Green Day: An Interview with NHGRI Director Eric Green

Abstract

GEN BiotechnologyVol. 2, No. 2 Asked & AnsweredFree AccessGreen Day: An Interview with NHGRI Director Eric GreenEric D. Green and Kevin DaviesEric D. Green*Address correspondence to: Eric D. Green, National Human Genome Research Institute, National Institutes of Health, 31 Center Dr., Bldg. 31, Rm. 4B09, Bethesda, MD 20892, USA, E-mail Address: egreen@nhgri.nih.govNational Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland, USA.Search for more papers by this author and Kevin DaviesGEN Biotechnology, New Rochelle, New York, USA.Search for more papers by this authorPublished Online:18 Apr 2023https://doi.org/10.1089/genbio.2023.29093.edgAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Eric Green, Director of the National Human Genome Research Institute (NHGRI).For more than a decade, Eric Green, has served as the director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH). A physician scientist by training, Eric studied at Washington University School of Medicine, and did postdoctoral training from genome science pioneer Maynard Olson. He joined NIH's National Center for Human Genome Research in 1994 (later renamed NHGRI) and played a leading role in the Human Genome Project. In 2009, Green succeeded Francis Collins, becoming the NHGRI's third director. In 2020, Green and his colleagues published the latest iteration of the Institute's Strategic Vision.1In this wide-ranging interview with GEN Biotechnology Executive Editor Kevin Davies, recorded in February 2023 as part of GEN's virtual event, The State of Genomics & NGS, Green shares his excitement about recent advances in genome biology and next-generation sequencing (NGS) technology, as well as his assessment of where the human genomics community should go next.(This interview has been edited for length and clarity.)Eric, if I was to ask you to give a state of the union summary of where genomics is now in 2023, how would you frame it?Green: I would frame it with words like exhilarating, certainly! But I would immediately follow it with words like challenging—I mean good challenging, as when you are hungry to get to the next stage and tackle things. Genomicists are optimists; we do audacious things. We like challenges. It is also exhilarating because we have so much to celebrate… We think about technology—next-generation sequencing (NGS) … Suddenly that means, for reasonably modest amounts of money, you can generate immense amounts of data. We are now victims of our own success. There are massive challenges with respect to how to handle data, where to put data, and analyze data. Cloud computing is front and center.Now that we have the human genome sequence laid out in front of us, we should be able to understand everything about genome function. But it is not that simple. Our complexity is not in our gene number, but in how we use our genes. That is a language we are still trying to understand. How do we move from genome function to understand how variants in our genomes influence that function?We are beginning to understand how that variation affects our traits. It affects our health, who gets which diseases. We are now at nearly 6000 rare diseases with respect to knowing their genomic basis. Back when the Human Genome Project began, that number was only 61 … 61 to 6000 is exhilarating! But then you realize those are rare diseases. We need to tackle common diseases that are far more complicated. Multiple genomic variants are involved. That is a huge challenge. But we are making progress.In 2022, several new NGS companies emerged. And we had the complete human genome finally laid out. It must feel particularly exhilarating to be riding the crest of this wave?I believe that technology pushes all of this. Technology is a catalytic thing—we can get a lot of information about genomic variation across different human populations. Now, we have clever sequencing assays to be able to understand genome function, epigenomic marks, different things to understand gene expression. So, you learn a lot about the biology. You can adapt it to figure out variation and start using new insights for medical applications. As a physician scientist, it comes full circle and allows us to start using these tools that we once thought were just going to be for scientists.This technology should be used as part of health care. That is exhilarating but challenging. Why? Because health care is challenging. Every health care ecosystem is facing challenges of how do we bring genomics into health care for everyone in an equitable manner? How do we change routine practice, which is never easy?The H3Africa project recently concluded. How would you put that into perspective? And what is the need to improve diversity in the future of human genomic analysis?Let us first talk about diversity in general. We are playing catch-up in genetics and genomics—some of our earliest efforts involved lots of samples from individuals of European descent. That is just inadequate, both for scientific reasons and for social reasons. We need to improve the diversity of our research participants so that we learn about all the unique nuances of genomic variation as it occurs in different subpopulations across the world. We are doing that in the United States, but I think the world community of genomicists is also helping us. We have improved things significantly. I think that is a fixable problem.Then there is the issue of the diversity of our workforce and our community…. We want genomics to benefit all humankind in all countries. We do not want to do this by providing this from the United States. We want to have this locally, eventually using genomics as part of medicine. [We] asked, what can we do to help? Africa was one of the areas that we and the Wellcome Trust viewed would be an opportunity to be helpful.We got H3Africa funded through the NIH Common Fund. NHGRI contributed significantly to H3Africa as an institute and helped co-lead it on behalf of NIH. The Wellcome Trust partnered with us, as did the African Society of Human Genetics, a little >10 years ago. I got involved early on with Francis Collins, who was then NIH director, and Charles Rotimi, who was then an investigator [now scientific director] in our Intramural Research Program.The key aspect of H3Africa was not just about studying African genomes or studying diseases relevant to Africa.2 It was about empowering the scientific enterprise in Africa—the scientists and institutions to do genomics so that they could see the fruits of genomics and guide it into health care. It was about capacity building. It was not about dropping into Africa, getting a bunch of DNA samples, flying back to Boston or New York or Houston, and analyzing them. It was about empowerment.This is where it comes full circle. One of many grand challenges in genomics is data analysis. Generating the data has become pretty straightforward. But data analysis, especially with cloud computing, is very democratizing because all people need is access to the data. They do not need a big fancy laboratory. In some cases, they just need a laptop.One of the things we learned about H3Africa was to prioritize the development of networks of computational and data scientists. As happened in Africa, where they realized they did not want to develop a lot of landlines for telephones, they were able to leapfrog by going immediately to cellphones, which empowered communication in Africa. An area of emphasis when we stood up H3Africa was called H3ABioNet—a network of computational scientists. That group has been pivotal for some of the major advances we have seen over the 10 years of the program. In the longer term, we have been working with governments and other international organizations to sustain this because H3Africa has reached the end of its funding under that name.Various things are blossoming. But it is in a different place now than what it was before. We learned you do not need a big fancy laboratory to do cutting-edge genomics. You need to empower data scientists and provide them the tools to help them perform complicated studies in data analysis.Even here in the United States, we are trying to get lots of other institutions doing genomics by emphasizing data science. Maybe their institution does not have the best laboratory infrastructure and DNA sequencing instruments. But we have got plenty to engage these people. By providing access to these data and becoming very productive, scientists in data science will also help to diversify our workforce. We need the entire genomics workforce to start resembling society here in the United States and society around the world.Over the past year or so, we have seen several companies entering the NGS field. How significant is this expanded choice that researchers have?I might even modify “exhilarating” and change it to “euphoric”! I think having multiple platforms—when there is good competition and prices go down—means everybody benefits. It also means that you can do significant genomics research, even in areas that do not naturally attract a lot of funding. On pure economic grounds, competition is wonderful—it drives prices down, drives innovation, and keeps people on their toes.Every one of these NGS platforms is a bit different—they all have pluses and minuses. So, we go from having a toolbelt with one tool that you throw at a problem to now you can use a combination of tools. And then turn to your computational scientists and say, OK, I have got three different data types coming off three different instruments. How can you make that jigsaw puzzle come together more efficiently and more accurately?Twenty-two years ago, you were at an NHGRI retreat (in 2001) when the term “the $1000 genome” was first coined. We now have companies proclaiming the $200 genome and even lower. How significant is it that the price has fallen that low?I love the story, and I love the fact that NHGRI gets to take credit for having the chutzpah to put out “the $1000 genome” phraseology! It was an audacious challenge—I go back to when I was a postdoc in the late 1980s, it seemed unfathomable that we could sequence the human genome in the next couple of decades (Fig. 1). Of course, we did…FIG. 1. Sold on sequencing.Eric Green with his mentor, Maynard Olson, at Washington University School of Medicine, St Louis, where he was a postdoc from 1988 to 1992. (Courtesy: E. Green.)Our institute will take a good amount of credit, both for the chutzpah and the visionary leadership, and then we started our technology development program, which continues to the present time. We just laid out the ability for scientists to bring us “crazy” ideas. Then we had a separate announcement for “super crazy” ideas and even “ridiculously crazy” ideas! People were willing to take risks. The rest is history!3I would also give credit to the private sector. I admire tremendously the venture capitalists who were willing to invest, and the bright minds that formed companies around these earliest ideas. It is a real credit to how the public effort, funded by our institute, partnered with the private sector. It was clear we were doing some very risky things the private sector was not prepared to do, and that is what we should be doing. But then they were immediately capitalizing on our developments and licensing those advances and putting instruments together. That the public–private partnership all formed around the rallying cry of a “$1000 genome” was galvanizing.It obviously happened far faster than anybody anticipated. I think it is one of the best examples of technological advances in the history of NIH. I used to say that a lot—and then I saw what happened with COVID-19 vaccines! So, we have got some competition here! If that is where we go down in history, as being up there in the top few, then I am also proud of that!One of the flagship successes of your intramural research program at NHGRI is the telomere-to-telomere (T2T) human genome sequence. Why was it so important to complete that project? What did we learn that we perhaps did not know before?Adam Phillippy is one of our wonderfully talented intramural investigators, and he joined forces with several extramural investigators, Karen Miga (UC Santa Cruz), Evan Eichler (University of Washington), and Michael Schatz (Johns Hopkins University). This is all intertwined with our big extramural program—the Human Genome Reference Program—which is constantly improving the human reference genome.Why is this so important? First, if there is ever a genome [sequence] on this planet that deserves perfection, I think we can be arrogant and say it is the human genome! We deserve the best. I mean, we are humans!The Human Genome Project ended [in 2003] because we felt we had done the best we could do at the time with the tools available. But the wording was “essentially complete,” not “end-to-end” complete! We knew that those darn telomeres and centromeres and complicated genomic regions were not going to be sequenced well with Sanger-based sequencing methods. Rather than delay the party, we wanted to celebrate and move on. We acknowledged we were still missing about 8% of the sequence. We tinkered away, filling gaps, but it really did require a new generation of NGS instruments.It also required a new set of computational tools—innovation in data science and computational biology. And a new generation of investigators who saw this as a remarkable challenge and brought new ideas. It took 18–19 years to do it. The tenaciousness of those folks, and the younger investigators investing in their early careers, is admirable.4It turns out, not surprisingly, that there is important stuff in that 8% [that was initially missing in the human genome sequence]. There are genes in that 8%—I mean, leave no gene behind! So, we found new genes. Also, Evan Eichler was telling us 20 years ago that part of the reason why these complicated regions are so important is because they are structurally complex, but that also makes them mischievous. Sometimes they do things that they should not be doing that then leads to genetic disease.There are individuals with health conditions because of structural rearrangements [in their genomes], which we need to understand. Although it is still expensive to get a T2T genome sequence, there is no reason to think that it will not become something that might be available diagnostically—maybe for $1000 or less. Whether it takes 5–10 years, this research continues to be important. We should imagine a day where we can sequence a patient's entire diploid genome and have complete insights. I think that is the next grand challenge.What is the pangenome and why is it important?In 2023, there are going to be some major publications in this area. This is going to become part of the language of genomics. The idea of pan is not totally new. Studies in cancer genomics require the assimilation of lots of genome sequences of a certain kind of cancer… The pangenome is basically an attempt to take reference sequences from different human populations and represent the variations that they have among themselves. We are working hard to figure out how to explain this to the general public and use it in educational ways. It is really this idea of representing the diversity of human genomic variation on a backbone of a reference genome.For the past 10 years, we have also seen extraordinary advances in CRISPR and genome editing. You are a physician by training. Did you ever imagine we would potentially be seeing patients in the clinic treated with this new form of precision medicine?First, genome editing is spectacular. We take advantage of those [CRISPR] technologies at the institute because it becomes a very facile laboratory tool for trying to untangle the complexities of genome function. We are also very interested in applications for gene therapy. And certainly what we are seeing in sickle cell disease and some other areas are breathtaking…As a physician, it is overwhelming. I love sickle cell disease as the example. Remember, the day the Human Genome Project began [in 1990], there were 61 rare diseases for which we knew the gene mutation. Sickle cell disease was one of them. I do not feel we brought enough advances to those patients; but finally, genetics and genomics are delivering those therapies. We should all applaud it. I hope this continues to scale in a very robust way.How has the field of genomics progressed in terms of diagnostics?Shortly after I became director of NHGRI 13 years ago, one of the first workshops I held was focused on research projects in newborn genome sequencing, which led to one of the first programs I launched as director called NSIGHT (for Newborn Sequencing in Genomic Medicine and Public Health). The program looked at genome sequencing of healthy newborns, but we had a grant or two on genome sequencing of acutely ill newborns. Those were some of the first studies in neonatal intensive care units (NICUs) to demonstrate that if you could do it quickly enough, you could save lives. That was one of the most successful aspects of that program…The idea that this has now begun to be done routinely in the NICU, not only here in the United States but around the world, is coming full circle.That is just one venue of the use of whole-genome sequencing for diagnostics. Routinely now, thousands and thousands of patients every month with rare conditions getting their genome sequenced—and in 30%, 50%, I am hearing up to 60% of the time, you can figure out what is wrong with them. That is changing diagnostic medicine in a manner that I would have never predicted would happen in my lifetime. Maybe after the Human Genome Project, I said, in my lifetime, but certainly not in my professional career. And it is here, and I am still in my professional career!In closing, how far have we come since the double helix 70 years ago? Perhaps more importantly, what do we still have to learn about the biology of the genome?If you think about this arc of advances, starting with the discovery of the double helix, I think we marveled and celebrated (as we should) that we understood the structure [of DNA]. And then when the genetic code got elucidated, we figured out part of DNA's language. Of course, now we know it is just a small part of the language, with so much more to learn.Now, we can lay out the letters of genomes. But that is still just part of the journey. We can make advances to take this all the way to patient care. But we still have to figure out what is all of the embedded code in these letters. We absolutely know it is not just the genes. We are going to be surprised at some mechanisms we will learn about in the future. And we know that some of that is going to be biologically and medically relevant. I think that is what keeps us going.But if I think back on this progression from the double helix to the molecular biology revolution to the Human Genome Project and where we are now, the biggest difference is this: when I got involved in genomics, it was still very boutique. The Human Genome Project was completed by a relatively small community of scientists (Fig. 2).FIG. 2. The Human Genome Project's International Human Genome Sequencing Consortium, circa May 2002.(Courtesy: E. Green.)Now in 2023, genomics is mainstream in all of biomedical research and increasingly mainstream as we think about translational and clinical research. And it is becoming more mainstream in medicine. You are also starting to see it becoming mainstream in society, in part because it is touching health care. And once you touch health care, it is relevant for everybody… We certainly saw how genomics was mainstream during the COVID-19 pandemic, whether it related to diagnostics, tracking variants, or developing vaccines.So everywhere you look, genomics is mainstream. That is very gratifying, both because we have seen how far it has come, but we also see what its impact is.