榴莲视频

Researchers continue to make strides in the field of genomics, bringing revolutionary treatments and diagnostic tools to patients, while providers and regulators grapple with the ethical issues that arise as a result. As part of our occasional series of interviews with federal healthcare officials, 榴莲视频 Washington Editor Joyce Frieden sat down with Eric Green, MD, PhD, director of the in Bethesda, Maryland, to discuss his career, the latest advances in genomics, and his hopes for the future of his chosen field.

The following transcript of the interview, which was conducted with a public relations person present, has been edited for length and clarity.

Thanks for taking the time to speak with us! Tell us about yourself and how you ended up in your current position.

Eric Green, MD, PhD: You're welcome! I was born and raised in St. Louis, and then went off to the University of Wisconsin for my undergraduate degree. I came back to Washington University [in St. Louis] for the MD/PhD program, and then decided to train in clinical pathology. I had a little bit of a vague interest in this very early field -- molecular diagnostics.

After the first year, you go off and do postdoctoral research 90% of the time, and this was in 1988, a year after the word "genomics" was coined and 2 years before the Human Genome Project was launched. And I happened to be at Washington University, where there were some world class leaders in genomics. And so I joined one of the labs there, and the rest is history because I sort of made a career of it. A year and a half to 2 years into [my postdoc there], the Human Genome Project began and Washington University was funded as one of the first genome centers. I was on the front line, running one of two major projects as a postdoc, and eventually joined the faculty.

When Francis Collins came here to direct this institute, he [recruited me], so I came here 29 years ago, and for almost half that time, I've been the director.

In your time at the Institute, what progress has been made in the use of genomics for diagnosing and treating disease?

Green: Let's start with cancer, which is a disease of the genome. When I went to medical school, so much of what you did around cancer was determined by what part of the body you cut it out of. If you cut it out of the breast, it usually set you down this path, but if you cut it out of the liver, it's something else, and if you cut it out of a bone, it's something else.

Nowadays, if you ask an oncologist in most cases, "Is it more informative to know where I cut it out, or if I gave you a genomic signature of that tumor?," they want the signature. Because what we're learning more and more is that that's the best way to predict prognosis and figure out the best options for treatment. The literature is now filled with story after story of "We found these tumors in the bone and they look like a breast cancer and there's no primary breast cancer, but we treated it like it was a breast cancer and it worked." So the tissue of origin is becoming much less important.

The second example is rare genetic diseases, including some famous ones like sickle cell, cystic fibrosis, and Huntington's disease. They're relatively simple from a genomic level because it's basically the breakage of a single gene through a mutation in one gene.

When the Genome Project started, we only knew about 61 of those diseases for which we knew what gene was mutated. But now we know almost 6,000. That has set up as a circumstance where when you encounter a patient, especially a perplexing patient -- and some people have been undiagnosed for decades -- you just sequence the genome. It's not that expensive, less than $1,000, and the diagnostic yield is going up every year. We're getting better and better at figuring this out. Sometimes it gives you insights on how to treat, and sometimes it ends a patient's diagnostic odyssey -- at least they have a diagnosis.

The third example is with prenatal genetic testing, where they're mostly looking for gross chromosomal abnormalities -- aneuploidy, like trisomy 21, famously known as Down syndrome. For that you need a reliable way to access fetal DNA, which [previously] was either an amniocentesis or chorionic villus sampling. Either of these is invasive, and I'm told it's not pleasant, and also there's a small risk of [miscarriage].

What's different now? Well, biologically, nothing's different, but technologically, everything's different. It turns out that the placenta naturally sheds small amounts of cell-free DNA into the maternal blood. Twenty years ago, we had no ability to detect those teeny bits of DNA that naturally float around in maternal blood, but now we do because we have new methods for sequencing DNA. So now, the pregnant person gets a blood draw, they take an extra tube at 8 to 12 weeks, and they separate the liquid part -- it has cell-free DNA, some from the fetus and some from Mom. They sequence the DNA exquisitely sensitively and they just look for whether everything is uniform. If they detect anything that's really abnormal, they'll repeat it, and look more carefully, and they may do an amniocentesis.

This is called non-invasive prenatal testing, or NIPT. And the commercial sector saw this as a grand opportunity, so there have been multiple companies offering this, and it has driven the cost down. The obstetrics professional societies have said this is great even though their members are losing money, because they realize the test doesn't need to be so invasive. As a result, 5 million to 7 million pregnant women a year worldwide are thought to be getting this non-invasive test.

The fourth area is pharmacogenomics -- say I'm hypertensive and I'm going to take a hypertensive medication and I have a choice of 10 drugs. Which drug should I take? It has nothing to do with the pathophysiology of the hypertension; it has to do with my drug metabolism pathways and how I clear drugs out of my system. It could be that Drug A, I clear very poorly so I become toxic when I take it, and Drug B I might "hyper-clear" so it's won't be effective, and Drug C is one that I clear perfectly fine so I'll stay within the therapeutic range. So the important distinction is pharmacogenomics.

How are things going in terms of clinician awareness? Are enough doctors aware of and using genomics for medical testing and treatment?

Green: No, they're not, and that's a big priority for the Institute. And we're working very hard. It's not only medical education -- it involves the whole healthcare delivery ecosystem, which as you know, oftentimes is not face to face with your doctor; it's face-to-face with your nurse, your pharmacist, or your physician assistant. There's an entire workforce that we need to be moving along. And of course, we're doing this at a time where the science is moving very fast.

I have a son who is a third-year medical student. I wish I could say that what he learned in the first 2 years of medical school was enough genomics to be prepared for the future that his father's describing, but he did not. And he's at a first-rate medical school. I'm not faulting the school; this is a hard problem for them. We can't just say, "Medical schools, it's your problem," because trying to change the medical school curriculum is like trying to change the federal government. But these students are smart, lifelong learners, so we need to put out the tools to help them learn genomics as they go along.

Not to mention the fact that a lot of physicians out there, including my medical classmates who are practicing medicine, never heard the word "genomics" once in medical school, because the word didn't exist until right after they graduated. So it's one of the things we're doing.

I do think more and more clinicians are becoming aware. More patients with rare diseases are getting referred to medical specialists or other physicians who do know about getting the genome sequenced. I was told recently that it was thought that in the United States, roughly 25,000 patients with rare conditions or suspected rare conditions will get their genome sequenced each year, and that number is probably matched internationally.

You've talked about genomics' progress in testing. What about for treatment of disease?

Green: It was believed that some of the earliest gene therapy successes would come with with things that are in blood, and the reason for that is because bone marrow is accessible -- painful, but accessible. So let's talk about two extremes, both diseases where there was a lot of hype: sickle cell and cystic fibrosis. And in the case of sickle cell, the tissue where all the action is, is in the blood, which is made in the bone marrow. In cystic fibrosis there are many organs involved, but most seriously the lungs, which are not very accessible or [easy to culture]. And so it is interesting to watch what has played out.

If you look at sickle cell disease, the successes we're seeing now is you can take a patient with sickle cell, remove some of their bone marrow using the gene editing technique [known as] CRISPR to fix the sickle cell mutation in the laboratory, and then you're putting their cells back in their bone marrow. Then they're making normal hemoglobin and they're cured.

In the case of cystic fibrosis, there's still hope around gene therapy, but actually the things that have created progress in recent years have been the development of new drugs.

Are there guardrails that should be put around this technology?

Green: I think there are some very well discussed guardrails around genome editing. It is the difference between somatic cells -- those are body cells -- bone marrow, brain cells, that's all body and that's fine. You can do a lot of stuff with that and it's not as concerning. It's when you go to the germline; that's where the guardrail is. Do not go to the germline, or sperm or egg, and manipulate those. The gentleman in China, he created these twins and made the first CRISPR babies. The Chinese are keeping it hush-hush what their fate is, but there's lots of reasons to be nervous.

So tell us about your budget. How big is it, and what do you spend the money on?

Green: We are a relatively small institute at NIH, probably in the bottom five or six in terms of size, although we think we have an intellectual footprint that is rock-star in terms of size. I mean, genomics is everywhere. Some people think I must have 10% or 20% of the NIH budget because genomics is everywhere, but we're only 1.4% of the NIH budget. It's still a big chunk of change -- about $656 million. Do we wish it could be higher? Of course, but by and large we've had a budget that has allowed us to do a tremendous amount. And we leverage a lot more activity in because we're invited to a lot of collaborative projects going on in other parts of NIH.

Of that $656 million, 20% of it stays here for a pretty big on-campus program we have in genetics and genomics. About 5% of it is to run the Institute, and 75% goes out to "extramural" grants -- we're giving out grants all around the world, mostly in the United States, but some abroad as well. We're doing everything from developing technologies for sequencing and analyzing DNA, to developing data resources to sharing all this data worldwide, to understanding how every nucleotide, every base genome works, and figuring out how variants in our DNA affect our health and disease.

How do you feel about the role that patients are playing in directing funding for disease research?

Green: What's happening across all of biomedical research -- and NIH is leading on this as much as everybody else -- is to bring the patients into the conversation more. I think NIH would be the first to say that for too long, we kept at an arm's distance from patients. And in the long run, that's just not going to work, particularly for patients with rare diseases. And by the way, that's why they're aggregating; you're seeing more and more rare disease communities aggregating together, and that's what's leading to major programmatic changes.

Just this morning I was at a meeting with [one NIH institute director] who spends hours every week having to deal with different advocacy groups in [his disease] community. I don't deal with advocacy groups because I don't own any disease. That can be both a blessing and a curse.

People often raise concerns regarding privacy when it comes to genetic test results. Is that a concern for you?

Green: I think sometimes people will carve out genetics and make it seem like it's completely different when it comes to privacy, and I realize it has some differences because if nothing else, it gives you insights about your relatives. However, there are a lot of other things about you besides genetics, and our medical records are getting increasingly electronic. Boy, you can learn a lot about a person just by looking at their medical records! People seem very concerned about somebody seeing their genome sequence, but they're less concerned about somebody seeing their medical records. Believe me, I can do a much better job of interpreting some of these medical records than interpreting their genome today.

What keeps you up at night?

Green: I have great concerns around equity, and around exacerbating health disparities. We won't be perfect but one of the battle cries of the Institute is making genomics mainstream and equitable in medicine. We don't want to just be mainstream for those who've gone to Johns Hopkins or those who get their medical care at Washington University, but I think about all the nooks and crannies of the medical ecosystem.

Another one of our biggest priorities is to diversify our workforce. I mean every aspect of the genomics workforce, from a science communicator, to a leader, to a physician, to a scientist, to a nurse, to a pharmacist -- just all of it, because we need our entire tent of people touching genomics to reflect society. In genomics, it's particularly important because we just don't think we're going to engage the communities and convince everybody to be comfortable with genomics as part of their medical care unless the individuals who they're talking to resemble them more.

And on the other side, what makes you excited to go to work every morning?

Green: I'm surrounded by terrific people and I believe what we're doing is changing the world. So I think that makes a big difference to be with people who truly are committed and are passionate about what we're doing.

I hitched my wagon at a very early stage in my career, with this remarkably vague idea that genomics could one day change the practice of medicine. And I guarantee you then -- which would have been 1988 -- or when the Human Genome Project ended 20 years ago, in 2003, I really didn't believe I would see the fruits of it affecting medicine in any real way in my lifetime. Not only is it in my lifetime, it's while I'm still professionally active and I get to be basically in the top genomics position in the country. Just to have this happen on my watch, it's amazing. It has come full circle from an incredibly vague idea of why I want to do any of this, to actually feel like I've moved the needle.

Thanks again for speaking with us!

Green: You're welcome; come back any time!

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