Sydney Brenner, a South African-born biologist who helped determine the nature of the genetic code and shared a Nobel Prize in 2002 for developing a tiny transparent worm into a test bed for biological discoveries, died on Friday in Singapore. He was 92.
He had lived and worked in Singapore in recent years, affiliated with the government-sponsored Agency for Science, Technology and Research, which confirmed his death.
A witty, wide-ranging scientist, Dr. Brenner was a central player in the golden age of molecular biology, which extended from the discovery of the structure of DNA in 1953 to the mid-1960s. He then showed, in experiments with a roundworm known as C. elegans, how it might be possible to decode the human genome. That work laid the basis for the genomic phase of biology.
Later, in a project still coming to fruition, he focused on understanding the functioning of the brain.
“I think my real skills are in getting things started,” he said in his autobiography, “My Life in Science” (2001). “In fact, that’s what I enjoy most, the opening game. And I’m afraid that once it gets past that point, I get rather bored and want to do other things.”
As a young South African studying at Oxford University, he was one of the first people to view the model of DNA that had been constructed in Cambridge, England, by Francis H. C. Crick and James D. Watson. He was 22 at the time and would call it the most exciting day of his life.
“The double helix was a revelatory experience; for me everything fell into place, and my future scientific life was decided there and then,” Dr. Brenner wrote.
Impressed by Dr. Brenner’s insights and ready humor, Dr. Crick recruited him to Cambridge a few years later. Dr. Crick, a theoretical biologist, liked to have with him someone he could bounce ideas off. Dr. Watson had played this role in the discovery of DNA, and Dr. Brenner became his successor, sharing an office with Dr. Crick for 20 years at the Medical Research Council Laboratory of Molecular Biology at Cambridge.
The fundamental elements of molecular biology were uncovered during this period, many of them by Dr. Crick or Dr. Brenner. Their chief pursuit for 15 years was to understand the nature of the genetic code.
Dr. Brenner made a decisive contribution to solving the code with an ingenious series of experiments in which he altered the DNA of a virus that attacks bacteria.
He showed that by making a series of three mutations, the virus would first lose, then regain, its ability to make a certain protein, as if the cell’s reading of the DNA “tape” had come back into correct phase. The experiment showed that DNA is a triplet code, with each group of three DNA letters specifying one of the 20 kinds of amino acids of which proteins are composed. Dr. Brenner gave these triplets the name codon.
Other researchers were then able to figure out which codon specified each of the 20 amino acids. It fell to Dr. Brenner to identify two of the three triplets that signal “Stop” to the cell’s protein-making machinery.
Dr. Brenner was also the first to conclude that there must be some means for copying the information in DNA and conveying it to the cellular organelles that manufacture proteins. That intermediary, now known as messenger RNA, was discovered in 1960 in an experiment devised by Dr. Brenner and others.
With the fundamental problems of molecular biology solved, as they saw it, Dr. Brenner and Dr. Crick looked for new areas of inquiry. Dr. Brenner decided to approach the brain, but he realized he needed a simpler animal to study than the fruit fly, a standard organism used in laboratories.
He settled on Caenorhabditis elegans, or C. elegans, a tiny, transparent roundworm that dwells in the soil, eats bacteria and completes its life cycle in three weeks. That worm has spun off many developments, starting with the decoding of the human genome.
Using the worm, Dr. Brenner and his colleagues first worked out methods for breaking a genome into fragments, multiplying each fragment in a colony of bacteria, and then decoding each cloned fragment with DNA sequencing machines. His colleagues John Sulston and Robert Waterston completed the worm’s genome in 1998, and they and others used the same methods to decode the human genome in 2003.
Another major project, made possible because of the worm’s transparency, was to track the lineage of all 959 cells in the adult worm’s body, starting from the single egg cell. This feat, accomplished so far for no other animal, made clear that many cells are programmatically killed during development, leading to the discovery by H. Robert Horvitz of the phenomenon of programmed cell death.
The topic assumed an importance that transcended worm biology when it emerged that programmed cell death is supposed to occur in damaged human cells, and that cancer can thwart this process.
For their work on programmed cell death, Dr. Brenner, Dr. Sulston (who died last year) and Dr. Horvitz were awarded the Nobel Prize in Physiology or Medicine in 2002. But many people, including Dr. Brenner himself, believed he should have been awarded a Nobel much earlier for his and Dr. Crick’s work on the genetic code.
“On more than one occasion, in fact, he has claimed that he is delighted to have been awarded two Nobel Prizes — the first he never received!” his biographer, Errol C. Friedberg, wrote.
Sydney Brenner was born to Jewish immigrants in Germiston, a small town near Johannesburg, on Jan. 13, 1927. His father, Morris, a cobbler who could not read or write, had fled Lithuania to escape conscription in the czar’s army. His mother, Leah (Blecher) Brenner, was an émigré from Latvia.
Sydney was taught to read by a neighbor. When a customer at his father’s shop learned that Sydney, at age 4, could read English fluently but that his father could not afford to send him to school, the customer paid the boy’s tuition.
At 15, Sydney won a scholarship to study medicine at the University of the Witwatersrand in Johannesburg. The scholarship covered only his fees, but he managed to afford university life by earning the equivalent of five cents a day by attending synagogue to help form a minyan, the quorum of 10 men required for public prayer.
During his medical training he became interested in scientific research while growing disenchanted with clinical medicine. After finishing medical school in 1951, he won a scholarship to Oxford to work on bacteriophages, the viruses that attack bacteria.
The scholarship required him to return to South Africa. In 1952, he married a fellow South African, May (Covitz) Balkind, who was divorced and had a son by an earlier marriage. She went on to a career as an educational psychologist, and she and Dr. Brenner had three children of their own.
Dr. Crick was eventually able to find Dr. Brenner a post in Cambridge, and in 1956 he returned with his family to England for good.
Dr. Crick, a physicist by training, was a theoretician, but Dr. Brenner was deeply interested in the practice of biology as well. He loved the laboratory, and he loved designing elegant experiments. As a student in South Africa, he had built his own centrifuge. If he had wanted to stain a cell, he first had to synthesize the dye.
At Oxford, “he threw himself into bacteriophage research with the energy of a man digging a tunnel out of prison,” Horace Freeland Judson wrote in “The Eighth Day of Creation” (1979), a history of molecular biology.
Dr. Brenner’s most ambitious project after the genetic code — understanding the brain of the worm — was in a formal sense a failure. His colleague John White, after a decade peering through a microscope, established that the worm’s brain consists of 302 neurons, with more than 7,000 connections between them. But the job of then computing the worm’s behavior, which was Dr. Brenner’s goal, has so far proved too daunting.
Dr. Brenner’s wife died in 2010. His survivors include their three children, Belinda, Carla and Stefan. His stepson, Jonathan Balkind, died last year.
In the early 1990s, Dr. Brenner went to work at the Scripps Research Institute in San Diego on a fellowship. In 1996, with a multimillion-dollar grant from the Philip Morris Company, he established and directed the nonprofit Molecular Sciences Institute in Berkeley, with a mission, in part, to track research in various genome sequencing projects.
From 1994 to 2000 he wrote an opinion column for the journal Current Biology. He originally called it Loose Ends but later changed the name to False Starts when it was moved to the front of the publication.
Dr. Brenner held positions at Cambridge and at the Salk Institute in San Diego, where he was appointed, as he termed it, “extinguished professor.”
He had divided his time between Cambridge and California until, with his health declining, he took up permanent residence in Singapore while working as an adviser to the research agency. In 2003 he was named an honorary citizen of Singapore. He had been advising the Singapore government on science policy since the 1980s and was instrumental in the founding of the Molecular Engineering Laboratory there.
British and Singaporean news organizations said that Dr. Brenner, a former heavy smoker, had been treated for lung disease in recent years.
Known for his wit, Dr. Brenner boasted that aside from science, “the other thing I’m rather good at is talking.”
It was hard for any listener not to fall under his spell. He spoke slowly and precisely in a lingering South African accent, his sentences long and perfectly constructed and often ending with a joke. Insights into the nature of the cell would alternate with his playful inventions, like Occam’s broom — “to sweep under the carpet what you must to leave your hypotheses consistent” — or Avocado’s number, “the number of atoms in a guacamole.”
For a short time he had been director of the Cambridge Laboratory of Molecular Biology, but he did not much enjoy working as an administrator.
“You become a mediator between two impossible groups,” he said, “the monsters above and the idiots below.”
https://www.nytimes.com/2019/04/05/obituaries/sydney-brenner-dead.html
2019-04-05 17:31:23Z
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