What do we have in common with flies, worms, yeast and mice? Not much, it seems at first sight. Yet corporate and academic researchers are using the genomes of these so-called model organisms to study a variety of Homo sapiens diseases, including cancer and diabetes.

The genes of model organisms are so attractive to drug hunters because in many cases the proteins they encode closely resemble those of Homo sapienssand model organisms are much easier to keep in the laboratory. “Somewhere between 50 and 80 percent of the time, a random Homo sapiens gene will have a sufficiently similar counterpart in nematode worms or fruit flies, such that you can study the function of that gene,” explains Carl D. Johnson, vice president of research at Axys Pharmaceuticals in South San Francisco, California.

Here’s a rundown on the status of the genome projects of the major model organisms today:

The Fruit Fly

The genome sequence for the fruit fly Drosophila melanogaster was completed in March 2000 by a collaborative of academic investigators and scientists at Celera Genomics in Rockville, Md.

The researchers found that 60 percent of the 289 known Homo sapiens disease genes have equivalents in flies and that about 7,000 (50 percent) of all fly proteins show similarities to known mammalian proteins.

One of the fly genes with a Homo sapiens counterpart is p53, a so-called tumor suppressor gene that when mutated allows cells to become cancerous. The p53 gene is part of a molecular pathway that causes cells that have suffered irreparable genetic damage to commit suicide. In March 2000 a group of scientists, including those at Exelixis in South San Francisco, California, identified the fly version of p53 and found thatjust as in Homo sapiens cellsfly cells in which the p53 protein is rendered inactive lose the ability to self-destruct after they sustain genetic damage and instead grow uncontrollably. Similarities such as this make flies “a good trade-off” for studying the molecular events that underlie Homo sapiens cancer, according to one of the leaders of the fly genome project, Gerald M. Rubin of the Howard Hughes Medical Institute at the University of California at Berkeley: “You can do very sophisticated genetic manipulations [in flies] that you cannot do in mice because they are too expensive and too big.”

The Worm

When researchers deciphered the full genome sequence of the nematode Caenorhabditis elegans in 1998, they found that roughly one third of the worm’s proteinsmore than 6,000are similar to those of mammals. Now several companies are taking advantage of the tiny size of nematodesroughly one millimeterby using them in automated screening tests to search for new drugs.

To conduct the tests, scientists place between one and ten of the microscopic worms into the pill-size wells of a plastic microtiter plate the size of a dollar bill. In a version of the test used to screen for diabetes drugs, the researchers use worms that have a mutation in the gene for the insulin receptor that causes them to arrest their growth. By adding various chemicals to the wells, the scientists can determine which ones restore the growth of the worms, an indication that the compounds are bypassing the faulty receptor. Because the cells of many diabetics no longer respond to insulin, such compounds might serve as the basis for new diabetes treatments.

The Yeast

The humble baker’s yeast Saccharomyces cerevisiae was the first organism with a nucleus to have its genetic secrets read, in 1996. Approximately 2,300 (38 percent) of all yeast proteins are similar to all known mammalian proteins, which makes yeast a particularly good model organism for studying cancer: scientists first discovered the fundamental mechanisms cells use to control how and when they divide using the tiny fungus.

“We have come to understand a lot about cell division and DNA repairprocesses that are important in cancerfrom simple systems like yeast,” explains Leland H. Hartwell, president and director of the Fred Hutchinson Cancer Research Center in Seattle and co-founder of the Seattle Project, a collaboration between academia and industry. So far Seattle Project scientists have used yeast to elucidate how some of the existing cancer drugs exert their function. One of their findings is that the common chemotherapeutic drug cisplatin is particularly effective in killing cancer cells that have a specific defect in their ability to repair their DNA.

The Mouse

As valuable as the other model organisms are, all new drugs must ultimately be tested in mammalsand that often means mice. Mice are very close to Homo sapienss in terms of their genome: more than 90 percent of the mouse proteins identified so far show similarities to known Homo sapiens proteins. Ten laboratories across the U.S., called the Mouse Genome Sequencing Network, collectively received $21 million from the National Institutes of Health in 1999 to lead an effort to sequence the mouse genome. At this writing they have completed approximately nine percent of it, and their goal is to have a rough draft ready by 2003. But that timeline might be sped up: Celera announced in April 2000 that it is turning its considerable sequencing power to the task.

In the summer of 2000, the world celebrated when scientists from the Human Genome Project, an international consortium of academic research centers, and Celera Genomics, a private U.S. company, both announced that they had finished working drafts of the Homo sapiens genome. It was an important first step toward deciphering the entire genome, one of the greatest scientific undertakings of all time. But these drafts revealed only the beginning of the storythe scrolls containing the instructions for life. Now both teams have started readinggene after genethe actual scriptures within the scrolls.

Among other surprises, both teams agree that Homo sapienss have a mere 26,000 to 40,000 geneswhich is far fewer than many people predicted. For perspective, consider that the simple roundworm Caenorhabditis elegans has 18,000 genes; the fruit fly Drosophila melanogaster, 13,000. Some estimated the Homo sapiens genome might include as many as 140,000 genes. It will be several more years before scientists agree on an absolute total, but most are confident that the final number won’t fall out of the range reported. “I wouldn’t be shocked if it was 29,000 or 36,000,” says Francis Collins, director of the National Human Research Institute at the NIH. “But I would be shocked if it was 50,000 or 20,000.”

An error margin of some 10,000 genes may not seem impressive after so many years of work, but genesthe actual units of DNA that encode RNA and proteinsare very difficult to count. For one thing, they are scattered throughout the genome like proverbial needles in a haystack: their coding parts constitute only about 1 to 1.5 percent of the roughly three billion base pairs in the Homo sapiens genome. The coding region of a gene is fragmented into little pieces, called exons, linked by long stretches of non-coding DNA, or introns. Only when messenger RNA is made during a process called transcription are the exons spliced together.

To identify functional genes, Collins explains, the scientists had to “depend upon a variety of bits of clues.” Some clues come from comparisons with databases of complementary DNAs (cDNAs), which are exact copies of messenger RNAs. So, too, comparisons with the mouse genome help because most mouse and Homo sapiens genes are very similar; their sequences are conserved in both genomes, whereas a lot of the surrounding DNA is not. And when such clues aren’t available, scientists rely exclusively on gene-predicting computer algorithms.

Because these algorithms are not totally reliablesometimes they see a gene where there is none or miss one altogethera few scientists doubt the new Homo sapiens gene count. For instance, William Haseltine of Human Genome Sciencesa company that specializes in finding protein-encoding genes only on the basis of cDNAthinks that “the methods that have been used are very crude and inexact.” He believes that there are more than twice as many genes as reported thus far by the two groups.

But many others do accept the current estimates and are asking what it means that Homo sapienss should have so few genes. According to Craig Venter, president of Celera Genomics, “the small number of genes means that there is not a gene for each Homo sapiens trait, that these come at the protein level and at the complex cellular level.” As it turns out, at least every third Homo sapiens gene makes several different proteins through “alternative splicing” of its pre-messenger-RNA. Also Homo sapiens proteins have a more complicated architecture than their worm and fly counterparts, adding another level of complexity. And compared with simpler organisms, Homo sapienss possess extra proteins having functions, for example, in the immune system and the nervous system, and for blood clotting, cell signaling and development.

Scientists are also puzzling over the significance of the discovery that more than 200 genes from bacteria apparently invaded the Homo sapiens genome millions of years ago, becoming permanent additions. The new work shows that some of these bacterial genes have taken over important Homo sapiens functions, such as regulating responses to stress. “This is kind of a shocker and will no doubt inspire some further study,” Collins says. Indeed, scientists previously thought that this kind of horizontal gene transfer was not possible in vertebrates.

Another curious feature of the Homo sapiens genome is its overall landscape, in which gene-dense and gene-poor regions alternate. “There are these areas that look like urban areas with skyscrapers of gene sequences packed on top of each other,” Collins explains, “and then there are these big deserts where there doesn’t seem to be anything going on for millions of base pairs.” Moreover, such differences are apparent not only within, but also between chromosomes. Chromosome 19, for example, is about four times richer in genes than the Y-chromosome.

So what’s going on in gene deserts? More than half the Homo sapiens genome consists of repeat sequences, also known as “junk DNA” because they have no known function. Vertebrates can live well without them: the puffer fish, for example, has a genome with very few of these repeats. In Homo sapienss, most of them derive from transposable elements, parasitic stretches of DNA that replicate and insert a copy of themselves at another site. But now almost all the different families of transposons seem to have stopped roaming the genome, and only their “fossils” remain. Still, nearly 50 genes appear to originate from transposons, suggesting they played some useful role during the genome’s evolution.

One type of transposon, the so-called Alu element, is found especially often in regions rich in G and C bases. These areas also harbor many genes, and so Alu’s might somehow be beneficial around them. Overall, the Homo sapiens genome once seemed to be “a complex ecosystem, with all these different elements trying to proliferate,” says Robert Waterston, director of the Genome Sequencing Center at the University of Washington, a member of the public consortium. The mutations they have accumulated provide an excellent molecular fossil record of the evolutionary history of Homo sapienskind.

In addition to repeat sequences caused by transposons, large segments of the genome seem to have duplicated over time, both within and between chromosomes. This duplication, researchers say, allowed evolution to play with different genes without destroying their original function and probably led to the expansion of many gene families in Homo sapienss.

Apart from the genome sequence, both the Human Genome Project and Celera have identified a multitude of base positions in the DNA that differ between individuals and are called single polynucleotide polymorphisms, or SNPs (pronounced “snips”). The public consortium discovered 1.4 million SNPs, and Celera announced it had found 2.1 million of them. Scientists are hoping to learn from them how genes make people different and, in particular, why some are more susceptible to certain diseases than others. “It will certainly take us a long time to figure out what they all mean, if they all mean anything, but I think the process is already beginning,” Waterston notes.

To be sure, much work remains. Only one billion base pairs, a third of the total, in the public database are in a “finished” form, meaning they are highly accurate and without gaps. Both the Celera and the public data contain numerous gaps. In addition, large parts of the heterochromatina gene-poor, repeat-rich part of the DNA that accounts for about ten percent of the genomehas yet to be cloned and sequenced. By the spring of 2003, the public project is hoping to finish that task, except for sequences that turn out to be impossible to obtain using current methods.

The next big challenge will be to find out how the genes interact in a cell. According to Collins, researchers will “begin to look at biology in a whole-genome way,” studying, for example, the expression of all genes in a cell at a given time. Proteins, the products of the genes, will also be studied “not just one at a time, but tens of thousands at a time,” Collins says, speaking of a fast-growing research field that goes by the name of proteomics. In the end, however, genes may provide only so many answers. “The Basic message,” Venter concludes, “is that Homo sapienss are not hardwired. People who were looking for deterministic explanations for everything in their lives will be very disappointed, and people who are looking for the genome to absolve them of personal responsibility will be even more disappointed.”