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American Association for the Advancement of Science
Those three million or so letters in the human genome sequence may have seemed like a lot of information to handle. But, consider the trillions of cells in the human body, each with thousands of genes working together-in combinations changing from one cell type to another and from one moment to the next.
"If the goal of the human genome project was to define genes, an important goal of the next phase is to determine how these genes, and the proteins they encode, are connected together in large regulatory and signaling circuits inside the cell," said Trey Ideker of the Whitehead Institute. "If you think of electronics, it's like we know where the transistors are, but not how they're wired up."
Scientists are sorting all this out using gene labs on chips approximately the size of a postage-stamp, called "DNA microarrays," that can provide a profile of all the genes being expressed in a given cell. The results are helping to shed light on health conditions from infectious disease to brain disorders, scientists reported during a series of seminars on "Microarrays and Functional Genomics" at the AAAS Annual Meeting.
To understand how microarray chips work, think of the DNA double helix as a zipper that can be unzipped down the middle, splitting the molecule into two single strands. A microarray chip is covered with "unzipped" DNA sequences representing thousands of genes. To see whether a sample of genetic material contains any of those genes, researchers first process the sample to "unzip" its active genes and tag them with a fluorescent marker.
When this material is washed over the microarray chip, the single strands of DNA zip themselves up with their complementary strands on the chip. A scan of all the zipped genes on the chip then reveals which genes were active in the sample, and the degree of their activity.
Using this technology, Jonathan Pevsner of the Kennedy Krieger Institute and the Johns Hopkins School of Medicine has identified gene expression patterns in the brain associated with Down's Syndrome, autism, and other disorders.
"A big question with brain disorders is 'why does the patient have these deficits?' If we could understand what genes are abnormally regulated, that would provide us with markers and therapeutic targets," Pevsner said.
A marker for a disorder like autism may be particularly useful, according to Pevsner, so that it might be possible someday to use a blood test to determine whether someone is autistic.
Eric Hoffman of Children's Hospital, in Washington D.C., said he is "pushing the limit with microarrays," by studying the different domains of gene expression within a single cell. One such domain is the junction where a nerve joins to a muscle cell. This information may have implications for treating Lou Gehrig's disease, or Spinal Muscular Atrophy (also known as "floppy baby syndrome"), according to Hoffman.
Hoffman is also studying a group of people who are likely to develop type 2 diabetes. As the test subjects do special exercise regimens and then "detrain," returning to their pre-workout conditions, Hoffman is studying gene expression in their muscle tissue. His findings may be useful for helping to prevent circulatory problem in diabetes, in which blood clotting is related to changes in the muscle tissue, he said.
Gary Schoolnik of Stanford University Medical School has turned up some key genes in the tuberculosis bacterium that allow the pathogen to adapt to conditions in its human host. There, holed up inside cells called macrophages, the bacterium can rest in a latent stage for years, before it transforms to its active, disease-causing state.
Drugs that targeted these adaptation-related genes might prevent M. tuberculosis infections from ever taking hold, according to Schoolnik. E. M. Marcotte of the University of Texas has also identified some possible drug targets in the TB bacterium, while reconstructing the networks of interactions among the protein products of TB genes.
Microarray research still faces some important logistical hurdles, in order to reach its full potential. A central issue in the AAAS seminars was how researchers can share information, so as not to needlessly repeat each other's work when they need to determine what a certain gene is doing in a certain type of cell.
Achieving this goal will require developing the right kind of databases, and a common standard for what kind of information to include about how the researchers obtained microarray results. (By analogy, to know how someone baked a chocolate cake, a list of ingredients wouldn't be enough. You'd need to know how long it was baked for, and at what temperature.)
Ultimately, researchers would like to have every gene's jobs identified throughout the body, and their interactions with other genes mapped out for the whole genome. Ideker calls this project the "interactome." Efforts are also underway to map out the "proteome," the network of interactions among the proteins encoded by our genes.
Advance interviews possible upon request.
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MEDIA NOTE: The Microarrays and Functional Genomics Seminars during the AAAS Annual Meeting in Denver are scheduled from 8:00 a.m. - 6:00 p.m. Mountain Time, Saturday, 15 February, and Sunday, 16 February. Eric Hoffman, Trey Ideker, E.M. Marcotte, Jonathan Pevsner, and Gary Schoolnik will speak on Sunday, 16 February from 8:30 a.m. - 5:30 p.m. in Ballroom 4 on the Ballroom Level of the Colorado Convention Center. Press registration is located in the AAAS Press Center in Room C-101 of the Colorado Convention Center.
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