing tells them they ought not to be doing,” such as tackling the biology of an entire organism cell by cell.
“If the founders or oldest gods of molecular biology comprise a pantheon of sorts, then among them, Sydney is surely the clever one, the trickster figure, the Loki, Anansi or Coyote,” said Roger Brent, formerly president of Brenner’s Molecular Sciences Institute and now a biologist at the Fred Hutchinson Cancer Research Center in Seattle. “By making mischief and devising practical jokes that lay bare the pomposity and stupidity of others, the trickster continually shakes up the established order and readies it for change.”
Brenner is also known for his legendary love of both wordplay and discussion. For example, he instructed students to “neurox” rather than Xerox papers. He invented Occam’s broom “to sweep under the carpet what you must in order to leave your hypotheses consistent.” And in dealing with bureaucrats, Brenner finds that inverted phrases, such as “pay-related performance,” can reduce them to silence. Many of his entertaining essays are collected in the volume “Loose Ends.”
“Late-night science — and sleep — were often endangered by Sydney,” said Horvitz, recalling his time working at the LMB in the mid-1970s. “A number of times when I was working at 2 or 3 a.m. and desperate for a cup of tea, I would go to the tea room only to find myself soon joined by Sydney, attracted by the rattle of the spoon in the teacup. In Sydney’s (but not my) view, 2 a.m. was an excellent time to talk! I learned to stir silently.”
Junk Versus Trash
In the mid-1980s, scientists began to talk about sequencing the entire human genome. Brenner knew that only about 10 percent of the human genome codes for proteins; the remainder he called junk DNA. (Some called it trash DNA, but Brenner pointed out that trash is thrown out. Vertebrates have kept this noncoding DNA, so it is junk, the stuff you keep but put in the attic.) He sought ways to reduce the cost of sequencing by focusing on the protein-coding regions. Opponents argued this approach would miss noncoding regions that include sequences controlling gene expression. So Brenner began searching for a vertebrate with a similar set of genes to Homo sapiens but with smaller amounts of junk DNA, so that sequencing would be quicker and cheaper. He found it in the Japanese puffer fish, Takifugu rubripes, which has a genome one-eighth the size of the human genome. Brenner and his colleagues published the fish’s full sequence in 2002, and it has been used extensively in studies of gene evolution.
In 1979, Brenner became director of the LMB, a move he considers one of the worst mistakes of his life. Prodded by tight budgets, Brenner instigated changes that the LMB staff resisted, and he argued with the MRC management over access to laboratory space after his retirement. The situation deteriorated, and he resigned the directorship in 1986.
As his connections with the LMB faded, Brenner established bases elsewhere. In 1981,with Crick’s encouragement, Brenner became a nonresident fellow of the Salk Institute in La Jolla, California, and he later joined the faculty of the Scripps Research Institute, also in La Jolla. Brenner created a third Californian location for himself, the Molecular Sciences Institute, in Berkeley. Most recently, Brenner has been appointed a senior fellow at the Janelia Farm Research Campus of the Howard Hughes Medical Institute. His main interests, however, moved to Asia.
Throughout his career, Brenner has been actively involved in science policy. He was a key figure in the acrimonious debates over the potential dangers of recombinant DNA as well as early discussions about the human genome project. With Brenner’s encouragement, the Singapore government chose to focus on basic biological research, opening the Institute for Molecular and Cell Biology in 1987 and completing Biopolis, a 2.5-million-square-foot research complex, in 2003. Japan followed suit, creating the Okinawa Institute of Science and Technology, and Brenner became its president in 2005. “What impressed me about Sydney with Singapore’s senior officials was his witticisms putting them at ease,” said Chris Tan, founding director of the Singapore institute.
Through all these developments, Brenner has continued to do research. Since 2000 he has focused on using genome sequence data to investigate evolutionary relationships. After almost 70 years doing research, Brenner is as enthusiastic as ever in pursuing his quest to find out how organisms are encoded by their genes.
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