Genes that fit everyone

NIH division paves path toward genomic medicine

Kimberely Sirk
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BETHESDA, Md.—In a commitment toprogressing the next generation of medicine via the human genome, the U.S.National Institutes of Health (NIH) has committed close to half a billiondollars toward supporting newer and faster gene sequencing efforts. Officialssay that while this does not represent a promise of increased money, it doesrecognize that dramatic drops in the cost of gene sequencing will now enable fundsto be spent with more precision.
The $461 million in resources wasannounced through the National Human Genome Research Institute (NHGRI), whichis part of the NIH. The four-year plan expands its flagship Large-Scale GenomeSequencing Program to focus on medical applications "to begin to explore thefront edge of genomics, which will move us into genomic medicine," says Dr.Eric Green, director of the NHGRI. Four components of the Genome SequencingProgram are recipient of the funds.
The base cost of gene sequencing has, according to expertsat the NHGRI, dropped exponentially. Now that sequencing is becoming lessexpensive, those close to the projects see a day where perhaps thoseevaluations will become part of the medical mainstream.

"Even though we have been trumpeting the fact that thousands ofgenomes are being sequenced and will continue to be sequenced, the truth isthat the power of the studies that are necessary to really understand thegenomic basis of common disease, those studies need to be powered by thousandsand thousands and very large sample sizes far beyond what has been possible,"says Dr. Mark Guyer, deputy director and interim director of the Institute forExtramural Research for the NHGRI. "So the challenge to the large-scale sequencingcenters over the next four years is going to be to figure out the best way totake advantage of their unique sequencing capability to do things, tounderstand things that no other approach can do."
Most of the $461million—specifically, $319 million—will be divided among existing projects atthree large genome-sequencing centers: the Broad Institute in Cambridge, Mass.;the Genome Institute at Washington University in St. Louis, Mo.; and the HumanGenome Sequencing Center at Baylor College of Medicine in Houston, Texas. Thefunding level will begin at $86 million the first year of the four-yearspending plan, and drop each year after the first.
Guyer explains that the current practice of the NHGRI is togradually decrease funding over the life of an allocation. In the first year ofthis funding, he says, the Broad Institute will receive $35.9 million, theGenome Institute will receive $28.4 million and the team at the Baylor Collegeof Medicine will receive $21.3 million. These centers were part of the HumanGenome Project, and all continue further work in cataloging human genes.
"I want to emphasize that I framed the funding levels in terms ofthe first year awards," he continues. "Beyond that first year, we plan tocontinue a practice that we've actually been pursuing for several years nowwhich is to gradually reduce the base funding for these three centers each yearover the four years of the program.
"It's probably not that well-known, but the remarkable increases in sequenceproduction that these three groups have achieved over the last several yearshave come about even though their funding levels were being slowly decreased,"he continues. "We believe that the cost of sequencing will continue to decline,and that will allow the NHGRI program to continue its high level ofproductivity at even lower costs. Doing this allows NHGRI to continue toredirect money from the large-scale sequencing efforts into other new scientificpriorities as they arrive."
In addition, approximately $20million will be dedicated to the development of genome sequence analysissoftware. The resulting capabilities can be used by researchers outside oflarge sequencing centers that may not currently be able to transform sequencedata into clinically useful information.

Those close to the project say that making thedata relevant in the clinical setting is what's most critical to bringing theseadvancements into the clinical setting.
Dr. Brad Ozenberger,program director for the Genomic Medicine component of the Genomic SequencingProgram, points out that this is not a disease discovery, or a geneassociation discovery project per se.
"In our history, the large-scale centers have been adept atproducing and putting them together and pushing the technology and discovery,"Ozenberger says, "whereas this program is really the next step of where theactual sequencing technology, and even the disease area is less important thanexploring the methods of bringing genomic sequencing into the clinic workflowto the benefit of individual patients."
About 20 percent of the fundingwill be used to establish two new programs. The first, the Mendelian DisordersGenome Centers, will have as its purpose the identification of the geneticbasis of Mendelian diseases. Although many Mendelian diseases are rare, withsome impacting less than 200,000 individuals, they provide a clear look at thefunction of a given gene in the body, since they have as their genesis amutation of just one human gene. Of the estimated 6,000 human Mendelian diseases,the cause of fewer than half is known.
The second new program, theClinical Sequencing Exploratory Research Project, will address the ethical,medical and societal effects of using genomic sequencing in a clinical setting.According to Guyer, the NHGRI will contribute $40 million over the four years to thiseffort, and the National Cancer Institute will contribute about another $8million over that time to co-support research on questions related to cancer.

The grantees in this program are the Baylor College of Medicine in Houston,Brigham and Women's Hospital in Boston, Children's Hospital of Philadelphia,the University of North Carolina at Chapel Hill and the University ofWashington in Seattle.
An additional group may be funded in the near future, but Guyerwas unable to disclose additional details on that effort as this issue went topress.
Green said in a telebriefing about the funding commitment that inthe decade since the human genome was sequenced, the scientific communitylearned a tremendous amount about how the genome works and how alterations init can cause disease.
"We continue to believe that this growing body of knowledge willultimately transform the practice of medicine," Green said. "At the same time,genomics sometimes gets criticized for not yet curing enough diseases and assuch, some claim that the Human Genome Project was a disappointment. I wouldpoint out that it took approximately 66 years from the first human-poweredflight in 1903 by the Wright Brothers, to humans then landing on the moon in1969, and it took about 80 years to manufacture the first antibiotic,penicillin, following Louis Pasteur's development of the germ theory of diseasein the mid-1800s. I think it is important to maintain the very real perspectivethat it takes considerable time and continual systematic effort to deliverresults from that first scientific triumph. We believe that genomics is on sucha steady course of progress en routeto the delivery of medically important advances."
Indeed, when asked about what the next decade in this field willhold, Guyer says the potential of this field should not be oversold. Instead,he adds, the future can been seen to hold the promise of what he called "geneticallyinformed medicine."

Kimberely Sirk

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