Brown belongs high in the privileged group that deals with entire genomes because he chose to work on the most thoroughly analyzed of the several model organisms that geneticists use for experiments. Bypassing the small gray laboratory mouse (Mus musculus), the tiny fruit fly (Drosophila melanogaster), and the even tinier roundworm (Caenorhabditis elegans), Brown zeroed in on baker's yeast (Saccharomyces cerevisiae), also known as brewer's yeast, a microscopic, single-celled organism that looks like a blob.
Biologists enjoy working with yeast because it is almost as tractable as the bacteria and viruses that researchers used to devise recombinant DNA technology in the 1970s yet has many of the characteristics of mammalian cells. Everything in yeast's environment can be controlled with ease. At the same time, yeast genes can be manipulated in any way a researcher desires. Genes can be knocked out, added to specific chromosomes, replaced with other genes, and made to produce proteins on command. These operations are so efficient that yeast geneticists have gained a head start over most other groups.
The Yeast Genome
About a decade ago, several European labs decided to cooperate on an ambitious plan: They would decipher all the DNA in the entire yeast genome. After they divvied up the yeast cell's six chromosomes, each lab agreed to tackle a different chunk of them. The international effort eventually involved about 600 scientists, including some American and Japanese teams.
In 1996, the yeast community proudly published the result of its work: the complete set of genetic instructions for making a yeast cell"a fantastic milestone," says Brown. These instructions were spelled out in 12 million base pairs, or subunits, of DNA encoding roughly 6,000 genes (genome-www.stanford.edu/Saccharomyces). "Whatever a yeast needs to do its job is somewhere in those 12 million or so base pairs," Brown says.
Until then, no one had ever sequenced the entire DNA of any eukaryote (an organism whose cells have a true nucleus and many other features of animal cells). This achievement marked the start of a grand voyage of discovery that is leading through the genomes of several other model organisms, including the roundworm (whose sequence was completed in December 1998) and the fruit fly (March 2000), right up to the gigantic, almost mythical human genome, whose sequence was announcedin rough draftin 2001.
Many of the genes in these simpler organisms bear an uncanny resemblance to those of humans. Unlike human beings, however, these organisms can be grown rapidly, and their genes can be mutated at willa quality that researchers find essential, since mutations that stop a particular gene from functioning make it possible for scientists to figure out what the normal gene's function would be. Furthermore, model organisms can be mated in any way that suits an experimenter, and their offspring analyzed with ease. That is how scientists have deciphered several genetic pathways that are also found in human cells.
How Similar Are We To Baker's Yeast?
It is hard enough to accept that little creatures such as worms and flies are, as one researcher put it, "our relatives," but what about baker's yeast? What can we possibly have in common with this humble cell, really just a fungus, which is generally used to make dough rise or to brew beer?
The answer is stunning: We are so similar to yeast, in some of our genes, that human DNA can be substituted for the equivalent yeast geneand it works just as well. This was first demonstrated in 1985, when Michael Wigler and his associates at Cold Spring Harbor Laboratory "rescued" a mutant yeast cell that lacked an essential developmental gene, the yeast equivalent of the human ras gene, by inserting the human gene into it.
This "remarkable result," wrote David Botstein, a yeast researcher at Stanford, "indicated a profound conservation not only of [DNA] sequence but also of detailed biological function" over at least a billion years of evolution from yeast to human. More than 70 additional human genes have proved able to repair various mutations in yeast, he said. Botstein's conclusion: "What is true for yeast is also true for human."
Just like human cells, yeast cells go through cycles of growth and divisionand the genes that regulate these cycles in yeast are practically identical to ours. In fact, nearly everything we know about the human cell cycle, and much that we know about human cancer, was originally learned in yeast.
Such knowledge used to be gained slowly and painfully. When scientists examined the newly sequenced yeast genome a few years ago, they were shocked to find that even though more was known about yeast than any other model organism, two-thirds of yeast's genes had never been identified beforeand nobody had any idea what their functions might be.
"One of the great things about the genome sequencing projects is that they make it obvious we're still in the frontier days of biology," says Brown. "At the same time, these projects provide us with a very useful tool that allows us to explore large sets of genes and to discover their properties."
Most of the genes in organisms that scientists study "are really not understood at all in terms of their roles," he notes. "And for humans, it's 90 to 95 percent of the genes that we haven't a clue about. That's just a reminder of how much we don't know."
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