By Monica Heger
This story was originally published Feb. 9.
The National Human Genome Research Institute has created a blueprint for how it plans to bring genomics into the clinic over the next 10 years. And while the agency believes that sequencing will play a major part in that roadmap, officials said that many improvements will be necessary before next-gen platforms find widespread clinical use.
The purpose of the so-called "base-pairs-to-bedside" plan, published last week in Nature, is to set a broad agenda for the next 10 years in genomics research, NHGRI's director Eric Green told In Sequence. It follows on a strategic plan the NHGRI published in 2003, and will serve as a guide to the types of projects NHGRI will fund over the next several years.
The biggest difference from NHGRI's 2003 plan is that the 2011 version is "more specific in describing a path toward clinical applications," Green said. Based on the plan, which was developed with feedback from the scientific community, NHGRI is now in the process of "setting a research agenda that will help move us down a path toward genomic medicine," he said.
Green and his NHGRI colleagues said in the report that over the next 10 years, new technology — including faster, more accurate, and cheaper sequencing — will play a major role in making genomic medicine a reality. Additionally, disease sequencing projects will help uncover the genetic causes of most Mendelian diseases as well as some complex diseases, and lead to new drug targets and better diagnostics. Cancer will likely be the first area where sequencing is widely adopted in the clinic, Green said.
However, while Green and colleagues estimate that next-generation sequencing technology has enabled a price reduction of about three to four orders of magnitude, "sequencing a whole human genome remains much too expensive for most human disease studies, each of which can involve thousands or tens of thousands of individuals," they write. Furthermore, they note that even in the case of well-understood coding regions, "sequencing errors complicate downstream analyses, and current sequencing error rates hinder reliable analysis of the remaining, poorly understood 98 percent of the genome."
Green and co-authors note that "very low cost and extremely high accuracy will be critical for the routine clinical use of genome sequencing" in applications such as genetic screening of newborns.
It's likely that a new generation of sequencing technology will be developed for use in the clinical setting. "The technologies in clinical labs will be different than the kinds of things in genome centers," Green told In Sequence. Currently, none of today's available platforms are well-suited for clinical deployment, he added. As far as the third-generation sequencing technologies, he said it is still too early to tell which, if any, will be particularly suited for clinical applications. "We need to see how those mature, how they get commercialized, and how they perform in research first."
While new sequencing technology and platforms will be needed, the biggest hurdle will be data analysis. "It's no longer a huge challenge to generate the data," Green said, but knowing which variants are clinically relevant is still a challenge.
For this reason, exome sequencing and targeted resequencing will continue to be important tools. However, in the end, those are "valuable interim" approaches, Green said. Targeted sequencing "makes complete sense to me now, but the cost drivers are going to shift and the knowledge is going to go up," he said. "With time, we'll figure out which noncoding variants are medically relevant" and there won't be any reason not to sequence the whole-genome.
Aside from technology development, NHGRI anticipates that research related to understanding the biology of disease will take off. Genomic research over the past six years has greatly advanced researchers' understanding of the biology of genomes, and while there is still more to be understood, it's likely that research over the next 10 years will focus primarily on understanding disease.
The use of sequencing to pinpoint the disease-causing genes of Mendelian disorders and to gain a better understanding of complex diseases will be a priority. "Genome sequencing could be used to determine the genetic variation underlying the full spectrum of diseases, from rare Mendelian to common complex disorders, through the study of upwards of a million patients," the authors wrote.
Going forward, Green said that NHGRI funding for sequencing projects would shift toward humans, rather than model organisms. "When it comes to large-scale sequencing and sequence analysis, we'll increasingly be looking at humans because we will be more focused on clinical applications…We don't need to have the genome institute fund model organisms. That's the bread and butter of many other institutions."
As an example of the agency's funding priorities, Green cited NHGRI's recent allotment of $90 million for its Genome Sequencing and Analysis Centers program, including the Clinical Sequencing Exploratory Research program that will focus on applying sequencing to clinical care (IS 12/21/2010).
In terms of the first types of sequencing applications to reach the clinic, Green predicted these would be related to cancer genomics. "Where you're going to see the most complete stories develop quickly and where genetic analysis will become the standard of care, is in dealing with diagnostic and therapeutic decision-making with respect to cancer," he said. "And it's not going to be one type of cancer, but multiple types."
This trend is already emerging. For example, researchers recently used sequencing to guide the treatment decision in a case of rare tongue cancer (IS 9/28/2010).
Critical to bringing these technologies to a clinical setting will be adoption by physicians, Green said. He said that while there are "huge challenges" and "physician concern about how this is going to be operational," he is optimistic.
"People resonate with genomic advances," he said. "So I'm hopeful that people will get excited about this strategic plan."
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