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Citation: The Albert Lasker Award for Special Achievement in Medical Science

For 50 years of brilliant creativity in biomedical science – exemplified by his legendary work on the genetic code; his daring introduction of the roundworm Caenorhabditis elegans as a system for tracing the birth and death of every cell in a living animal; his rational voice in the debate on recombinant DNA; and his trenchant wit.

Sydney Brenner likes beginnings. In the course of his career, he has opened up several major fields. While many scientists are gearing up to explore the new frontiers he has pioneered, Brenner's brain is already fidgeting and scouting around for a fresh path.

In the early 1960s, Brenner emerged as one of the influential leaders of the classical period of molecular biology, the era from 1953 (discovery of the double helix) to 1966 (elucidation of the genetic code). His discoveries are legendary and appear in every biology textbook. He established the existence of messenger RNA (mRNA) – the "working tape" copy of genetic material from which cells make proteins – and found that each amino acid in a protein is specified by a set of three building blocks, or nucleotides, in the RNA chain, which he termed "codon." He showed that the nucleotide sequence in mRNA dictates the order of amino acids, and that each mRNA chain contains the instructions for a particular protein. He also deciphered the stop codons, which terminate protein synthesis.

These insights laid the foundation for the genetic revolution. They have paved the way to our current detailed understanding of how genes control cellular activities, and how disease can occur when gene function goes awry. Brenner received the 1971 Albert Lasker Basic Medical Research Award for these contributions.

Having contributed significantly to the budding field of molecular genetics, he abandoned it in favor of a new adventure in the mid 1960s. "Once we understood about DNA, the code, and making proteins, a lot of detail had to be filled in, but we thought that most of the important problems had been solved," he says. "We could leave it to the hordes of other people to continue. We wanted to do something more interesting."

He turned to embryonic development and the nervous system. In seeking an organism to study, he wanted an animal in which he could map the complete wiring of the nervous system and make mutations to study the function of individual genes. He chose the roundworm Caenorhabditis elegans. This organism is composed of a fixed number of cells, each of which performs the same task from individual to individual. Furthermore, each cell in the developing organism gives rise to a predictable set of cells in the adult, offering the possibility of building a flow chart of each cell's fate.

Brenner figured out how to work with C. elegans in the lab. Because the animal is a hermaphrodite, making mutants requires procedures that differ from those employed with, for example, fruit flies. Using these techniques, Brenner and postdoctoral fellow John Sulston (now at the Sanger Centre in England) set to work unraveling how C. elegans grows and specializes on its trajectory from a single cell to a full-grown worm.

The researchers found that some cells kill themselves during embryonic development. By exploiting the relative ease of probing the roles of single genes in C. elegans, postdoctoral fellows such as Robert Horvitz (now at MIT) began untangling the molecular mechanism that underlies this controlled cell suicide, also called apoptosis. That work opened the door to understanding this phenomenon, which plays a critical role in many organisms' embryonic development and also guards against cancer. Brenner and postdoctoral fellows in his lab have exploited C. elegans to launch the study of many additional complex physiological phenomena, including aging, nerve cell function, and transmission of chemical signals from the outside of a cell to its inside.

The group also elucidated the detailed wiring of the nervous system, the first and thus far only such diagram for any animal. The researchers cut the worms into literally thousands of thin slices and viewed them with an electron microscope. By stacking up the resulting cross-sectional pictures, they could trace each neural connection. With this method, they uncovered exactly how nerve cells link to each other in the entire animal.

Brenner's team also started to pinpoint where particular genes lay on the worm's six chromosomes. This work gave rise to the C. elegans genome project, spearheaded by former Brenner postdoctoral fellows Sulston and Robert Waterston (now at Washington University School of Medicine), in which scientists spelled out the complete sequence of the organism's DNA. This endeavor, completed in 1998, produced the first whole genome sequence of an animal.

In these ways, Brenner elevated this obscure worm from the pages of zoology books to a central place in experimental biology. "There are maybe 1,000 people working in C. elegans now," he says. "Things really took off."

Brenner studied C. elegans until the mid-1980s. By that time, "There were lots of talented young people who could do things better than I could," he recalls. Furthermore, he's most interested in new fields, he says, making a chess metaphor: "The exciting thing about science is the opening game. C. elegans is in the middle game. I thought I would like to do something different."

So he switched to study genomes of other organisms, and started working on the human genome. In 1986, he thought up the then-novel approach of focusing on DNA sequences that encode proteins (as opposed to the vast stretches that have no known function). This approach funnels sequencing efforts toward the parts of the genome that represent the working components of the cell. He then spurred the UK to employ this method.

Having made his mark on the human genome project, Brenner turned to the pufferfish, an organism with its genes organized compactly. "It has no junk DNA," he says. "In one-eighth the size of the human genome, it's got all of the genes." Because many pufferfish genes substitute effectively for mouse genes, comparing the regions shared by pufferfish and mouse genes can reveal which parts are most important: those sequences that evolution has left unchanged. "What appeals to me is that, in a sense, the DNA contains a historical record of the organism," he says. "You can reconstruct the past with contemporary sequences." The goal is to untangle how organisms evolved from one another, and he is currently tackling this task.

In addition to ferreting out interesting scientific challenges, Brenner has made significant contributions to keeping the gears of inquiry running smoothly. During the early days of recombinant DNA research, as investigators were developing the ability to cut and paste together different pieces of DNA and transfer genes from one organism to another, some people feared the creation of dangerous new breeds of microbes. As a result, several governments declared a moratorium on these types of experiments.

Eventually, the UK decided that the work could proceed, but the scientists had to take steps to prevent the microbes from escaping from the labs into the outside environment. Brenner devised a completely different solution to the potential problem. "They were thinking about physical containment," he says, "But you could have biological containment: you could work with disabled strains." Such a version of the microbes wouldn't survive well outside the lab, he reasoned.

To prove that this approach would work, Brenner took an unconventional tack and tested some genetically weakened bacteria on himself. "I drank them," he says. Always a rigorous experimentalist, "I measured how much of the disabled strain came through my intestines." It survived very poorly compared to the bacteria that normally inhabited his body.

He points out that this technique of transferring genes from one organism to another allowed people to work safely with dangerous germs such as HIV. A viral genome is much safer in a bacterium such as Escherichia coli than in its normal viral packaging. "It took people a long time to realize that cloning it in E. coli makes it safer rather than more dangerous," says Brenner.

Underlying Brenner’s interest in molecular genetics, embryonic development, the nervous system, genomes, and evolution is his curiosity about how the internal description of an organism – its genes – generates a fully functioning living thing. This topic – at the heart of biology – differs from all other sciences, he says. "It's a very particular subject because the changes are made in the gene script, but they're meaningless at that level. They have to be run in the organism and tested in the world." He founded a multidisciplinary research organization, The Molecular Sciences Institute, in 1996 to probe these issues through a combination of genomic biology research and computation and simulation.

Brenner presents his views about biology with humorous analogies, some of which he has detailed in a series of columns that appear as a regular feature in Current Biology. In one of these, the co-discoverer of the DNA double helix, Francis Crick, throws up his hands in frustration at failing to understand how the fruit fly's wings develop from an embryonic organ. "God knows how these imaginal discs work," cries Crick, according to Brenner. Because only God knows, Crick ends up visiting him and asking for an explanation. Brenner envisions God's response: "Well", comes the reply, "We took a little bit of this stuff and we added some things to it and . . . actually, we don't know, but I can tell you that we've been building flies up here for 200 million years and we have had no complaints."* Unlike other complex engineering feats, building a living organism does not follow a strict recipe. Flexibility, in fact, plays a central role in organisms' evolution.

Brenner comments on scientific culture as well as concepts, conjuring up fanciful scenes to illustrate his points. One column leads into a discussion about how science differs from country to country, and ends with a whimsical illustration of how audiences in different places respond to a seminar speaker who takes off his pants mid-speech. In England, the audience sits impassively; in Germany, everyone rises and removes their trousers; in France, a uniformed guard asks the speaker to leave; in Italy, the pants get stolen.

Brenner has woven a colorful and richly textured scientific tapestry from threads of intense curiosity, imagination, intellect and determination. His legacy reaches into many areas of inquiry, and promises to stretch well into the future.

*S. Brenner. "Francisco Crick in Paradiso." Current Biology 1996, 6:1202.

Citation text by Evelyn Strauss, Ph.D.

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