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Q&A: NHGRI Director Eric Green on Progress of Genomic Medicine

Eric Green, NHGRI director

NEW YORK (GenomeWeb) – Fifteen years ago, the International Human Genome Sequencing Consortium declared the Human Genome Project completed, two years after the publication of a draft sequence and initial analysis of the genome, and a year before the publication of a finished version of its euchromatic portion.

Eric Green was intimately involved in the project, in particular as director of the National Institutes of Health Intramural Sequencing Center and as chief of the National Human Genome Research Institute Genome Technology Branch. In late 2009, he became NHGRI's director, following Francis Collins, who was appointed as director of NIH. In a recent interview, Green reflected on how genomics has already changed the practice of medicine and what is still to come. Below is an edited version of the conversation.

At a White House event in 2000 to announce the first draft of the human genome, much hope was expressed that the project would pave the way for new cures for a variety of diseases. Can you mention a few examples of where it has had its greatest impact on medicine to date?

I'd probably list two, and a third is on the horizon. What's happening with rare diseases is transformative. It is now fairly routine that if you have a patient with a seemingly rare disease for whom you do not know the diagnosis, sequencing the genome as a means of identifying the genomic basis for the disease is now getting fully implemented. And it's not just being done as part of research, now we're starting to see this being done in routine clinical care.

The other example where this is now absolutely mainstream is in the use of noninvasive prenatal testing. And there, by sheer numbers, the uptake is incredible: a projected 3 million to 5 million pregnant women around the world this year will get that test. That's probably the number one implementation of genomic medicine, and it is all a consequence of new technologies related to DNA sequencing having been developed since the end of the Human Genome Project.

The big, big, big thing on the horizon is cancer. There is no question that we have wonderful examples of cancer genomics changing how we diagnose and manage certain types of cancer, but it's not ubiquitous for all types of cancer yet. I think we're at the beginning of a paradigm change in cancer diagnosis and management, and it's going to become commonplace that cancer care and genomic analysis are going to go hand in hand. I think we're just at the tip of the iceberg.

What about common complex diseases, such as heart disease or diabetes?

We're not there yet, and I think the jury is out on how much will change and how much won't change. The first step is to better understand the genomic architecture of disease. And there is just no question we've gotten well down that road in the case of cancer. And now, for other diseases, we are going down that road, and I think in some cases, we've made progress in terms of getting to associated regions, and in some cases, getting to actual variants that are conferring risk.

What we are learning is that it's incredibly complicated because there are lots and lots of variants that are playing a role, and pathways that are influencing these diseases, and we also know that these diseases are incredibly heterogeneous. Hypertension is many diseases, diabetes is many diseases, even Alzheimer's and autism are many diseases. It's also complicated because much of the variation we think might be influencing these pathways is in noncoding regions of the genome, and our understanding of these noncoding regions is certainly in its early days, we have a lot more to learn.

Even in the next 10 years, when we sequence genomes, I think where we will get the real clinical influence will be around rare diseases, around cancer, increasingly pharmacogenomics, and there is a lot more to come. I usually name common diseases at the end of the list because I'm just not certain what the timetable is going to be for those.

New DNA sequencing technologies have played a big role in how we got to where we are now. Did you foresee 15 years ago how quickly these would be implemented?

No. I don't think any of us did. We had this 2003 strategic plan at NHGRI, but I don't think any of us envisioned that 15 years later, roughly now, we would be crossing the $1,000 genome threshold, plus or minus. So no, it has shocked all of us.

When I started working in genomics, this whole idea of the Human Genome Project was way cool, so I got involved in it in the very beginning, in 1990. And I thought that maybe we can lay a foundation, so that the next generation, meaning my kids, will eventually use some of this stuff in how they practice medicine. And here I am in the middle of my career, and now we are beginning to see genomic medicine being implemented. I never thought we would see medicine influenced by genomics in my career.

There were some early research efforts to kick this off. In 2005, GenomeWeb published an article with the headline "Medicine Green: NHGRI to Dabble in Personalized Medicine." It covered your announcement of the clinENCODE project, which planned to study 400 individuals, including sequencing 30 megabases of their genomes.

This eventually became ClinSeq. At the time, it was actually a little controversial: we were going to start sequencing some of people's genomes. All the concerns about that sort of melted away, and stuff like that became commonplace. The ClinSeq program continues, it eventually went to exomes, and now they have 1,000 people or more.

Shortly after I became director of NHGRI, we started the Clinical Sequencing Exploratory Research program, CSER. In fact, ClinSeq was adopted into the CSER consortium, even though it was an intramural project, but it was sort of ahead of its time, if you will. These were the first projects where we were test-driving genome sequencing in clinical research.

Were these projects the precursors for the All of Us Research Program, which aims to study 1 million people in the US, including their genomes?

If you asked me what NHGRI did that was the most direct precursor of the All of Us program, it would be our Electronic Medical Records and Genomics (eMERGE) program. The reason I say that is that eMERGE was the one that said, if we take people that are getting routine medical care, and we have access to their electronic medical records, and on top of that, we get genomic information, can we somehow use all that data to learn things? The key thing of All of Us is not only a million people, and not only getting all of their genomic data, it's linking all of this with their electronic medical records. eMERGE was really the pilot to show that you can learn an awful lot from electronic medical record data if you get it from enough people and you couple it with genomic data and biospecimens.

Fifteen years from now, what do you expect we will have learned from the All of Us project that will have an impact on healthcare?

Fifteen years from now, I'm very confident that it's going to be fairly routine to have access to people's basic genomic information and genome sequence data. Also, I believe that many people will be collecting clinical data about themselves by various monitoring mechanisms, like iPhones or mobile health devices. In fact, I just saw a TV ad for an EKG monitor that people with arrythmias can now buy to do at-home EKGs, and they can get the information sent to their physician, which I think is really fascinating. My point is, I really want to push genomics, but I think just as much that mobile health devices are going to become mainstream. And then, on top of it, clearly, much more interoperable electronic medical records. We're going to be living in a world where part of routine medicine is going to be accessing all these different types of data, and physicians are going to have access to mobile data, genomic data, all coupled with much better organized electronic medical record data. What All of Us is doing is creating a platform of data on which we can do research that will discover things, but will also start teaching us how to harness all that data as part of routine medical care.

What needs to be done to make all this data easier for doctors to use?

There is just no way a practicing physician is going to do the kind of analyses that are going to be done by All of Us. But there will be algorithms that say, 'OK, you automatically do these analyses on data on your patients and if you see A, B, or C, that's going to tell you that this person is prediabetic, or this person needs to be better managed for this.' It's going to be a whole different way of practicing medicine where a lot of proactive data is available to healthcare professionals. They have to have systems in place to synthesize it and to give executive reports. But I think it's going to be driven by what's discovered by All of Us-like activities.

A recent survey by GenomeWeb and the Personalized Medicine Coalition revealed that the public is not very much aware of precision medicine, the All of Us program, genetic testing, the Genetic Information Nondiscrimination Act, et cetera. How are you planning to change that?

First of all, the outreach effort of All of Us is going to be significant. That's going to be broadly about precision medicine. Also, there are various things we have going on at the institute to try to enhance genomic literacy of the general public, K-16, and healthcare professionals, because even though [the latter] may be aware of precision medicine, they don't really know what that means and they don't really know about how to deal with genomic data.

Where do you see the role of the NIH, and other government agencies, at a time when people have increasingly access to their own genomic information through commercial services?

We have to deal with the new reality. It's not all going to be commissioned by healthcare professionals, people are going to access this, and in some ways, All of Us is going to teach us lessons, too. You're going to have a bunch of people that are going to have a lot of genomic data about themselves, and we're going to have to start figuring out what that looks like. And we've got previews of it from people who have gone out to direct-to-consumer groups and have gotten their own genomic data and have gone to physicians.

The other reality is, right now, most genomic data is generated as part of research studies, and then there is some genomic data generated by these direct-to-consumer groups. It is projected by many that this balance is going to completely shift, so the bulk of human genome sequence data is going to be generated as part of routine healthcare. For example, the Global Alliance for Genomics and Health has a BioRxiv paper that projects this will happen by 2022/23. And that's going to be very interesting because it is unclear whether we will have access to even do research on that data, how to best get access, and how we integrate all that data. And that will bring opportunities, but it will also bring some big challenges.