Brenner, Sydney (1927- )

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Brenner, Sydney (1927- )

South AfricanEnglish molecular biologist

Sydney Brenner is a geneticist and molecular biologist who has worked in the laboratories of Cambridge University since 1957. Brenner played an integral part in the discovery and understanding of the triplet genetic code of DNA . He was also a member of the first scientific team to introduce messenger RNA , helping to explain the mechanism by which genetic information is transferred from DNA to the production of proteins and enzymes . In later years, Brenner conducted a massive, award-winning research project, diagramming the nervous system of a particular species of worm and attempting to map its entire genome.

Brenner was born in Germiston, South Africa. His parents were neither British nor South AfricanMorris Brenner was a Lithuanian exile who worked as a cobbler, and Lena Blacher Brenner was a Russian immigrant. Sydney Brenner grew up in his native town, attending Germiston High School. At the age of fifteen, he won an academic scholarship to the University of the Witwatersrand in Johannesburg, where he earned a master's degree in medical biology in 1947. In 1951, Brenner received his bachelor's degree in medicine, the qualifying degree for practicing physicians in Britain and many of its colonies. The South African university system could offer him no further education, so he embarked on independent research. Brenner studied chromosomes , cell structure, and staining techniques, built his own centrifuge, and laid the foundation for his interest in molecular biology .

Frustrated by lack of resources and eager to pursue his interest in molecular biology, Brenner decided to seek education elsewhere, and was encouraged by colleagues to contact Cyril Hinshelwood, professor of physical chemistry at Oxford University. In 1952, Hinshelwood accepted Brenner as a doctoral candidate and put him to work studying a bacteriophage , a virus that had become the organism of choice for studying molecular biology in living systems. Brenner's change of location was an important boost to his career; while at Oxford he met Seymour Benzer, with whom Brenner collaborated on important research into gene mapping, sequencing, mutations and colinearity. He also met and exchanged ideas with James Watson and Francis Crick , the Cambridge duo who published the first paper elucidating the structure of DNA, or deoxyribonucleic acid , the basic genetic molecule. Brenner and Crick were to become the two most important figures in determining the general nature of the genetic code.

Brenner earned his Ph.D. from Oxford in 1954, while still involved in breakthrough research in molecular biology. His colleagues tried to find a job for him in England, but he accepted a position as lecturer in physiology at the University of the Witwatersrand and returned to South Africa in 1955. Brenner immediately set up a laboratory in Johannesburg to continue his phage research, but missed the resources he had enjoyed while in England. Enduring almost three years of isolation, Brenner maintained contact with his colleagues by mail.

In January 1957, Brenner was appointed to the staff of the Medical Research Council's Laboratory of Molecular Biology at Cambridge, and he and his family were able to settle in England permanently. Brenner immediately attended to theoretical research on the characteristics of the genetic code that he had begun in Johannesburg, despite the chaotic atmosphere. At the time, the world's foremost geneticists and molecular biologists were debating about the manner in which the sequences of DNA's four nucleotide bases were interpreted by an organism. The structure of a DNA molecule is a long, two-stranded chain that resembles a twisted ladder. The sides of the ladder are formed by alternating phosphate and sugar groups. The nucleotide bases adenine, guanine, thymine, and cytosineor A, G, T, and Cform the rungs, a single base anchored to a sugar on one side of the ladder and linked by hydrogen bonds to a base similarly anchored on the other side. Adenine bonds only with thymine and guanine only with cytosine, and this complementarity is what makes it possible to replicate DNA. Most believed that the bases down the rungs of the ladder were read three at a time, in triplets such as ACG, CAA, and so forth. These triplets were also called codons, a term coined by Brenner. Each codon represented an amino acid, and the amino acids were strung together to construct a protein. The problem was in understanding how the body knew where to start reading; for example, the sequence AACCGGTT could be read in several sets of three-letter sequences. If the code were overlapping, it could be read AAC, ACC, CCG, and so forth.

Brenner's contribution was his simple theoretical proof that the base triplets must be read one after another and could not overlap. He demonstrated that an overlapping code would put serious restrictions on the possible sequences of amino acids. For example, in an overlapping code the triplet AAA, coding for a particular amino acid, could only be followed by an amino acid coded by a triplet beginning with AAAAT, AAA, AAG, or AAC. After exploring the amino acid sequences present in naturally occurring proteins, Brenner concluded that the sequences were not subject to these restrictions, eliminating the possibility of an overlapping code. In 1961, Brenner, in collaboration with Francis Crick and others, confirmed his theory with bacteriophage research, demonstrating that the construction of a bacteriophage's protein coat could be halted by a single "nonsense" mutation in the organism's genetic code, and the length of the coat when the transcription stopped corresponded to the location of the mutation. Interestingly, Brenner's original proof was written before scientists had even determined the universal genetic code, although it opened the door for sequencing research.

Also in 1961, working with Crick, François Jacob , and Matthew Meselson, Brenner made his best-known contribution to molecular biology, the discovery of the messenger RNA (mRNA). Biologists knew that DNA, which is located in the nucleus of the cell, contains a code that controlled the production of protein. They also knew that protein is produced in structures called ribosomes in the cell cytoplasm , but did not know how the DNA's message is transmitted to, or received by, the ribosomes. RNA had been found within the ribosomes, but did not seem to relate to the DNA in an interesting way. Brenner's team, through original research and also by clever interpretation of the work of others, discovered a different type of RNA, mRNA, which was constructed in the nucleus as a template for a specific gene, and was then transported to the ribosomes for transcription. The RNA found within the ribosomes, rRNA, was only involved in the construction of proteins, not the coding of them. The ribosomes were like protein factories, following the instructions delivered to them by the messenger RNA. This was a landmark discovery in genetics and cell biology for which Brenner earned several honors, including the Albert Lasker Medical Research Award in 1971, one of America's most prestigious scientific awards.

In 1963 Brenner set out to expand the scope of his research. For most of his career, he had concentrated on the most fundamental chemical processes of life, and now he wanted to explore how those processes governed development and regulation within a living organism. He chose the nematode Caenorhabditis elegans, a worm no more than a millimeter long. As reported in Science, Brenner had initially told colleagues, "I would like to tame a small metazoan," expecting that the simple worm would be understood after a small bit of research. As it turned out, the nematode project was to span three decades, involve almost one hundred laboratories and countless researchers, make C. elegans one of the world's most studied and best understood organisms, and become one of the most important research projects in the history of genetics.

Brenner's nematode was an ideal subject because it was transparent, allowing scientists to observe every cell in its body, and had a life cycle of only three days. Brenner and his assistants observed thousands of C. elegans through every stage of development, gathering enough data to actually trace the lineage of each of its 959 somatic cells from a single zygote. Brenner's team also mapped the worm's entire nervous system by examining electron micrographs and producing a wiring diagram that showed all the connections among all of the 309 neurons. This breakthrough research led Brenner to new discoveries concerning sex determination, brain chemistry, and programmed cell death. Brenner also investigated the genome of the nematode, a project that eventually led to another milestone, a physical map of virtually the entire genetic content of C. elegans. This physical map enabled researchers to find a specific gene not by initiating hundreds of painstaking experiments, but by reaching into the freezer and pulling out the part of the DNA that they desired. In fact, Brenner's team was able to distribute copies of the physical map, handing out the worm's entire genome on a postcard-size piece of filter paper.

Brenner's ultimate objective was to understand development and behavior in genetic terms. He originally sought a chemical relationship that would explain how the simple molecular mechanisms he had previously studied might control the process of development. As his research progressed, however, he discovered that development was not a logical, program-driven processit involved a complex network of organizational principles. Brenner's worm project was his attempt to understand the next level in the hierarchy of development. What he and his assistants have learned from C. elegans may have broad implications about the limits and difficulties of understanding behavior through gene sequencing. The Human Genome Project, for instance, was a mammoth effort to sequence the entire human DNA. James Watson has pointed to Brenner's worm experiments as a model for the project.

Brenner's research has earned him worldwide admiration. He has received numerous international awards, including the 1970 Gregor Mendel Medal from the German Academy of Sciences, the prestigious Kyoto Prize from Japan, as well as honors from France, Switzerland, Israel, and the United States. He has been awarded honorary degrees from several institutions, including Oxford and the University of Chicago, and has taught at Princeton, Harvard, and Glasgow Universities. Brenner is known for his aggressiveness, intelligence, flamboyance, and wit. His tendency to engage in remarkably ambitious projects such as the nematode project, as well as his ability to derive landmark discoveries from them, led Nature to claim that Brenner is "alternatively molecular biology's favorite son and enfant terrible."

While still in Johannesburg in 1952, Brenner married May Woolf Balkind. He has two daughters, one son, and one stepson. In 1986, the Medical Research Council at Cambridge set up a new molecular genetics unit, and appointed Brenner to a lifelong term as its head. Research at the new unit is centered on Brenner's previous work on C. elegans and the mapping and evolution of genes.

See also Bacteriophage and bacteriophage typing; Genetic code; Genetic identification of microorganisms; Genetic mapping; Microbial genetics

Brenner, Sydney

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BRENNER, SYDNEY (1927– ), British scientist and Nobel laureate. Brenner was born in Germiston, South Africa, and studied medicine at the University of the Witwatersrand in Johannesburg, which incorporated a medical B.Sc. course and stimulated his interest in research. He published his first paper at age 18 and obtained an M.Sc. in cytogenetics in 1947 before becoming an M.D. in 1951. He received his Ph.D. in bacterial viruses from Oxford University in 1954, where his contacts with Francis Crick and Jim Watson determined the direction of his research interests, further stimulated by a visit to the U.S. on a Carnegie Corporation Traveling Fellowship. After a brief return to South Africa he joined the Medical Research Council's Laboratory of Molecular Biology in Cambridge in 1956, of which he was director in 1979–86. He directed the molecular genetics unit in 1986–91. In 1996 he was appointed president and director of science at the Molecular Sciences Institute, La Jolla, California, and in 2000 distinguished research professor at the Salk Institute, La Jolla. He used the small worm (nematode) Caenorhabditis elegans and later the Japanese pufferfish Fugu to study the genetic control of nervous system development. He and his colleagues correlated gene mutations with developmental abnormalities initially by anatomical and later by gene-cloning techniques. These studies helped establish the important principle that the origin of human diseases can be investigated by detecting mutant genes and the abnormal proteins these genes encode. They foreshadowed the medical benefits anticipated from mapping the human genome. He was awarded the Nobel Prize for medicine in 2002 (jointly with Robert Horwitz and John Sulston). His honors include frs (1965), Lasker awards (1971 and 2000), Gairdner awards (1978 and 1991), and the Harvey Prize of the Israel Technion (1987).

[Michael Denman (2nd ed.)]