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For decades, scientists have been teasing out the secrets of the human genome, hoping to learn more about what makes the body function and why things sometimes go wrong.
Now, scientists are on the brink of identifying genes that play a major role in a variety of diseases, thanks to recent rapid advances in DNA sequencing technology, according to Dr. David Altshuler, director of the program in medical and population genetics at the Broad Institute of MIT and Harvard.
Altshuler talked about "expectations for improved therapies in the era of genomic medicine" at the final installment of the "Midsummer Nights' Science" lecture series held at the Broad Institute on Aug. 1.
Researchers at the Broad and around the world are using new sequencing technology to look for genes that are linked to the development of diseases such as diabetes, multiple sclerosis, lupus, bipolar disorder and autism, among many others.
The new research builds on the 2003 completion of the human genome sequence, which showed that while most humans share the vast majority of their genetic sequence (about 99.9 percent), variations known as single nucleotide polymorphisms, or SNPs, occur within the other .1 percent of the genome. Those variations are what make each individual unique.
Technology has advanced rapidly: Only a few years ago, a scientist could only hope to study one or a few SNPs out of the millions that exist; today, hundreds of thousands of SNPs can be tested at the same time, allowing scientists to systematically screen DNA samples from numerous patients with the same disease. If common variations are found to track with the disease, that may indicate that those genes play a role in the underlying biology of the disorder.
"You couldn't do this a year ago. You couldn't even do it a few months ago," Altshuler said. "This is the first time such studies could be done in a systematic way."
Altshuler described one disease in which the approach has already proven particularly informative. Researchers around the world have identified three different genes that carry common variants that influence age-related macular degeneration, a common form of blindness. In a paper soon to be published, researchers at Broad and the Massachusetts Eye and Ear Infirmary have calculated the risk of an individual's developing the disease based on these genetic variants, and found striking differences in risk that can now be predicted by simple genetic tests.
"My guess is that we will be doing a lot of this in the coming years," Altshuler said.
But to Altshuler, the major benefit of the genomic studies is not predicting the risk of becoming ill but developing new treatments based on the genetic information.
Right now, "we know much too little about the root causes of disease, and the treatments we have are seldom curative," he said.
Once scientists identify genes involved in disease, they can develop drugs targeting the proteins coded by those genes.
Of course, it is important to remember that most diseases are influenced by a number of factors, including environment, behavior and just pure luck, Altshuler said.
For a few diseases that are caused by a single mutation, such as Huntington's, genetic inheritance is the determining factor. But most diseases are influenced by a variety of genetic and non-genetic factors. For example, research has shown that the risk of developing type 2 diabetes is about 50 percent determined by genetics and 50 percent due to other factors.
That's why the use of tests for certain genes that influence disease requires careful thought, Altshuler said. People who test positive for a gene that gives them an increased risk of developing type 2 diabetes, for example, might just give up and embrace an unhealthy lifestyle, thinking the gene determined their outcome. In contrast, Altshuler and colleagues recently showed that carriers of a risk gene for diabetes could still benefit from lifestyle intervention, in work published in a paper in the New England Journal of Medicine.
"Any single gene or combination of genes will be risk factors, not deterministic predictors," he said.
And for diseases influenced by a huge number of genes, it may be nearly impossible to track down the genes responsible.
"There will be cases where a modest number of genes are found â€¦ it is also very likely that for other diseases there will be hundreds or thousands of genes," each of which plays a very small role in the disease, Altshuler said.
He predicted that while some diseases will be shown to have clear-cut genetic contributors, "there are probably some diseases that will remain intractable to every approach we try for the next 25 years."
In addition to being a founding member of the Broad Institute, Altshuler is an associate professor at Massachusetts General Hospital and Harvard Medical School. He received his B.S. from MIT, his Ph.D. from Harvard University and his M.D. from Harvard Medical School.
The Aug. 1 lecture was the last of the Midsummer Nights' Science series, but the Broad Institute plans to offer more public lectures in the future. Like other lectures in the series, the final event drew a full house to the auditorium in the lobby of Broad Institute's new Kendall Square building at 7 Cambridge Center.
"We're incredibly gratified that people would take time out of their day to come here and talk about science," Altshuler said.