In 2003, just two years after the official publication of the human genome draft, the National Human Genome Research Institute (NHGRI) outlined its plans for studying this promising new scientific resource. Nearly 1,000 sequenced genomes later, the institute has drawn out a new vision, published today in the journal Nature, for exploring the human genome.  

Eric Green, NHGRI’s director, says this plan is much more specific than the one that came before. It lays out specific domains of research activity, including understanding the genome, how it works, and how we can use this knowledge to further the science and practice of medicine. Green talks with TR about what he hopes to see happen in the next few decades and the major hurdles to getting there.

TR: It’s been a decade since the publication of the human genome. What can we expect to see over the next 10 years?

Green: The timetable is still wide open, but we can imagine that we will start to see spectacular advances in our understanding of how the genome works, how disease works, and how genomic changes are associated with disease. But truly changing medicine will take more than 10 years.

What do you mean by how the genome works?

What is the functional wiring of genome? We know all the genes, for the most part. But we have barely scratched the surface in understanding the two-thirds of elements that aren’t genes. We need to catalog them and understand their choreography. How does variation in these elements play a role in disease? Evidence continues to suggest that the majority of variants associated with common diseases are in noncoding regions of DNA, so understanding how they actually confer risk for disease will be critically important.

What will be the biggest challenge over the next five to 10 years?

At the moment, the biggest challenge is in data analysis. We can generate large amounts of data very inexpensively, but that overwhelms our capacity to understand it.

At the other end of the spectrum, we need to infuse genomic information into medical practice, which is really hard. There are issues around confidentiality, education, electronic medical records, how to carry genomic information throughout lifespan and make it available to physicians.

How do you hope to solve the data problem?

We don’t have a magic bullet. And it’s not just genomics facing this challenge; all of NIH is facing similar issues. First we need to solve the hardware issue with enough bandwidth to push data around and enough servers to store it.

But we also need to start thinking about how to train people, both health-care professionals and scientists, to be facile in bioinformatics. We need to foster development of professionals who have expertise analyzing large data sets of the size that biologists haven’t had to think about. We need to entice smart people into genomics.

The NHGRI and other genomics centers around the world are currently working on the 1,000 Genomes project, an effort to sequence and analyze 1,000 human genomes. Your new plan proposes a study of a million people. Why so many? Is that realistic?

The more we understand about the genomic architecture of disease, the more we see that some diseases will result from collections of rare variants. So we need more and more statistical power to find causative variants.

Once upon a time, 1,000 genomes sounded crazy. Now there is talk of people sequencing 1,000 genomes a week in their own labs. What ends up being more limiting is what has to happen at either end; getting samples from well-phenotyped individuals [people whose medical history and other traits are well-characterized] and then doing the analysis of their genome.

Right now, genome sequencing is still largely limited to research. One of the goals you outline in the plan is to transition sequencing into clinical applications. How will you do this?

We are starting with pilot projects. We have issued a number of grant requests; one of them focuses on the clinical applications of large-scale sequencing. A big barrier will be how to meld genomic info into the development of electronic medical records. 

One of the criticisms of the Human Genome Project is that after 10 years of research, it hasn’t yet yielded new medical treatments. Is that a valid criticism?

I feel bad if our enthusiasm and euphoria over completing the genome project was misinterpreted to mean that we would have cures 10 years later. But we have made unbelievable progress. Looking back from 2003, genomics is in such a different place.

Our new plan is meant to be realistic. We don’t want to make promises that spectacular advances in medicine will happen over the next five to 10 years. It’s more like over the next 10 to 20 years.

Can you give an example disease that illustrates the success of genomics?

Crohn’s disease. Ten years ago, this disease was so opaque. But a modest number of studies completely changed the course of the investigation of that disease. The research has pointed toward drugs that previously wouldn’t have been linked to the disease. Similar things are happening in diabetes and heart disease.