Rise of next-gen genomics

The Human Genome Project was just the start; NIH is pushing hard on the genomics envelope

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Five years ago, the Human Genome Project came to an end, but most of the questions it raised have not been answered and the mountains of data it spawned have barely been scratched.
There are, after all, between 20,000 and 25,000 genes to deal with. And so, in the shadow of that project, major new genomics-related initiatives are coming forth to delve deeper, some of the chief among them being the Human Microbiome Project, the 1000 Genomes Project and the Multiplex Initiative—all of which enjoy significant participation or sponsorship by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH).

"The Human Genome Project raised huge questions and has opened many untapped areas of study," notes Dr. Alan Guttmacher, acting director of NHGRI. "So part of what we, academia and private industry are doing is engaging in the natural intellectual next steps of trying to answer the questions that we can finally start answering—now that we have the entire genome in hand."

The basic ongoing mission is twofold, Guttmacher notes: Get a better grasp of basic human biology and use greater knowledge of the genome to improve human health. Both are critical missions for drug discovery and development, even if there have been few huge breakthroughs in the short run.

"A couple of years ago, people would act like, 'We have the genome today, shouldn't we have a bunch of new drugs tomorrow? And that's the problem with every major invention in human history—going back to the telegraph, locomotive or, more recently, the Internet," Guttmacher says. "People overestimate the short-term impact and underestimate the long-term impact."

The Human Genome Project started the ball rolling for drug discovery and development in the new "genomic era," Guttmacher says. The International HapMap Project and the Encyclopedia of DNA Elements (ENCODE) project, which completed their phase 1 stages in 2005 and 2007, respectively, have helped researchers zero in even more on potential drug targets.

"In various genome-wide association studies so far, for example, we have huge amounts of a data that we didn't have before to help us understand biology better," Guttmacher adds. "The result is we are already seeing many more opportunities and ideas for new therapeutic approaches and new drugable targets."

Human Microbiome Project

One of the most anticipated new initiatives is the Human Microbiome Project (HMP), which some people have already dubbed the "Second Human Genome Project." Part of the NIH Roadmap for Medical Research, HMP is charged with the mission to comprehensively characterize the human microbiota and analyze its role in human health and disease.

In broad terms, HMP has four goals: Determine whether individuals share a core human microbiome; understand whether changes in the human microbiome can be correlated with changes in human health; develop new technological and bioinformatic tools to support these goals; and address the ethical, legal and social implications raised by human microbiome research.

"The human microbiome is largely unexplored," notes Dr. Elias A. Zerhouni, director of the NIH, "but understanding it is essential to understanding how microorganisms interact with the human body to affect health and disease." If the HMP is successful in its goals, he says, it could transform prevention, diagnosis and treatment of human illness.

"We now understand there are more microbial cells than human cells in the human body. The Human Microbiome Project offers an opportunity to transform our understanding of the relationships between microbes and humans in health and disease," says Dr. Alan M. Krensky, the director of the Office of Portfolio Analysis and Strategic Initiatives, which oversees the NIH Roadmap for Medical Research.

The challenge will be making the HMP manageable, because as daunting as the Human Genome Project was, the HMP will be bigger and tougher, says Dr. Claire Fraser-Liggett, director of the University of Maryland's Institute for Genome Sciences. With a multitude of organisms and interactions to explore genomically, rather than a single genome itself, simply establishing a defined endpoint for HMP will be a major undertaking. Also, optimum sampling strategies will need to be identified early on and analysis will have to go hand-in-hand with sequencing, she notes.

NHGRI recently announced it will fund up to $2 million this year for research on new technologies to obtain microbe samples for use in sequencing programs for HMP.
Just as technological advances helped the Human Genome Project complete its goals two years early, so too are new genomic and other advances making the HMP possible, notes Dr. Margaret McFall-Ngai, a professor of medical microbiology and immunology at the University of Wisconsin-Madison, and this next-gen technology will help make the "big can of worms" the NIH is opening with HMP a bit more manageable.

And if the can of worm ends up being bait to draw out new potential therapeutic avenues in the human microbiome, or perhaps even new drug targets, so much the better for the drug discovery and development industry.

1000 Genomes Project
Led by an international research consortium, the 1000 Genomes Project aims to create the most detailed and medically useful picture to date of human genetic variation and will do so by sequencing the genomes of at least 1,000 people from around the world. The project is receiving major support from the Wellcome Trust Sanger Institute in Hinxton, England, the Beijing Genomics Institute Shenzhen in China and the NHGRI, and data from the 1000 Genomes Project will be made easily and quickly available to the global scientific community through free public databases.

The project was announced in January and started the ball rolling without corporate partners. As of June, the project is a public-private effort with the addition of sequencing technology developers 454 Life Sciences of Branford, Conn., a Roche company; Applied Biosystems of Foster City, Calif; and Illumina Inc. of San Diego.

"What the consortium is trying to do with 1000 Genomes is possible only because of the new wave of sequencing technologies," notes Dr. Francisco de la Vega, vice president for SOLiD System applications and bioinformatics at Applied Biosystems. "Traditional sequencing for the human genome took so long and cost hundreds of millions, so it wasn't reasonable to consider sequencing more than a few genomes. But now we can, and by bringing on three different sequencing developers and possibly more corporate partners later on, the project can move forward more quickly and we can all have easier and faster access to technological improvements that will allow everyone to make even better sequencing tools."

"The additional sequencing capacity and expertise provided by the three companies in the pilot phase will enable us to explore the human genome with even greater depth and speed than we had originally envisioned, and will help us to optimize the design of the full study to follow," says Dr. Richard Durbin of the Wellcome Trust, who is co-chair of the consortium.

The 1000 Genomes Project builds upon the International HapMap Project, which produced a comprehensive catalog of human genetic variation organized into neighborhoods called haplotypes. But while the HapMap catalog only identifies genetic variants that are present at a frequency of 5 percent or greater, the catalog produced by the 1000 Genomes Project will map many more details of the human genome and how it varies among individuals, identifying genetic variants that are present at far lower frequencies. As such, the 1000 Genomes Project may help point out genetic variations that could impact genomic- and proteomic-based therapies in terms of factors like efficacy, availability and deliverability.

The Multiplex Initiative
Unlike the HMP and the 1000 Genomes Project, the Multiplex Initiative—a joint effort on NHGRI and NIH's National Cancer Institute—is geared almost exclusively toward testing, specifically the interest level of healthy, young adults in receiving genetic testing for eight common conditions. But because the study will also look at how people who take such tests interpret and use the results in their own healthcare decision-making, the study is important to at least one therapeutic arena.

"The Multiplex Initiative will provide insights that will be key to advancing the concept of personalized medicine," said Dr. Eric Green, NHGRI scientific director, when the initiative was launched just over a year ago. "As genomic technologies are introduced for wider use, researchers and clinicians will need to know how genetic susceptibility tests will be received by patients."

The initiative derives its name from the fact that participants will be offered free multiplex genetic testing—testing for multiple genetic conditions simultaneously.
Although the Multiplex Initiative doesn't have a direct impact on pharma research, knowing how people will respond to genetic testing is important given the use of genomic testing in some clinical trials, the increasing impact of incidental findings in clinical studies (see article on page 22) and the continuing quest toward personalized medicine and translational (or bench-to-beside) research. The important thing, NHGRI's Guttmacher notes, is to have many genomics efforts so we can find out as much as possible about our biology and treating our diseases.

"We are the National Institutes of Health, after all, and in doing so, many big genomics projects or getting involved in them, we figured, why not actually improve human health," Guttmacher jokes. "Genomics is going to be key to drug discovery and development. The drugs we have today really only target about 500 of our more then 20,000 genes. That's a lot of untapped druggable space there. We want to close the gap with new technologies and news ideas."

Know your 'omics
While genomics and proteomics may still be the big guns right now of the 'omics world, here are a few other up-and-comers that could impact drug discovery and development in important ways soon:
  • Metabolomics—The study of the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signaling molecules and secondary metabolites) found within a biological sample.
  • Glycomics—The comprehensive study of glycomes and their genetic, physiologic, pathologic and other aspects, this 'omics area poses far more complexity and challenges potentially than genomics and proteomics, given that genes have four building blocks and proteins have 20, but saccharides have a multitude of them.
  • Lipidomics—The large-scale study of non-water-soluble metabolites, using technologies such as electrospray ionization, mass spectrometry and liquid chromatography-mass spectrometry.
  • Transcriptomics—This area examines the set of all messenger RNA molecules, or transcripts, produced in one cell or a population of them. Unlike the genome, which is roughly fixed for a given cell line (excluding mutations), the transcriptome can vary with external environmental conditions.
NIH to fund genome-to-clinic studies
The National Institutes of Health will spend up to $19.2 million in the coming two fiscal years on two programs for the Genes, Environment and Health Initiative that aim to help move information from genome-wide association studies into the world of clinical medicine.

One program, called "Implementation Planning Grants for Educational, Behavioral, or Social Studies for Translation of Genetic Factors in Common Diseases," will support research on initiatives studying how healthcare providers and consumers interpret information from genetic studies, as well as the behavioral or psychosocial aspects of clinical application of genetic findings.

The other program, called "Translation of Common Disease Genetics into Clinical Applications," will fund studies that focus on prevention, therapeutic interventions and development of diagnostic, predictive, clinical trial and epidemiologic tools based on findings from genetic studies of common diseases. DDN

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