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The State of Genomics and NGS
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The State of Genomics and NGS
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Language: EN.
Segment:0 .
FAY LIN: My name is Fay Lin, and I'm senior editor of GEN Biotechnology. GEN Biotechnology launched in early 2022, publishing exceptional research, reviews, opinion, and analysis across the biotech spectrum from genomics and synbio to artificial intelligence and drug development. The journal benefits from a combination of academic leadership and professional editing. The first four issues of the journal have amassed approximately 40,000 full text downloads and featured groundbreaking original research on gene editing and livestock, CRISPR-based pest control, base editing in a single AAV vector, and cost-effective 3D printing.
FAY LIN: But wait, there's more. We've also featured exclusive interviews with biotech AI CEOs, topical views and news articles, insights from financial analysts, and news features from GEN reporters covering the state of aging research with the launch of the ARK Institute, and advances in organs-on-chips. We'll consider any manuscript reporting novel and interesting results in the biotech field.
FAY LIN: We offer fast and constructive peer review. And we hope you'll consider submitting your paper to GEN Biotechnology. [MUSIC PLAYING]
KEVIN DAVIES: To kick off The State of Genomics & NGS and provide a big picture view of where we are in genomics, we really couldn't think of anyone better than to visit Eric Green, the director of the National Human Genome Research Institute or NHGRI. Eric is a physician-scientist. He joined the NH Genome Center in 1994 and played a leading role in the Human Genome Project. In 2009, he succeeded Francis Collins, becoming the NHGRI's third director.
KEVIN DAVIES: In 2020, Green and his colleagues published in Nature the latest iteration of the NHGRI's strategic vision. We cover a lot of ground in this interview, and I really hope you enjoy the conversation. To kick off The State of Genomics & NGS, we couldn't think of a better place to start than the office of the director of the National Human Genome Research Institute.
KEVIN DAVIES: I'm with Eric Green, the director. Eric, thank you so much for inviting us up to launch this event.
ERIC GREEN: And thanks for coming. We love having home field advantage. We love having you here.
KEVIN DAVIES: And the matching outfit is a nice touch as well.
ERIC GREEN: Yes, and we should tell people that that was deliberate and they'll be really impressed, but it was totally accidental.
KEVIN DAVIES: So the event is called The State of Genomics & NGS, and I imagine in your day job you give a lot of these sorts of State of the Union type addresses to a variety of different audiences around the country and probably overseas as well. 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?
ERIC GREEN: I think I'd frame it with words like exhilarating certainly, but I would immediately follow it with words like challenging. And I don't mean challenging bad. I mean, challenging good. Challenging make you hungry to get to the next stage and tackle things. I mean, genomicists are optimists. Genomicists do audacious things, so we like challenges. But it's also exhilarating because we just have so much to celebrate, so much to look back on, and realize how much has been accomplished.
ERIC GREEN: I think about the State of the Union, if you will, for genomics. It goes across that full spectrum of activities. And every one of the cases, it's exhilarating, but it's also challenging. We think about technology. Next-generation sequencing, these incredible technologies that we've seen. Remarkable, exhilarating, breathtaking.
ERIC GREEN: But all of a sudden, that means for reasonably modest amounts of money, you can generate immense amounts of data. We could sequence many, many genomes, whether they're human genomes or even more of other species genomes when they're smaller. What does that mean? These have got a lot of data. We've now brought upon ourselves, victims of our own success, these massive challenges with respect how to handle data, where to handle data, where to put data, where to analyze data, and now cloud computing is front and center.
ERIC GREEN: Huge challenges we're dealing with. And you think about exhilarating. We have this sequence laid out in front of us, and we now should be able to understand everything about genome function. It's not that simple, right? Huge challenges. Our complexity is not in our gene number. Our complexity is how we use our genes, and that's a language we're still trying to understand and use.
ERIC GREEN: Huge challenge, but we're making progress. And then we think about how do we move from genome function to understanding how variants, differences in our genomes influence that function. That's a whole other set of challenges that we're tackling. But we want to tackle those because as we make progress, we begin to understand how that variation affects our traits. It affects our health. It affects who gets which diseases.
ERIC GREEN: And then you get major advances. Like with rare diseases, we're now nearly 6,000 rare diseases. We know the genomic basis of it, and you don't have to go back that far. Just go back to the day the Human Genome Project began. There were only 61 rare diseases. We knew the gene that was mutated in that disease 61 to 6,000. Exhilarating!
ERIC GREEN: But then you look and you realize, well, yeah, but that's rare diseases. We need to tackle common diseases, and common diseases are far more complicated. Multiple genes are involved. Multiple genomic variants are involved. That's a huge challenge, but we're making progress.
KEVIN DAVIES: Last year, 2022, seemed to be a particularly exciting year. There were new companies coming into the space. You had the complete human genome sequence finally, only took another 20 years but finally laid out. So it must feel particularly exhilarating to be riding the crest of this wave.
ERIC GREEN: Well, and I'm of the belief, of course, that technology pushes all this. I mean technology is the catalytic thing, and you're absolutely right. And the technology not only gives us capabilities at the very basic end of things. All these technologies, by the way, not only read out the sequence so we can to get a lot of information about variation across different human populations.
ERIC GREEN: But all those technologies get adapted with all sorts of clever assays that brilliant genomicists think of to be able to understand genome function, epigenomic marks, different things to understand about gene expression, so on and so forth. So you learn a lot about the biology. You can adapt it all to start to figure out variation. And then that brings you in the realm of actually having these insights.
ERIC GREEN: And of course, when it's gotten cheap enough and the insights are there, it allows us to start to use these for medical applications, which, as a physician scientist, of course, then comes full circle and allows us to start to use these tools that we once thought were just going to be for scientists to actually be used as part of health care. Of course, that's exhilarating, but it's challenging. Why?
ERIC GREEN: Because health care is challenging. And every health care ecosystem in any country of this world is now facing the challenges of how do we bring genomics into health care for everyone in an equitable fashion and how do we change routine practice, which is never easy no matter what the nook or cranny of medicine is it's always difficult to change things.
KEVIN DAVIES: That's a nice segue to my next question. I wanted to talk about diversity. The H3Africa project was a very important initiative that has recently concluded. How would you put that into perspective? How are you building upon it? And perhaps you could talk more broadly about the need to expand and improve the diversity in the future of human genomic analysis.
ERIC GREEN: Yeah, so let's break diversity down into a couple dimensions because they're all important. They all interrelate. Let me get to H3Africa in a minute. I mean, let's just first talk about just diversity in general. We are playing catch-up in genetics and genomics, and that some of our earliest efforts just happened to involve lots and lots of samples from individuals of European descent.
ERIC GREEN: And that's just not adequate at both for scientific reasons and for social reasons. And so we need to improve 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. And we're doing that in the United States, but I think the world community of genomicists are helping us. And I think we've improved this significantly, and there's some challenges with that, but there's lots of progress.
ERIC GREEN: And I think that's a fixable problem. Then there, of course, is the issue of the diversity of our workforce and the diversity of our community. And again, many dimensions of that, whether you're just looking at United States or you're looking globally. But certainly, we want genomics to benefit all of humankind in all countries.
ERIC GREEN: And we don't want to do this by providing this from the United States. We want to have this right there locally and for eventually using genomics as part of medicine. And you look across the world as we've done and we say, what can we do to help? What could we do to facilitate? And Africa was one of the areas that we and the Wellcome Trust viewed would be an opportunity for us to be helpful.
ERIC GREEN: So we got together, the NIH through our common fund. And I should point out NHGRI contributed significantly to H3Africa as an institute, but we helped colead it on behalf of NIH, on behalf of the whole program. And we put some of our own funds, but the main funds out of the NIH came out of the NIH common fund and the Wellcome Trust partnered with us, and so as did the African Society of Human Genetics.
ERIC GREEN: And this started a little over 10 years ago. This was a project I got involved with very early on in partnership with Francis Collins who was then NIH director and Charles Rotimi who was then an investigator in our intramural program. Actually, most recently, has been appointed to be the director of our intramural program. And working with the Wellcome Trust and the African Society of Human Genetics, we launched this project in Africa.
ERIC GREEN: And the key aspect of H3Africa, it was not about studying African genomes and not about just studying diseases that are relevant to Africa. It was about empowering the scientific enterprise in Africa, the scientists and the institutions to do genomics so that they could do those studies and eventually could see the fruits of genomics find its way into health care. It was very much about capacity building.
ERIC GREEN: And it was not about dropping in Africa, getting a bunch of DNA samples, flying back to Boston or New York, or Houston and analyze them. No, no, that was not. It was about empowering, and so we learned a lot. And we're using some of those. This is where it comes full circle. One of the things we learned, and it relates to what I said earlier is the huge-- one of many grand challenges in genomics now is data analysis.
ERIC GREEN: Generating the data has actually gotten pretty straightforward. But data analysis, especially with cloud computing, is very democratizing because all people need to do is get access to the data. They don't need a big fancy laboratory. In some case, they just need a laptop. One of the things we learned about in H3Africa was to prioritize the development of networks of computational and data scientists because as happened in Africa where they realized they didn't want to develop a lot of landlines for telephones.
ERIC GREEN: They were able to leapfrog it by going immediately to cell phones, and so that actually empowered communication in Africa. Similarly, one of the big areas of emphasis when we stood up H3Africa was something called H3ABioNet, which is basically a network of computational scientists. And that has really been key and pivotal for some of the major advances we've seen over the 10 years of the H3Africa program.
ERIC GREEN: In addition to that, longer term, we've been working with governments and other international organizations to sustain this because H3Africa has come to its end of its funding under that name. And now, various things are blossoming up that will be other projects that will carry it on. But it's in a very different place now than what it was before.
ERIC GREEN: And then one of the lessons we learned from that is you don't need a big fancy laboratory to do cutting edge genomics. You need to empower data scientists and provide them the tools to help us lift all these complicated studies in data analysis. And so even here in the United States, we're trying to now facilitate. Let's get lots of other institutions doing genomic science by emphasizing data science because maybe their institution doesn't have the kind of laboratory infrastructure for having a lot of fancy laboratory work in sequencing instruments, but we've got plenty to engage these people just by having them have access to this data and become very productive, cutting-edge scientists in the data science realm.
ERIC GREEN: That will help also diversify our workforce, which is a very big priority for the institute we need the entire genomics workforce to start resembling society here in the US and society around the world. And that'll be very important.
KEVIN DAVIES: Excellent. Let's pivot a little bit to talk about the state of NGS. For many years, it seemed we had a major short read platform and a couple of important long read platforms. We'll talk about those in a second. But over the last 12 months or so, we've had a relative glut of new entrants coming into the field. So users, some of your fundees now have a wealth of choices that they didn't have perhaps 12 or 24 months ago. How significant would you say is this new wealth of choice that customers and researchers have?
ERIC GREEN: I might even modify my exhilarating word and change it to euphoric. I mean, I think having not only multiple different platforms. When there's good competition and prices go down, everybody benefits. I mean, and it also means that you can do significant genomics research, even in areas of science that don't naturally attract a lot of funding. And that's so valuable. So just pure economic grounds, competition is wonderful.
ERIC GREEN: It drives prices down. It drives innovation. It keeps people on their toes. That's wonderful, but that's not the only reason. And the other thing that I think sometimes gets lost in the conversations, although it certainly will come up when we talk about telomere-to-telomere sequencing, is that every one of these platforms is a little bit different.
ERIC GREEN: And every one of these platforms brings with it new things that you can do. They all have pluses and minuses. Not any one of them is perfect, but the complementarity is powerful. And so it really goes from having a tool belt of just one tool that you throw at a problem, now you can start reaching on your tool belt and do a combination of things.
ERIC GREEN: And then turn to your computational scientists and say, OK, I've got three different data types coming off of three different sequencing instruments. How can you piece them together to make that jigsaw puzzle come together more efficiently and more accurately? No question, if we did not have that set, that suite of different technologies, we would not have the ability to do the kind of sequencing.
ERIC GREEN: We can now do high-accuracy telomere to telomere. So just on scientific grounds, it's exhilarating but then on monetary grounds, I get euphoric because I can all of a sudden now see people that next-gen sequencing was out of reach. Financially, it's getting well within reach.
KEVIN DAVIES: Let's talk about the cost of genome sequencing. I remember watching a grainy video of you and a 100 other genome advocates 21 years ago, 22 years ago at Airlie House. It was one of the retreats you had right after the celebration of the job.
ERIC GREEN: We didn't have HD video back then.
KEVIN DAVIES: You didn't have HD video back then, but what you did do is somebody there coined on a whiteboard the $1,000 genome. That was the first time I could trace back that term and that seemed insane because the price tack for the first genome, of course, had been in the billions. But not only have we reached that particular threshold, we now have companies proclaiming the $200 genome and one potentially saying that a sufficient throughput, you can maybe get it down to 100.
KEVIN DAVIES: And NHGRI has played for many, many years a hugely vital role in catalyzing the development of these new technologies. So first of all, I guess are you pinching yourself that we've got the cost of a human genome down into the low hundreds, and B, how significant is it now that the price is that low?
ERIC GREEN: Yeah, no, I love the story and I even love the way you tell it because you're right. It was like 21 years ago, but it feels like it was just yesterday. First thing is I love the fact that NHGRI gets to take credit for having the chutzpah of putting out the phraseology $1,000 genome at a time when people like you probably thought, what are they drinking? What punch has gotten into them?
KEVIN DAVIES: Yeah, or worse.
ERIC GREEN: Just because you sequenced the first human genome and the Genome Project, just you're getting out of your element, and here's a $1,000 genome. But I think there was this chutzpah-like element to it of throw down an audacious challenge, probably something as crazy as sequencing that first human genome. And I guess, I have to go back then to when I was a postdoc in 1988-1989.
ERIC GREEN: It also seemed unfathomable that we could sequence the human genome in the next couple of decades and, of course, we did. So I think we put out that, and it became a battle cry that I do think people rallied around. Now, I will immediately point out that our institute will take a good amount of credit both for the chutzpah aspect of it, for the visionary leadership, and then we started our technology development program, which continues to the present time, where we just laid out the ability for scientists to bring us crazy ideas.
ERIC GREEN: And then we had a separate announcement for super crazy ideas. And then we even had a separate announcement for ridiculously crazy ideas. And it was staged in that way so people were willing to take risks. And the rest is history on the academic front and those funding fronts, but I would also immediately always like to pause and give credit to the private sector.
ERIC GREEN: I mean, I have to admit I admire tremendously the venture capitalists who are willing to then put in money, some of the bright minds that form companies around some of these earliest ideas. And to me, it's a real credit to how the public effort, funded by the government, in our case our institute, coupled with the private sector, which probably too often gets accused of being too greedy or only profit motive. No, no.
ERIC GREEN: I mean, this was a beautiful partnership where it was very clear. We were doing some very risky things they weren't prepared to do, and that's what we should be doing for. But then they were immediately capitalizing on our developments and licensing those advances and putting boxes together and then new boxes. To me, that public-private partnership all formed around the rallying cry of the $1,000 genome was galvanizing.
ERIC GREEN: It obviously happened far faster than I think anybody anticipated. But I think it's a great story. And in my heavily biased way, I think it's 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 and I'm going to say, all right, we got some competition here.
ERIC GREEN: [INTERPOSING VOICES]
ERIC GREEN: But you why? If that's where we go down in history as being up there in the top few, then I'm also proud of that.
KEVIN DAVIES: Are you still funding ridiculously crazy ideas for novel sequencing technologies.
ERIC GREEN: We've probably-- so I have to admit, we don't have it stratified like that. But we do fund some things where we acknowledge are pretty risky. And the other thing that we do, which is also, I think, very important. And this happened as recently as last week where we do continue to have conversations with these companies and the high-level people at these companies asking, what could we be helpful funding?
ERIC GREEN: What won't you fund? Because again in their R&D effort, they only want to put their development money on things where they can see a very clear path how it will influence their technology platform. And there still is space for they like government funding of innovative ideas and things that maybe are a little far out there. So we modify a little bit what we're asking for and our grantees come in with ideas, and our study sections and our advisory councils help guide that.
ERIC GREEN: So they're not stratified the same way, but we still are doing some stuff that is high risk.
KEVIN DAVIES: One of the flagship successes of your intramural program here, of course, and you touched on it a few minutes ago is the final completion of what people are calling the telomere-to-telomere human genome sequence. I think many people may have assumed that we had the full genome we had all those parties and celebrations and nature papers and science covers and so on.
KEVIN DAVIES: But there was still a number of important gaps in the sequence, which have pretty much now been concluded and wrapped up. We're going to hear from Karen Miga later in the event today. Adam Filippi was one of the key investigators. Why was it so important to complete that project, and what did we learn from it that we perhaps didn't know before?
ERIC GREEN: You're absolutely right. Adam Filippi is one of our wonderfully talented intramural investigators, but of course, the extramural investigators-- Karen Miga, Evan Eichler, and others who, and Michael Schatz who run the telomere-to-telomere consortium. They're all funded with our extramural dollars. So this is all intertwined with our big extramural program, which we call the Human Genome Reference Program, which is all about constantly improving the reference genome for humans.
ERIC GREEN: And that's also a very critical thing about what NHGRI needs to do. But you asked me, what's the significance of it? And we, obviously, last year, when this big splash was made, I worked extensively, not only with those investigators but, in particular, with my communications team of making sure we could tell the story. Not so much of like, well, you're just trying to get a headline again, been there, done that.
ERIC GREEN: No, no, no. There was a great story to tell. I think we did a really good job telling it, and it was reflected by how much media coverage we got on this. And you say why is this so important? And I always give several different answers, but I think they're all important to consider. First thing is if there's ever a genome on this planet that deserves perfection, I think we could be arrogant and just say it's the human genome.
ERIC GREEN: I mean, we could ask some questions about some other genomes and how much effort to go in to find every last base pair. But we deserve the best. I mean, we're humans. We figured this out. And we have to acknowledge, and we did and we were careful about it. And you go back and look at all the press clippings.
ERIC GREEN: I mean, the Genome Project ended because we felt we had done the best we could do at the time with the tools we had available with the human genome sequence, but the wording was essentially complete. The wording was not end-to-end complete. We knew that those darn telomeres and centromeres and complicated genomic regions were not going to be solved. We were not going to read through them with the Sanger-based sequencing methods we had at the time.
ERIC GREEN: And it was rather than just delay, delay, delay the party, we wanted to celebrate and we wanted to move on because we didn't feel we had anything immediately available to solve it. So Genome Project was declared over. Acknowledgment, we're still missing about 8%. And yeah, we tinkered away and we had people who have never given up tinkering away filling gaps and the gap numbers.
ERIC GREEN: But it really did require a new generation of instruments. We talked about that. That's the NGS celebration. It did require a new set of computational tools, recognizing this was not going to be easy even with new technology platforms. It wasn't just going to get spit out. It was going to require innovation and data science and computational biology.
ERIC GREEN: And to be honest with you, it was going to require a new generation of investigators who saw this as a remarkable challenge and brought new ideas to it and a new outlet. And all those fell together. And yes, it took the better part of 18, 19 years to do it, but with the tenaciousness of those folks, and you mentioned some of them. I mean, some of these are young investigators.
ERIC GREEN: They're investing their early careers in this. I think is admirable. And so we got it. Now, why is that important? Well, it turns out, perhaps not surprisingly, that there's important stuff in that 8%. There's genes in that 8%. I mean, leave no gene behind. I mean, again, this is the Human Genome.
ERIC GREEN: We are allowed to be arrogant and say, we want to know everything. We want to know everything about our biology. So we found new genes. I think the second thing is recognize, and we knew this and nobody tells the story better than Evan Eichler over the years. And he was telling us 20 years ago this was the case, is that part of the reason why these regions are so important, these really complicated regions that we can't sequence through them is because they're structurally complicated but that also makes them mischievous.
ERIC GREEN: And sometimes they do things that they shouldn't be doing, that then leads to genetic disease. And there are individuals with health conditions because of rearrangements or things that go on, and we need to understand those reasons. We can't just say, oh, it's too complicated. Now, they're medically important. And so what that means is we are now moving down a path where while it's still expensive to get a telomere-to-telomere genome sequence, no reason to think that that won't become something that might be available diagnostically.
ERIC GREEN: Maybe for $1,000 or less, and maybe it'll take five years. Maybe it'll take 10, whatever. I just think we're putting ourselves now on a trajectory why this research continues to be important, why we continue to support it is we should imagine a day where we can take a patient and we can sequence their entire genome, both sets of chromosomes, telomere to telomere, and have complete insights.
ERIC GREEN: And so I don't know how long that will take, but I think that's the next grand challenge.
KEVIN DAVIES: Just to close the loop on the technology front, a key enablement, as I understand it, was the maturation of long read sequencing technology. Would you just say a bit about that?
ERIC GREEN: Well, I mean, again, when the main next-gen technology that or the first set of them that came out were really effective at getting incredibly inexpensive short reads and short changed, a few bases kind of thing. And they got better and better in different ways. But what was really critically important, especially for reaching across complicated regions where the jigsaw puzzle just gets too challenging to put back together were these long read technologies that could just keep going and going and going and going and going and going.
ERIC GREEN: And even if it didn't do it at high accuracy, if we could get a bunch of them and then we could fix the we could fix the accuracy issues just by having redundancy, it was no longer a regular screwdriver. It was a Phillips head screwdriver. It was a tweezer. I mean, these were completely different tools in the tool kit of a computational biologist putting together a genome sequence.
KEVIN DAVIES: Yeah, reading a lot about the pangenome, I wanted to give you an opportunity to talk a little bit about that and why it's important.
ERIC GREEN: I love to talk about the-- if nothing else, the word because early 2023 or certainly as we go through 2023, there's going to be some major publications in this area. And I think this is going to become part of the language of genomics. The idea of pan is not a totally new idea. That's actually came out during cancer genomics where they started talking about needing to do simulations of lots of genomes of a certain kind of cancer, and they could put it all together.
ERIC GREEN: But a pangenome is basically an attempt to try to take reference sequences or representative or reference sequences from different human populations, and then represent them for the variation that they have amongst themselves. And so that is something that we're really working hard to try to figure out how to represent this and explain this to general public and use it in educational ways. But it's really this idea of representing the diversity of human genomic variation all on a backbone of the human genome reference.
ERIC GREEN: And so that's what a pangenome will be, attempts to represent human diversity in a reference.
KEVIN DAVIES: A couple of questions before we close. We've spent a lot of time in our interview today, Eric, talking about the advances in reading the genome. But over the last 5 or 10 years, there's also been extraordinary advances in editing or correcting the genome. You are a physician by training. I'm curious as to your personal views perhaps as to our new-found ability to perform precision chemistry literally on the double helix.
KEVIN DAVIES: And how do you put that into perspective? And did you ever imagine we'd potentially be seeing patients in the clinic with this new form? It's literally precision medicine.
ERIC GREEN: It really is. So let me first tell about genome editing. But then I want to also tell a story that I think is relevant for my career in some ways, especially as a physician. So first of all, the genome editing is spectacular. We take advantage of those technologies, a lot at the institute, especially in the laboratory because it becomes a very facile laboratory tool for trying to untangle the complexities of genome function.
ERIC GREEN: And of course, we're very interested in possible applications for gene therapy and certainly what we're seeing in sickle cell and some other areas are breathtaking. I can't let the institute take too much credit for it because most of those things are taking place in very disease-specific contexts by the institutes at NIH that tackle those diseases, although we do have intramural investigators who are certainly doing this.
ERIC GREEN: But I'm more of a spectator. A little bit of a funder but more of a spectator. And as a physician or as a human being, I would just say it's overwhelming. And I love sickle cell as the example because remember we talked about earlier that the day the Human Genome Project began, there were 61 rare diseases for which we actually knew what the gene mutation. And sickle cell was one of them and that was 1990.
ERIC GREEN: And I don't feel we brought enough in advances to those patients who have sickle cell. And finally, genetics and genomics is delivering those. And I think we should all applaud it and it's exciting, and I hope this just continues to scale in a very robust way. So I think I regard our Institute more a little bit involved but more as a spectator in those arenas. I will tell you at a very personal level that I trained as a pathologist particularly in laboratory medicine, and my attraction to genomics as a postdoctoral fellow when I was training as a pathologist was this not very well thought through.
ERIC GREEN: But at least enough to get me moving in that direction that, wow, genomics might one day change diagnostic medicine. And so to me, as I started to see the idea of and I could probably-- when the Genome Project began, I could probably could have said some naive things like, well, maybe one day if we actually had the sequence the human genome, we could use that in some way to diagnose somebody with a disease that we didn't know what they had by reading their genome.
ERIC GREEN: I don't think I could have articulated it much better than that. And I don't think if you would have asked me then, will that happen in your lifetime, Eric? I think I would have said, not a chance. I don't even know if we'll get done with a Genome Project. When I look back now and I think of very specific time points, and one of the time points I can't help but point out is shortly after I became director of this institute 13 years ago.
ERIC GREEN: One of the first workshops I held, one of the first things we got involved in was an examination of, should we be doing some research projects in newborn sequencing? And so we did launch. It was one of the very first programs I launched as NHGRI director, and it was then called NSIGHT. And it was a program that looked at both sequencing of healthy newborns, but we had a grant or two of sequencing of acutely ill newborns.
ERIC GREEN: And those were some of the first studies where they looked in the neonatal intensive care unit to demonstrate that if you could do it quick enough, you could save lives because every NICU almost always has a patient where they do not know what's wrong with that child, they have no clue how to treat the child, the baby, and they know because the neonatologists are pretty shrewd about this. They know they've got days before the child will expire.
ERIC GREEN: And that was one of the most successful aspects of that program, was the realization that if you could get it done quick and it has been done 24 hours now. And so to me, the idea that this is now beginning to be done routinely in neonatal intensive care units, not only here in the United States but other places in the world is like, oh, my God, I mean, this is coming full circle.
ERIC GREEN: And of course that's just one venue of the use of genome sequencing in some flavor for diagnostics. But of course, many, many patients routinely now, thousands and thousands of patients every month who have rare conditions either suspected or completely undiagnosed are getting their genome sequenced, and 25%, 30%, 50%, I'm hearing 60% of the time, you can figure out what's wrong with them. That's it.
ERIC GREEN: I mean, that's changing diagnostic medicine in a fashion that I would have never predicted would happen in my life span. Maybe after the Genome Project I said, well, maybe in my lifetime but certainly not in my professional career. And it's here and now and I'm still in my professional career
KEVIN DAVIES: We've been talking about the reducing cost of genome sequencing. We also have the reducing time of whole genome sequencing. We have a Guinness World Record of five hours, I think it is.
ERIC GREEN: And in some medical settings not as critical, but in a setting like a NICU, absolutely critical. And I mean, the fact that that could happen, it's just remarkable. So I will tell, I'm certain that when I write something about my career and looking back, there will be a featured element of never in my professional career did I think I would see that come full circle.
ERIC GREEN: So that now a pathology resident might be involved in interpreting genome sequences as part of their training. I mean that's phenomenal.
KEVIN DAVIES: We're broadcasting The State of Genomics & NGS as you know on February, the 28th. It's the 70th anniversary of the discovery of the double helix in Cambridge. Later on today, we'll have the great Matthew Cobb reflecting on the landmark events of 1953 in great detail. So Eric, in closing, I wondered if you could try to put into perspective, how far you think we've come since we laid eyes on the double helix?
KEVIN DAVIES: And perhaps more importantly, what do you what do we still have to learn about the biology of the genome?
ERIC GREEN: Well, what I would say is 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. And then when the genetic code got elucidated, we figured out part of its language. Of course, now, we know it's just part of the language. So much more language to learn. And then here, we said, now, we could lay out the letters of genomes.
ERIC GREEN: But we have to admit that is still just part of the journey and sure we can, along the way, make advances to take this all the way to patient care. But the big thing we still have to figure out is what is all of the embedded code in these letters. And we absolutely know it's not just the genes. And we absolutely know we're going to be surprised at some mechanisms we're going to learn.
ERIC GREEN: And we absolutely know that some of that is going to be biologically relevant and some of that's going to also be medically relevant, and I think that's what keeps us going. But if I think back on this progression from the double helix to the molecular biology revolution to the genomic era and the Genome Project and where we are now, I think the biggest difference I see is that when I got involved in genomics, in particular, and we saw molecular biology tools come into genomics, it was still very boutique.
ERIC GREEN: I mean, I think we all have to acknowledge the Human Genome Project was completed by a relatively small community of scientists, and it was very boutique. Everybody was watching it and looking around. And even when the Genome Project ended, there was still, well, I guess, I'm interested in genomics. I don't quite know how I'm going to use it. And now, you look at what's going on in 2023, as we celebrate all these incredible anniversaries, I think the one word that comes to mind, which I find very gratifying, is that genomics is now mainstream.
ERIC GREEN: And it's mainstream in all of biomedical research. It's increasingly mainstream as we think about translational research and clinical research. And it is becoming mainstream in medicine, just nooks and crannies right now. But there are enough of them to say absolutely this is absolutely mainstream. And also you're starting to see that it's becoming mainstream in society.
ERIC GREEN: And the reason for that in part is because it's touching health care. And once you touch health care, it's relevant for everybody. But also other aspects, whether it's ancestry or whether it's monitoring the food supply or food chain. Or certainly, we saw how genomics was mainstream during the COVID-19 pandemic, whether it related to diagnostics to be able to track variants in the virus, or tools of genomics were used to develop the vaccine.
ERIC GREEN: So everywhere you look, genomics is mainstream and that's very gratifying too, both because we've seen how far it's come, but we also see what its impact is.
KEVIN DAVIES: Eric Green, that's a brilliant way to kick off The State of Genomics & NGS. Thank you so much.
ERIC GREEN: Well, thanks for coming up and talking. And it's always delightful to spend time with you, Kevin.
KEVIN DAVIES: Well, thanks again to Eric Green for hosting that interview and giving us his time. Our next session is about to begin. It's a presentation from Niall Lennon on lessons learned from sequencing 500,000 human genomes at the Broad Institute. So I'll see you there. [MUSIC PLAYING]
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KEVIN DAVIES: To kick off The State of Genomics & NGS and provide a big picture view of where we are in genomics, we really couldn't think of anyone better than to visit Eric Green, the director of the National Human Genome Research Institute or NHGRI. Eric is a physician-scientist. He joined the NH Genome Center in 1994 and played a leading role in the Human Genome Project. In 2009, he succeeded Francis Collins, becoming the NHGRI's third director.
KEVIN DAVIES: In 2020, Green and his colleagues published in Nature the latest iteration of the NHGRI's strategic vision. We cover a lot of ground in this interview, and I really hope you enjoy the conversation. To kick off The State of Genomics & NGS, we couldn't think of a better place to start than the office of the director of the National Human Genome Research Institute.
KEVIN DAVIES: I'm with Eric Green, the director. Eric, thank you so much for inviting us up to launch this event.
ERIC GREEN: And thanks for coming. We love having home field advantage. We love having you here.
KEVIN DAVIES: And the matching outfit is a nice touch as well.
ERIC GREEN: Yes, and we should tell people that that was deliberate and they'll be really impressed, but it was totally accidental.
KEVIN DAVIES: So the event is called The State of Genomics & NGS, and I imagine in your day job you give a lot of these sorts of State of the Union type addresses to a variety of different audiences around the country and probably overseas as well. 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?
ERIC GREEN: I think I'd frame it with words like exhilarating certainly, but I would immediately follow it with words like challenging. And I don't mean challenging bad. I mean, challenging good. Challenging make you hungry to get to the next stage and tackle things. I mean, genomicists are optimists. Genomicists do audacious things, so we like challenges. But it's also exhilarating because we just have so much to celebrate, so much to look back on, and realize how much has been accomplished.
ERIC GREEN: I think about the State of the Union, if you will, for genomics. It goes across that full spectrum of activities. And every one of the cases, it's exhilarating, but it's also challenging. We think about technology. Next-generation sequencing, these incredible technologies that we've seen. Remarkable, exhilarating, breathtaking.
ERIC GREEN: But all of a sudden, that means for reasonably modest amounts of money, you can generate immense amounts of data. We could sequence many, many genomes, whether they're human genomes or even more of other species genomes when they're smaller. What does that mean? These have got a lot of data. We've now brought upon ourselves, victims of our own success, these massive challenges with respect how to handle data, where to handle data, where to put data, where to analyze data, and now cloud computing is front and center.
ERIC GREEN: Huge challenges we're dealing with. And you think about exhilarating. We have this sequence laid out in front of us, and we now should be able to understand everything about genome function. It's not that simple, right? Huge challenges. Our complexity is not in our gene number. Our complexity is how we use our genes, and that's a language we're still trying to understand and use.
ERIC GREEN: Huge challenge, but we're making progress. And then we think about how do we move from genome function to understanding how variants, differences in our genomes influence that function. That's a whole other set of challenges that we're tackling. But we want to tackle those because as we make progress, we begin to understand how that variation affects our traits. It affects our health. It affects who gets which diseases.
ERIC GREEN: And then you get major advances. Like with rare diseases, we're now nearly 6,000 rare diseases. We know the genomic basis of it, and you don't have to go back that far. Just go back to the day the Human Genome Project began. There were only 61 rare diseases. We knew the gene that was mutated in that disease 61 to 6,000. Exhilarating!
ERIC GREEN: But then you look and you realize, well, yeah, but that's rare diseases. We need to tackle common diseases, and common diseases are far more complicated. Multiple genes are involved. Multiple genomic variants are involved. That's a huge challenge, but we're making progress.
KEVIN DAVIES: Last year, 2022, seemed to be a particularly exciting year. There were new companies coming into the space. You had the complete human genome sequence finally, only took another 20 years but finally laid out. So it must feel particularly exhilarating to be riding the crest of this wave.
ERIC GREEN: Well, and I'm of the belief, of course, that technology pushes all this. I mean technology is the catalytic thing, and you're absolutely right. And the technology not only gives us capabilities at the very basic end of things. All these technologies, by the way, not only read out the sequence so we can to get a lot of information about variation across different human populations.
ERIC GREEN: But all those technologies get adapted with all sorts of clever assays that brilliant genomicists think of to be able to understand genome function, epigenomic marks, different things to understand about gene expression, so on and so forth. So you learn a lot about the biology. You can adapt it all to start to figure out variation. And then that brings you in the realm of actually having these insights.
ERIC GREEN: And of course, when it's gotten cheap enough and the insights are there, it allows us to start to use these for medical applications, which, as a physician scientist, of course, then comes full circle and allows us to start to use these tools that we once thought were just going to be for scientists to actually be used as part of health care. Of course, that's exhilarating, but it's challenging. Why?
ERIC GREEN: Because health care is challenging. And every health care ecosystem in any country of this world is now facing the challenges of how do we bring genomics into health care for everyone in an equitable fashion and how do we change routine practice, which is never easy no matter what the nook or cranny of medicine is it's always difficult to change things.
KEVIN DAVIES: That's a nice segue to my next question. I wanted to talk about diversity. The H3Africa project was a very important initiative that has recently concluded. How would you put that into perspective? How are you building upon it? And perhaps you could talk more broadly about the need to expand and improve the diversity in the future of human genomic analysis.
ERIC GREEN: Yeah, so let's break diversity down into a couple dimensions because they're all important. They all interrelate. Let me get to H3Africa in a minute. I mean, let's just first talk about just diversity in general. We are playing catch-up in genetics and genomics, and that some of our earliest efforts just happened to involve lots and lots of samples from individuals of European descent.
ERIC GREEN: And that's just not adequate at both for scientific reasons and for social reasons. And so we need to improve 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. And we're doing that in the United States, but I think the world community of genomicists are helping us. And I think we've improved this significantly, and there's some challenges with that, but there's lots of progress.
ERIC GREEN: And I think that's a fixable problem. Then there, of course, is the issue of the diversity of our workforce and the diversity of our community. And again, many dimensions of that, whether you're just looking at United States or you're looking globally. But certainly, we want genomics to benefit all of humankind in all countries.
ERIC GREEN: And we don't want to do this by providing this from the United States. We want to have this right there locally and for eventually using genomics as part of medicine. And you look across the world as we've done and we say, what can we do to help? What could we do to facilitate? And Africa was one of the areas that we and the Wellcome Trust viewed would be an opportunity for us to be helpful.
ERIC GREEN: So we got together, the NIH through our common fund. And I should point out NHGRI contributed significantly to H3Africa as an institute, but we helped colead it on behalf of NIH, on behalf of the whole program. And we put some of our own funds, but the main funds out of the NIH came out of the NIH common fund and the Wellcome Trust partnered with us, and so as did the African Society of Human Genetics.
ERIC GREEN: And this started a little over 10 years ago. This was a project I got involved with very early on in partnership with Francis Collins who was then NIH director and Charles Rotimi who was then an investigator in our intramural program. Actually, most recently, has been appointed to be the director of our intramural program. And working with the Wellcome Trust and the African Society of Human Genetics, we launched this project in Africa.
ERIC GREEN: And the key aspect of H3Africa, it was not about studying African genomes and not about just studying diseases that are relevant to Africa. It was about empowering the scientific enterprise in Africa, the scientists and the institutions to do genomics so that they could do those studies and eventually could see the fruits of genomics find its way into health care. It was very much about capacity building.
ERIC GREEN: And it was not about dropping in Africa, getting a bunch of DNA samples, flying back to Boston or New York, or Houston and analyze them. No, no, that was not. It was about empowering, and so we learned a lot. And we're using some of those. This is where it comes full circle. One of the things we learned, and it relates to what I said earlier is the huge-- one of many grand challenges in genomics now is data analysis.
ERIC GREEN: Generating the data has actually gotten pretty straightforward. But data analysis, especially with cloud computing, is very democratizing because all people need to do is get access to the data. They don't need a big fancy laboratory. In some case, they just need a laptop. One of the things we learned about in H3Africa was to prioritize the development of networks of computational and data scientists because as happened in Africa where they realized they didn't want to develop a lot of landlines for telephones.
ERIC GREEN: They were able to leapfrog it by going immediately to cell phones, and so that actually empowered communication in Africa. Similarly, one of the big areas of emphasis when we stood up H3Africa was something called H3ABioNet, which is basically a network of computational scientists. And that has really been key and pivotal for some of the major advances we've seen over the 10 years of the H3Africa program.
ERIC GREEN: In addition to that, longer term, we've been working with governments and other international organizations to sustain this because H3Africa has come to its end of its funding under that name. And now, various things are blossoming up that will be other projects that will carry it on. But it's in a very different place now than what it was before.
ERIC GREEN: And then one of the lessons we learned from that is you don't need a big fancy laboratory to do cutting edge genomics. You need to empower data scientists and provide them the tools to help us lift all these complicated studies in data analysis. And so even here in the United States, we're trying to now facilitate. Let's get lots of other institutions doing genomic science by emphasizing data science because maybe their institution doesn't have the kind of laboratory infrastructure for having a lot of fancy laboratory work in sequencing instruments, but we've got plenty to engage these people just by having them have access to this data and become very productive, cutting-edge scientists in the data science realm.
ERIC GREEN: That will help also diversify our workforce, which is a very big priority for the institute we need the entire genomics workforce to start resembling society here in the US and society around the world. And that'll be very important.
KEVIN DAVIES: Excellent. Let's pivot a little bit to talk about the state of NGS. For many years, it seemed we had a major short read platform and a couple of important long read platforms. We'll talk about those in a second. But over the last 12 months or so, we've had a relative glut of new entrants coming into the field. So users, some of your fundees now have a wealth of choices that they didn't have perhaps 12 or 24 months ago. How significant would you say is this new wealth of choice that customers and researchers have?
ERIC GREEN: I might even modify my exhilarating word and change it to euphoric. I mean, I think having not only multiple different platforms. When there's good competition and prices go down, everybody benefits. I mean, and it also means that you can do significant genomics research, even in areas of science that don't naturally attract a lot of funding. And that's so valuable. So just pure economic grounds, competition is wonderful.
ERIC GREEN: It drives prices down. It drives innovation. It keeps people on their toes. That's wonderful, but that's not the only reason. And the other thing that I think sometimes gets lost in the conversations, although it certainly will come up when we talk about telomere-to-telomere sequencing, is that every one of these platforms is a little bit different.
ERIC GREEN: And every one of these platforms brings with it new things that you can do. They all have pluses and minuses. Not any one of them is perfect, but the complementarity is powerful. And so it really goes from having a tool belt of just one tool that you throw at a problem, now you can start reaching on your tool belt and do a combination of things.
ERIC GREEN: And then turn to your computational scientists and say, OK, I've got three different data types coming off of three different sequencing instruments. How can you piece them together to make that jigsaw puzzle come together more efficiently and more accurately? No question, if we did not have that set, that suite of different technologies, we would not have the ability to do the kind of sequencing.
ERIC GREEN: We can now do high-accuracy telomere to telomere. So just on scientific grounds, it's exhilarating but then on monetary grounds, I get euphoric because I can all of a sudden now see people that next-gen sequencing was out of reach. Financially, it's getting well within reach.
KEVIN DAVIES: Let's talk about the cost of genome sequencing. I remember watching a grainy video of you and a 100 other genome advocates 21 years ago, 22 years ago at Airlie House. It was one of the retreats you had right after the celebration of the job.
ERIC GREEN: We didn't have HD video back then.
KEVIN DAVIES: You didn't have HD video back then, but what you did do is somebody there coined on a whiteboard the $1,000 genome. That was the first time I could trace back that term and that seemed insane because the price tack for the first genome, of course, had been in the billions. But not only have we reached that particular threshold, we now have companies proclaiming the $200 genome and one potentially saying that a sufficient throughput, you can maybe get it down to 100.
KEVIN DAVIES: And NHGRI has played for many, many years a hugely vital role in catalyzing the development of these new technologies. So first of all, I guess are you pinching yourself that we've got the cost of a human genome down into the low hundreds, and B, how significant is it now that the price is that low?
ERIC GREEN: Yeah, no, I love the story and I even love the way you tell it because you're right. It was like 21 years ago, but it feels like it was just yesterday. First thing is I love the fact that NHGRI gets to take credit for having the chutzpah of putting out the phraseology $1,000 genome at a time when people like you probably thought, what are they drinking? What punch has gotten into them?
KEVIN DAVIES: Yeah, or worse.
ERIC GREEN: Just because you sequenced the first human genome and the Genome Project, just you're getting out of your element, and here's a $1,000 genome. But I think there was this chutzpah-like element to it of throw down an audacious challenge, probably something as crazy as sequencing that first human genome. And I guess, I have to go back then to when I was a postdoc in 1988-1989.
ERIC GREEN: It also seemed unfathomable that we could sequence the human genome in the next couple of decades and, of course, we did. So I think we put out that, and it became a battle cry that I do think people rallied around. Now, I will immediately point out that our institute will take a good amount of credit both for the chutzpah aspect of it, for the visionary leadership, and then we started our technology development program, which continues to the present time, where we just laid out the ability for scientists to bring us crazy ideas.
ERIC GREEN: And then we had a separate announcement for super crazy ideas. And then we even had a separate announcement for ridiculously crazy ideas. And it was staged in that way so people were willing to take risks. And the rest is history on the academic front and those funding fronts, but I would also immediately always like to pause and give credit to the private sector.
ERIC GREEN: I mean, I have to admit I admire tremendously the venture capitalists who are willing to then put in money, some of the bright minds that form companies around some of these earliest ideas. And to me, it's a real credit to how the public effort, funded by the government, in our case our institute, coupled with the private sector, which probably too often gets accused of being too greedy or only profit motive. No, no.
ERIC GREEN: I mean, this was a beautiful partnership where it was very clear. We were doing some very risky things they weren't prepared to do, and that's what we should be doing for. But then they were immediately capitalizing on our developments and licensing those advances and putting boxes together and then new boxes. To me, that public-private partnership all formed around the rallying cry of the $1,000 genome was galvanizing.
ERIC GREEN: It obviously happened far faster than I think anybody anticipated. But I think it's a great story. And in my heavily biased way, I think it's 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 and I'm going to say, all right, we got some competition here.
ERIC GREEN: [INTERPOSING VOICES]
ERIC GREEN: But you why? If that's where we go down in history as being up there in the top few, then I'm also proud of that.
KEVIN DAVIES: Are you still funding ridiculously crazy ideas for novel sequencing technologies.
ERIC GREEN: We've probably-- so I have to admit, we don't have it stratified like that. But we do fund some things where we acknowledge are pretty risky. And the other thing that we do, which is also, I think, very important. And this happened as recently as last week where we do continue to have conversations with these companies and the high-level people at these companies asking, what could we be helpful funding?
ERIC GREEN: What won't you fund? Because again in their R&D effort, they only want to put their development money on things where they can see a very clear path how it will influence their technology platform. And there still is space for they like government funding of innovative ideas and things that maybe are a little far out there. So we modify a little bit what we're asking for and our grantees come in with ideas, and our study sections and our advisory councils help guide that.
ERIC GREEN: So they're not stratified the same way, but we still are doing some stuff that is high risk.
KEVIN DAVIES: One of the flagship successes of your intramural program here, of course, and you touched on it a few minutes ago is the final completion of what people are calling the telomere-to-telomere human genome sequence. I think many people may have assumed that we had the full genome we had all those parties and celebrations and nature papers and science covers and so on.
KEVIN DAVIES: But there was still a number of important gaps in the sequence, which have pretty much now been concluded and wrapped up. We're going to hear from Karen Miga later in the event today. Adam Filippi was one of the key investigators. Why was it so important to complete that project, and what did we learn from it that we perhaps didn't know before?
ERIC GREEN: You're absolutely right. Adam Filippi is one of our wonderfully talented intramural investigators, but of course, the extramural investigators-- Karen Miga, Evan Eichler, and others who, and Michael Schatz who run the telomere-to-telomere consortium. They're all funded with our extramural dollars. So this is all intertwined with our big extramural program, which we call the Human Genome Reference Program, which is all about constantly improving the reference genome for humans.
ERIC GREEN: And that's also a very critical thing about what NHGRI needs to do. But you asked me, what's the significance of it? And we, obviously, last year, when this big splash was made, I worked extensively, not only with those investigators but, in particular, with my communications team of making sure we could tell the story. Not so much of like, well, you're just trying to get a headline again, been there, done that.
ERIC GREEN: No, no, no. There was a great story to tell. I think we did a really good job telling it, and it was reflected by how much media coverage we got on this. And you say why is this so important? And I always give several different answers, but I think they're all important to consider. First thing is if there's ever a genome on this planet that deserves perfection, I think we could be arrogant and just say it's the human genome.
ERIC GREEN: I mean, we could ask some questions about some other genomes and how much effort to go in to find every last base pair. But we deserve the best. I mean, we're humans. We figured this out. And we have to acknowledge, and we did and we were careful about it. And you go back and look at all the press clippings.
ERIC GREEN: I mean, the Genome Project ended because we felt we had done the best we could do at the time with the tools we had available with the human genome sequence, but the wording was essentially complete. The wording was not end-to-end complete. We knew that those darn telomeres and centromeres and complicated genomic regions were not going to be solved. We were not going to read through them with the Sanger-based sequencing methods we had at the time.
ERIC GREEN: And it was rather than just delay, delay, delay the party, we wanted to celebrate and we wanted to move on because we didn't feel we had anything immediately available to solve it. So Genome Project was declared over. Acknowledgment, we're still missing about 8%. And yeah, we tinkered away and we had people who have never given up tinkering away filling gaps and the gap numbers.
ERIC GREEN: But it really did require a new generation of instruments. We talked about that. That's the NGS celebration. It did require a new set of computational tools, recognizing this was not going to be easy even with new technology platforms. It wasn't just going to get spit out. It was going to require innovation and data science and computational biology.
ERIC GREEN: And to be honest with you, it was going to require a new generation of investigators who saw this as a remarkable challenge and brought new ideas to it and a new outlet. And all those fell together. And yes, it took the better part of 18, 19 years to do it, but with the tenaciousness of those folks, and you mentioned some of them. I mean, some of these are young investigators.
ERIC GREEN: They're investing their early careers in this. I think is admirable. And so we got it. Now, why is that important? Well, it turns out, perhaps not surprisingly, that there's important stuff in that 8%. There's genes in that 8%. I mean, leave no gene behind. I mean, again, this is the Human Genome.
ERIC GREEN: We are allowed to be arrogant and say, we want to know everything. We want to know everything about our biology. So we found new genes. I think the second thing is recognize, and we knew this and nobody tells the story better than Evan Eichler over the years. And he was telling us 20 years ago this was the case, is that part of the reason why these regions are so important, these really complicated regions that we can't sequence through them is because they're structurally complicated but that also makes them mischievous.
ERIC GREEN: And sometimes they do things that they shouldn't be doing, that then leads to genetic disease. And there are individuals with health conditions because of rearrangements or things that go on, and we need to understand those reasons. We can't just say, oh, it's too complicated. Now, they're medically important. And so what that means is we are now moving down a path where while it's still expensive to get a telomere-to-telomere genome sequence, no reason to think that that won't become something that might be available diagnostically.
ERIC GREEN: Maybe for $1,000 or less, and maybe it'll take five years. Maybe it'll take 10, whatever. I just think we're putting ourselves now on a trajectory why this research continues to be important, why we continue to support it is we should imagine a day where we can take a patient and we can sequence their entire genome, both sets of chromosomes, telomere to telomere, and have complete insights.
ERIC GREEN: And so I don't know how long that will take, but I think that's the next grand challenge.
KEVIN DAVIES: Just to close the loop on the technology front, a key enablement, as I understand it, was the maturation of long read sequencing technology. Would you just say a bit about that?
ERIC GREEN: Well, I mean, again, when the main next-gen technology that or the first set of them that came out were really effective at getting incredibly inexpensive short reads and short changed, a few bases kind of thing. And they got better and better in different ways. But what was really critically important, especially for reaching across complicated regions where the jigsaw puzzle just gets too challenging to put back together were these long read technologies that could just keep going and going and going and going and going and going.
ERIC GREEN: And even if it didn't do it at high accuracy, if we could get a bunch of them and then we could fix the we could fix the accuracy issues just by having redundancy, it was no longer a regular screwdriver. It was a Phillips head screwdriver. It was a tweezer. I mean, these were completely different tools in the tool kit of a computational biologist putting together a genome sequence.
KEVIN DAVIES: Yeah, reading a lot about the pangenome, I wanted to give you an opportunity to talk a little bit about that and why it's important.
ERIC GREEN: I love to talk about the-- if nothing else, the word because early 2023 or certainly as we go through 2023, there's going to be some major publications in this area. And I think this is going to become part of the language of genomics. The idea of pan is not a totally new idea. That's actually came out during cancer genomics where they started talking about needing to do simulations of lots of genomes of a certain kind of cancer, and they could put it all together.
ERIC GREEN: But a pangenome is basically an attempt to try to take reference sequences or representative or reference sequences from different human populations, and then represent them for the variation that they have amongst themselves. And so that is something that we're really working hard to try to figure out how to represent this and explain this to general public and use it in educational ways. But it's really this idea of representing the diversity of human genomic variation all on a backbone of the human genome reference.
ERIC GREEN: And so that's what a pangenome will be, attempts to represent human diversity in a reference.
KEVIN DAVIES: A couple of questions before we close. We've spent a lot of time in our interview today, Eric, talking about the advances in reading the genome. But over the last 5 or 10 years, there's also been extraordinary advances in editing or correcting the genome. You are a physician by training. I'm curious as to your personal views perhaps as to our new-found ability to perform precision chemistry literally on the double helix.
KEVIN DAVIES: And how do you put that into perspective? And did you ever imagine we'd potentially be seeing patients in the clinic with this new form? It's literally precision medicine.
ERIC GREEN: It really is. So let me first tell about genome editing. But then I want to also tell a story that I think is relevant for my career in some ways, especially as a physician. So first of all, the genome editing is spectacular. We take advantage of those technologies, a lot at the institute, especially in the laboratory because it becomes a very facile laboratory tool for trying to untangle the complexities of genome function.
ERIC GREEN: And of course, we're very interested in possible applications for gene therapy and certainly what we're seeing in sickle cell and some other areas are breathtaking. I can't let the institute take too much credit for it because most of those things are taking place in very disease-specific contexts by the institutes at NIH that tackle those diseases, although we do have intramural investigators who are certainly doing this.
ERIC GREEN: But I'm more of a spectator. A little bit of a funder but more of a spectator. And as a physician or as a human being, I would just say it's overwhelming. And I love sickle cell as the example because remember we talked about earlier that the day the Human Genome Project began, there were 61 rare diseases for which we actually knew what the gene mutation. And sickle cell was one of them and that was 1990.
ERIC GREEN: And I don't feel we brought enough in advances to those patients who have sickle cell. And finally, genetics and genomics is delivering those. And I think we should all applaud it and it's exciting, and I hope this just continues to scale in a very robust way. So I think I regard our Institute more a little bit involved but more as a spectator in those arenas. I will tell you at a very personal level that I trained as a pathologist particularly in laboratory medicine, and my attraction to genomics as a postdoctoral fellow when I was training as a pathologist was this not very well thought through.
ERIC GREEN: But at least enough to get me moving in that direction that, wow, genomics might one day change diagnostic medicine. And so to me, as I started to see the idea of and I could probably-- when the Genome Project began, I could probably could have said some naive things like, well, maybe one day if we actually had the sequence the human genome, we could use that in some way to diagnose somebody with a disease that we didn't know what they had by reading their genome.
ERIC GREEN: I don't think I could have articulated it much better than that. And I don't think if you would have asked me then, will that happen in your lifetime, Eric? I think I would have said, not a chance. I don't even know if we'll get done with a Genome Project. When I look back now and I think of very specific time points, and one of the time points I can't help but point out is shortly after I became director of this institute 13 years ago.
ERIC GREEN: One of the first workshops I held, one of the first things we got involved in was an examination of, should we be doing some research projects in newborn sequencing? And so we did launch. It was one of the very first programs I launched as NHGRI director, and it was then called NSIGHT. And it was a program that looked at both sequencing of healthy newborns, but we had a grant or two of sequencing of acutely ill newborns.
ERIC GREEN: And those were some of the first studies where they looked in the neonatal intensive care unit to demonstrate that if you could do it quick enough, you could save lives because every NICU almost always has a patient where they do not know what's wrong with that child, they have no clue how to treat the child, the baby, and they know because the neonatologists are pretty shrewd about this. They know they've got days before the child will expire.
ERIC GREEN: And that was one of the most successful aspects of that program, was the realization that if you could get it done quick and it has been done 24 hours now. And so to me, the idea that this is now beginning to be done routinely in neonatal intensive care units, not only here in the United States but other places in the world is like, oh, my God, I mean, this is coming full circle.
ERIC GREEN: And of course that's just one venue of the use of genome sequencing in some flavor for diagnostics. But of course, many, many patients routinely now, thousands and thousands of patients every month who have rare conditions either suspected or completely undiagnosed are getting their genome sequenced, and 25%, 30%, 50%, I'm hearing 60% of the time, you can figure out what's wrong with them. That's it.
ERIC GREEN: I mean, that's changing diagnostic medicine in a fashion that I would have never predicted would happen in my life span. Maybe after the Genome Project I said, well, maybe in my lifetime but certainly not in my professional career. And it's here and now and I'm still in my professional career
KEVIN DAVIES: We've been talking about the reducing cost of genome sequencing. We also have the reducing time of whole genome sequencing. We have a Guinness World Record of five hours, I think it is.
ERIC GREEN: And in some medical settings not as critical, but in a setting like a NICU, absolutely critical. And I mean, the fact that that could happen, it's just remarkable. So I will tell, I'm certain that when I write something about my career and looking back, there will be a featured element of never in my professional career did I think I would see that come full circle.
ERIC GREEN: So that now a pathology resident might be involved in interpreting genome sequences as part of their training. I mean that's phenomenal.
KEVIN DAVIES: We're broadcasting The State of Genomics & NGS as you know on February, the 28th. It's the 70th anniversary of the discovery of the double helix in Cambridge. Later on today, we'll have the great Matthew Cobb reflecting on the landmark events of 1953 in great detail. So Eric, in closing, I wondered if you could try to put into perspective, how far you think we've come since we laid eyes on the double helix?
KEVIN DAVIES: And perhaps more importantly, what do you what do we still have to learn about the biology of the genome?
ERIC GREEN: Well, what I would say is 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. And then when the genetic code got elucidated, we figured out part of its language. Of course, now, we know it's just part of the language. So much more language to learn. And then here, we said, now, we could lay out the letters of genomes.
ERIC GREEN: But we have to admit that is still just part of the journey and sure we can, along the way, make advances to take this all the way to patient care. But the big thing we still have to figure out is what is all of the embedded code in these letters. And we absolutely know it's not just the genes. And we absolutely know we're going to be surprised at some mechanisms we're going to learn.
ERIC GREEN: And we absolutely know that some of that is going to be biologically relevant and some of that's going to also be medically relevant, and I think that's what keeps us going. But if I think back on this progression from the double helix to the molecular biology revolution to the genomic era and the Genome Project and where we are now, I think the biggest difference I see is that when I got involved in genomics, in particular, and we saw molecular biology tools come into genomics, it was still very boutique.
ERIC GREEN: I mean, I think we all have to acknowledge the Human Genome Project was completed by a relatively small community of scientists, and it was very boutique. Everybody was watching it and looking around. And even when the Genome Project ended, there was still, well, I guess, I'm interested in genomics. I don't quite know how I'm going to use it. And now, you look at what's going on in 2023, as we celebrate all these incredible anniversaries, I think the one word that comes to mind, which I find very gratifying, is that genomics is now mainstream.
ERIC GREEN: And it's mainstream in all of biomedical research. It's increasingly mainstream as we think about translational research and clinical research. And it is becoming mainstream in medicine, just nooks and crannies right now. But there are enough of them to say absolutely this is absolutely mainstream. And also you're starting to see that it's becoming mainstream in society.
ERIC GREEN: And the reason for that in part is because it's touching health care. And once you touch health care, it's relevant for everybody. But also other aspects, whether it's ancestry or whether it's monitoring the food supply or food chain. Or certainly, we saw how genomics was mainstream during the COVID-19 pandemic, whether it related to diagnostics to be able to track variants in the virus, or tools of genomics were used to develop the vaccine.
ERIC GREEN: So everywhere you look, genomics is mainstream and that's very gratifying too, both because we've seen how far it's come, but we also see what its impact is.
KEVIN DAVIES: Eric Green, that's a brilliant way to kick off The State of Genomics & NGS. Thank you so much.
ERIC GREEN: Well, thanks for coming up and talking. And it's always delightful to spend time with you, Kevin.
KEVIN DAVIES: Well, thanks again to Eric Green for hosting that interview and giving us his time. Our next session is about to begin. It's a presentation from Niall Lennon on lessons learned from sequencing 500,000 human genomes at the Broad Institute. So I'll see you there. [MUSIC PLAYING]
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