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The Human Genome Race

A tale of the Tortoise and the Hare... and the fly and the worm and the mouse
aging



J. W. Stewart

Image: DOE HUMAN GENOME PROGRAM

GENES ARE ENCODED IN THE DNA by four bases, the letters of the genetic alphabet (A, T, G, C). Chromosomes contain the DNA; they are located in the nucleus of a cell.

Hang on to your seats. The race to sequence the human genome--now in its final laps--is speeding up. Some three weeks ago, the Maryland company Celera Genomics--a relative newcomer to the track, headed by Craig Venter--appeared to lurch ahead of the favored contestant, the publicly funded Human Genome Project. On April 6, Celera announced that after only seven months of work, they had deciphered close to all 3,000,000,000-odd base pairs, or letters of the genetic alphabet, in the human genome.

It was news that made some spectators ready to switch bets. But, in fact, the race is still too close to call. The Human Genome Project, which has steadily worked at cracking the human genome since 1990, is also near completion of a "working draft." And Celera's announcement doesn't necessarily mean they have got the prize yet.

Celera's researchers used a "shotgun approach." They took one person's DNA (the molecule that contains all genes), chopped it up into little pieces and determined the sequence of base pairs in each piece. Now, however, they have to put the pieces back together. Only when they complete this jigsaw puzzle will they have sequenced the genome. But using giant computers that crunch numbers day and night, Celerea may finish this assembly any week from now.



Image: ARTEMIS PHARMACEUTICALS

THE FRUIT FLY Drosophila melanogaster has been used by geneticists for almost 100 years. Now its genome sequence is fully known.

Regardless of who wins this sprint, the next race--to make sense of the genome--will be a marathon with many runners. This task will fall to a whole generation of biological, medical and information researchers. Just the first step, which researchers call annotation, could very well take many months. From the entire DNA sequence, they will need to find the 5 percent of it that actually contains genes. Looking for these estimated 80,000 to 140,000 genes among nonsense strings of base pairs will be like looking for needles in a haystack.

Then scientists will have to sort out what the individual genes do. And this is where yeast, worms and flies can help: Although they may not look it, these so-called model organisms share a lot of genetic information with humans. "I think about 40 percent of all yeast genes have a human counterpart or have a gene which is similar in function in humans," says Marc Cockett, executive director of Functional Genomics at Bristol-Myers Squibb. And these organisms are a lot easier to study than people: they breed faster, and their genes are easy to manipulate. Compared with animals like mice, they are cheaper to raise. Thus, by finding out how their genes work,we can learn a lot about our own genes.

So far geneticists have boarded three such species on the "Ark of Genomes," sequencing their genomes completely: Baker's yeast (Saccharomyces cerevisiae), the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. (Celera and the Berkeley Drosophila Genome Project just jointly published the fly genome last month in Science). Soon, the mouse--which from a genetic point of view is nearly human--will join this ship: its genome is sought in another race between the publicly funded mouse genome sequencing project and Celera. And the zebrafish, which is transparent when it is young and so lets researchers watch its organs grow, will probably be next in line.


Image: NIH

MICE ARE OFTEN MODELS for human diseases. A technique called gene knockout allows researchers to delete any of their genes at will. The mouse genome is next in line once the human genome is finished

The good news is that because the genes of these organisms are so similar to our own, they can help reveal new cures for genetic diseases. As much as 60 percent of the 289 known human disease genes have counterparts in Drosophila. Says Kevin Fitzgerald, a worm researcher at Bristol-Myers Squibb, "Some of the same genes and components that are responsible for cancer, breast cancer for instance, or Alzheimer's disease, are actually found, and they seem to function very similarly, in both worms and flies."

Even simple baker's yeast, which consists of only one cell to our billions, is playing a role in studies of how cancer treatments work. To date, yeast has taught scientists a lot about cell division and DNA repair, processes that go wrong in cancer. And researchers at the "Seattle project", an effort funded by the National Cancer Institute to find new anticancer drugs, are mutating genes in yeast cells--such as the ATM gene or the mismatch repair genes--that often lead to cancer in humans. Then they expose these mutated yeast cells to a whole range of chemical compounds used in cancer therapy to find which ones will kill them. The results give clues as to how these drugs work and how they can be improved.


Image: ZFIN

THE ZEBRAFISH is the simplest vertebrate animal studied by researchers in depth. While it develops, it is completely transparent.

Multicellular organisms lend themselves better to the study of other diseases, like Alzheimer's or diabetes. Drugs that help these and other conditions often interfere with so-called signaling pathways within cells. Along these pathways, many different messages--each of them taking the form of a protein--are passed, and each protein is a potential drug target. To find more of these targets--places where a medication might change the message or block the signal--researchers are looking for mutations in worms and flies.

"Let's say we want to find a new antidiabetic compound," explains Geoffrey Duyk, CEO of Exelixis, a California-based company that specializes in model organisms. "We know that in type II diabetes, most patients are essentially resistant to the action of insulin. So what you do in the model systems is you create one mutation, or a series of mutations, which makes those organisms resistant to the action of insulin. Then essentially what you are looking for is suppressor mutations, things which alter other genes, which change the sensitivity of the organism for insulin. And then you find the corresponding vertebrate genes and ask whether they do the same thing." And drugs acting on the products of these genes might have the same effect as the mutations--change the insulin response back to normal.

In the end, of course, understanding how the genes of a worm or fly work can never fully explain the human genome. "There is a second phase of any project, which is it needs to be extrapolated into mammalian cells. And that's independent of whether you are in yeast, in flies or in C. elegans," says Stephen Friend, president of Rosetta Inpharmatics in Seattle and formerly one of the coordinators of the Seattle project. But studying the genomes of other organisms stands to offer valuable, if indirect, lessons in understanding our own genes, once the race to read them is closed.

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