S3.22 The Past, Present and Future of the Human Genome Project
Kat: Hello, and welcome to Genetics Unzipped - the Genetics Society podcast, with me, Dr Kat Arney. In this episode we bring you an in-depth interview with Dr Eric Green, director of the US National Human Genome Research Institute and one of the key instigators of the Human Genome Project, to talk about the past, present and future of human genomics.
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Thirty years ago this month saw the birth of one of the most audacious research programmes in biology: The Human Genome Project, an ambitious plan to read the DNA sequence of the entire human genome (or as much of it as was technically feasible at the time). The idea was met with much criticism. Some thought the project was simply too vast and challenging to succeed, others saw it as little more than biological stamp-collecting, while sceptics couldn’t see how sequencing the human genome would be useful, and declared it a massive waste of money.
Ten years later, in June 2000 - after billions of dollars, countless hours of DNA sequencing, and a huge amount of effort from an international collaboration from 20 institutions in six countries - the first draft of the Human Genome was unveiled with a fancy event at the White House and a huge amount of media attention. The project officially came to an end in 2003 with the publication of an updated reference genome. And here we are today, twenty years on from that first announcement, with many thousands of human genomes sequenced, revealing in-depth knowledge about health, disease and human biology, with the benefits of genomics starting to filter into mainstream medicine.
Back in the summer I was lucky enough to sit down - virtually, of course - with Professor Sir Mike Stratton, director of the Wellcome Sanger Institute where the UK’s efforts in the project were focused, to chat about his perspective on the project as part of the Sanger’s Genome Lates series dedicated to the anniversary.
For this podcast we’re heading across the pond to speak with one of the key figures on the US side of the Human Genome project: Dr Eric Green, who has seen it through from its inception through to the published sequence and into what’s now the fully-fledged field of human genomics. Today, he’s the director of the US National Human Genome Research Institute, and a leading light in the world of genes, genomes and genome sequencing. I called him up to chat about the past, present and future of the human genome - starting by going all the way back to the beginning of the Human Genome Project.
Eric: I vividly remember many aspects of it, and keep in mind that it's not even just the origins of the Human Genome Project, it really is the origins of the field of genomics. Even the word genomics, which did not exist until 1987. That's when the word was actually coined - it first appeared in the scientific literature for the very first time in a brand new journal that was actually called genomics. And you could ask the question why in 1987, why in the late 1980s, was there a need to name a new field and to contemplate a big international audacious project that eventually became the Human Genome Project. And I would say it followed out a number of developments that took place over decades, actually of the previous century, you know, starting with the discovery of the double helical structure of DNA in the 1950s, the elucidation of the genetic code in the 1960s.
Eric: And then if you fast forward to the late 1970s and early 1980s, that's when the tools of molecular biology really took hold, that our methods for isolating DNA, for cloning DNA, for manipulating DNA and importantly, reading DNA for actually sequencing DNA and all of those tools and technologies, we're just finding wide use across the biomedical research landscape. To the point that people realize these are getting better and better, and might it make sense at some point, instead of trying to study human DNA one gene at a time to actually study all of it, to study the whole human genome and the idea of being comprehensive of taking a comprehensive view of an organism's DNA, which is its genome, is what gave rise to the birth of the field of genomics.
Kat: So there's a couple of questions that I have that come out of that. So one is the idea of the Human Genome Project - was the decision about, well, whose human genome do you start with, what do you mean by the human genome? And then also presumably, you know, to someone like me or you who are big fans of this, this seems like a no brainer. It's like, yeah, this is a big ambitious project. It's a tough project, but it's doable. But presumably there must have been some criticisms at the time. So, you know, what were the challenges particularly about deciding which genome to do, and then what people thought about this idea.
Eric: So to be honest with you, the notion of whose genome were we going to sequence was really not the question of the day. And let's put that aside, because I've a very funny story to tell you about that. When the Human Genome Project began, there was not significant attention to whose genome are we going to sequence anyway, that came later. But the other part of your question really relates to what was the thought of the day. And I would say that on the one hand, there was incredible enthusiasm about this idea of genomics and these new tools that were being developed for studying DNA, perhaps at a comprehensive level, and also the idea of a big organized project, by some. But there were detractors at the time in particular, and there were very prominent scientists who not only were opposed to the project, but actually, you know, counseled young scientists like me to stay away from it, that this was no place for somebody who wants to be a successful biomedical researcher.
Eric: And I think there was a lot of concerns. I think some of the concerns were that it wasn't intellectual enough, some people even joked that this was work that was more suitable for prisoners than for researchers. I think there was concerns about it being a big project and being big science and team science that, you know, worked well for Apollo missions, that worked well in physics and chemistry, but you know, biomedical researchers up until that point, never did big science projects. They were just unheard of. And I think that it was sort of viewed as not the right thing to do in the culture of biomedical research. Some of it was concerns that it would suck money away from individual investigators getting research dollars. And then some people believed it wasn't going to be useful. Some people believe it wasn't going to be successful. I mean, I think you saw many different negative attitudes, but I think by and large the majority, but it was a slim majority, I think were in favor of it. And that made it challenging at times because especially as somebody who was trying to build a career early on for myself, you know, there were detractors who really, weren't quite sure this was the right thing for someone like me to be pursuing.
Kat: And you did say that you do have a story about how you decided which genome to do when you actually got to it. So, tell me about that. So what was the first human genome?
Eric: I think when the genome project first got out of the gates, there was a recognition that someday some decisions would have to be made about whose genome we were actually going to sequence or how those choices were going to be made. But remember the project began at an initial phase that had really nothing to do with sequencing. It was not mapping, it was just about getting organized. And so there was just mostly a focus on getting maps constructed. And so for that, it really didn't seem as critical. And in fact, people were just using DNA libraries that were available, clone DNA. When I say library, I mean clones of DNA, big pieces of DNA, medium pieces of DNA. A lot of times, to be honest with you back then, the way some of these libraries were made would not be allowed now where either the investigator who knew how to make the library would draw their own blood to make the library from their data or else, sometimes the joke would be whoever the slowest member of the lab was, would be the one who would actually get a needle put in their arm to give the blood sample.
Eric: You know, in today's light, we would never do research that way. We would have much more of a consent process and so forth, but it was actually interesting that some of the greatest libraries of the day were made from the investigator whose hands were so good at the bench that they could make good libraries, but nobody thought much about it because this was just these very preliminary maps that would be used as a backbone for eventually doing the sequencing. One funny story that came out of it, I vividly remember at one of many strategy meetings that we had, that we were getting further and further into the project, to the point where there did need to be some decisions about what libraries were going to be made that might ultimately have clones in them that were going to be sequenced as part of the Human Genome Project.
Eric: So we had a big room of people and everyone's sort of talking about what are the characteristics for selecting the right person and how are you going to do all this and all the logistics. And literally somebody raised their hand and they said, "well, whatever we do, whoever gets picked to have their genome sequence as part of the Human Genome Project, that person better be normal." And then of course, we all looked around the room and wondered who is normal anyway? And how would you define normal? But it was sort of an odd comment that made us all sort of think for a second, what really that meant. No decisions were made then - at the end of the day, I think it's a little over half of the human genome sequence generated by the Human Genome Project was generated from one person.
Eric: The rest of it is a mosaic of lots of people. It is just a patchwork. That was what was produced because it came from clones from multiple different libraries made in multiple different places. But the majority of the clones came from one library that was deliberately made by the person with the best hands for making this kind of cloned library. It was called the bacterial artificial chromosome clone or BAC clones. And he happened to work at Roswell park cancer center, which is in Buffalo, New York. And so it turns out that that when they actually went to decide to make the DNA that was going to be used for making these BAC clones that were going to be used for sequencing the human genome, literally they placed an ad in a local newspaper for people to come in and be blood donors, and they collected a whole bunch of people who all consented to do this. And one of them got picked at random and that represents about half of the reference sequence that came out of the human genome project. So when you asked me whose genome got sequenced by the human genome project, it wasn't one person, but over half of it or so was just a blood donor in Buffalo, New York.
Kat: I did not know that, that is an amazing story. I'm intrigued about how this actually worked when you did get to the sequencing. Because you've talked about how these, these bacterial artificial chromosomes, these big libraries, we used to map out the genome. So to kind of work out what bits go where, and you know, what genes are probably where in what order. So when you start doing the sequencing, you can kind of slot the details in, but when it came to the actual sequencing, what was it like, what was it like to be working on a day to day basis doing this?
Eric: Well, keep in mind that the strategy that we started with on day one of the genome project evolves over time, o that by the very end, we were modifying that considerably to sort of complete the task. And of course, you know, looking back now three decades, because we are now this year celebrating the 30th anniversary of the launch of the Human Genome Project, I mean, it's almost laughable the way we started, but it was absolutely the only way to get going. And the way we started was by dividing up the genome chromosome by chromosome and different groups were responsible for different chromosomes. So my lab, where my big contribution to the Human Genome Project was making a map of human chromosome seven, other centers, other investigators, picked different chromosomes. It was all driven by these clones, which were going to be the key substrates for putting these maps together, that ultimately would provide the organizational framework for actually reading out all the letters of each chromosome and of the whole genome.
Kat: I'm intruiged about how the technology changed, even within the progress of the human genome. Because one of the things I discovered when I was researching my first book, Herding Hemingway's Cats, which is all about how our genes work and our genomes, was that I am as old as Sanger sequencing. So Fred Sanger's first method for DNA sequencing was published the year that I was born. And then when I did my undergraduate projects, I was actually working at the Sanger Institute and the Human Genome Mapping Project. So by that point, this was sort of early 2000s and seeing all the sequences come off of these little fluorescent bars and all this kind of stuff. And even just within my own lifetime and my own scientific lifetime, seeing how this has changed. So how was the acceleration of the technology through the project?
Eric: When the genome project got out of the gates in 1990, the absolute attitude was we will map the human genome and only map the human genome until revolutionary new sequencing technologies are available to even contemplate sequencing the human genome. And it was very, very strongly believed by most at the time that Sanger method or Maxam-Gilbert method or any of these other methods that were available at the time to limp us along were never going to be the methods that were going to be used for sequencing the human genome. Now funds were given to sequence smaller model organisms - yeast, bacteria, flies, worms - and those projects used Sanger sequencing. But again, they were test beds for just seeing how far Sanger sequencing could be pushed, for example. But the word on the street and in the project was we will wait to sequence the human genome when we have all new revolutionary DNA sequencing methods.
Eric: Well, what happened in those pilot projects was that they really evolutionarily improved Sanger based sequencing one step at a time, one improvement at a time, one evolutionary lunge at a time. And what happened was over a series of years, one evolutionary improvement after another eventually got to the point that Sanger sequencing with automation and various other machinery that came on board because the companies were being very good at developing better and better hardware. You almost had a mini revolution of that method, enough of a revolution that you could apply it to sequencing the human genome. And so, it really was by about the mid-point of the genome project, when people started to be converted, they said, you know what? We not only don't have a revolutionary new method yet. We don't need it. We have enough of evolutionary improvement of existing DNA sequencing methods that we can just push the accelerator, push it really hard, and maybe we can get the sequence out.
Kat: Did it actually feel like to be involved at the start? What was the atmosphere and the vibe at the time?
Eric: I think those of us who got involved in the genome project on day one, did so somewhat naïve. On the one hand you knew this was going to be high profile. We were very laser focused on what we were doing to try to accomplish it. But every time we would bring our head up and sort of look around, it was a little scary. The goals were audacious. The technologies were not quite there yet, the approaches really needed to be developed. And if you really thought about it, we really didn't have a guide book on how we were going to map and then sequence the human genome. One of the examples I've been giving recently is to remind people of that some of the earliest data that was being generated, sequence data from chromosome seven that my collaborator and I were working on together to start to build some of the earliest maps, that was sequence data derived by Sanger sequencing, where somebody was literally in handwriting, writing down the sequence, being read off an auto-radiogram, and then they wanted to send that sequence to me and the most efficient way to do it was to fax it.
Eric: So some of the earliest data that was generated among collaborators that I was involved with in the Human Genome Project involved a fax machine, which, you know, some people don't even know what those are these days let alone couldn't imagine that's how we would exchange data as part of the early Human Genome Project. But that's the truth. But it really reflected that we were just, we didn't even know how to crawl. We were just getting started. So every once in a while, we'd pick our head up, it'd be terrifying. You know, when moments in time came where there were key decisions, it's a little scary because you didn't really have a guide. It's one of the reasons why during the genome project, there was a regular opportunity to bring everybody together, restrategize and re-articulate the goals and the approaches because we needed to update them because we were making it up as we went along.
Kat: So we sort of get to the point where you've got the first draft and it's announced, and, you know, there was just huge fanfare. That was media circus. It was absolutely crazy. What was it like to live through that?
Eric: When the draft sequence of the human genome was announced, I think there was relief that the race was over, you know, all the tension around who was going to get credit was over. I think it was the right conclusion. And then, you know, immediately attention turned to writing up the papers, because that announcement came in June, the papers came out in February and, you know, get the journals involved, both science and nature. So I think all of that ended in a very good place. And, you know, to a large extent, it was sort of over at that point, any of these rivalries, I think it was very clear to us involved in the Human Genome Project, that the focus was going to be on finishing a high-quality sequence, went off and finished the task of the Human Genome Project, and we focused on getting to done and then eventually declaring the project over and then publishing a paper to say we're done and moving on because you know, when the genome project ended, it was great excitement about everything that was going to follow, a complete recognition that while we had completed a lot, the best was yet to come and in many ways, that was just the starting line.
Kat: And we talk about the completion of the Human Genome Project, but, you know, I've heard a lot of people talk that that was the draft. And obviously there's a lot in the human genome that wasn't able to be captured with the technology at the time. And I've heard people like you and Bernie who's at the European bioinformatics Institute talking about the platinum genome and mapping every nook and cranny and every sequence. And now we have the technology really dig into the regions that were impossible to do with the technology back then and sort of the late nineties, early 2000s. So is there still value in working towards this platinum genome or are there more interesting questions or maybe both?
Eric: I certainly have to say there's incredible value because I'm the director of the Institute that is putting a significant amount of money into generating higher and higher quality reference sequences. So putting my money where my mouth is, this is absolutely important. I do want to make a point that I think a draft sequence, the human genome was produced 20 years ago. I think when the genome project ended, I don't think that sequence was any longer a draft, I think, because what the sequence was reflected very high quality information. I mean, sky high accuracy for the parts of the human genome that we were able to sequence the time, which was, you know, well over 99%, but it was not complete. And so I think the word I would use as, you know, the genome project produced a nearly complete reference sequence of the human genome, but the technology at the time did not allow us to make it completely complete.
Eric: Interestingly, and as you may know, there's some very exciting developments going on right now, including a paper that just came out in nature, actually involving an investigator here at NHRI and a consortium he works with. We are now using brand new technologies that are allowing us to fill in regions that we previously couldn't access before. And so we're getting closer and closer to a truly complete sequence of the human genome. But even one representation of the human genome is not enough because it just represents either a person. Well, even a person can't be represented by a single human genome sequence, because we all have two copies of the human genome in ourselves. We have one we got from mom when we got from dad. So the real challenge now is how to not only just represent the human genome sequence, but represent the variation, at least the most common variations of it that exists across humankind across the globe. And so there's lots of technologies being developed for this both experimental, but also computational to how to represent the diversity of human genome sequences that really are represented by our species.
Kat: Yeah, I've talked a lot before about moving from the concept of the human genome to the global genome. And then you've got people working on things like, you know, the cancer genome and digging down into individual tissues and mutations and all these kinds of things. It's the way the technology is starting to enable us to capture this diversity and variability I think is just incredible.
Eric: Right? And it's actually very important. You know, some of it is just intellectually interesting and we want to understand how we represent different people and variation that exists and how that variation changes or, you know, may account for differences in our traits. But it also is really important we have that information as a comparator when we start to genomic data as part of healthcare, you need to make sure comparisons about when you encounter DNA differences, you need the comparisons to be accurate to that individual's ancestral group to know whether or not it is possibly relevant medically for them or not. And so there's also medical reasons why we need these very high quality reference sequences from people from different ancestral groups.
Kat: I'd also then like to talk a little bit about what the future is of the human genome. So what direction are we heading in?
Eric: It really is important to stress the difference of where we are now. The field of genomics even 17 years ago when the human genome project ended was very small and very limited, Even at NIH where we were really the only Institute of 27 that funded human genomics research. You know, by 2011, when we published our second strategic vision and it started to be disseminated, but now, oh my goodness, everybody does genomics. Every NIH Institute funds genomics, every research funder around the world funds genomics. And if you even look at other countries, either they were doing no genomics and now they're doing genomics or if they were doing it, very limited, and now all nooks and crannies of biomedical research are involved in human genomics research. And so it's almost impossible to do strategic planning across all of genomics. And in fact, we focused only on the very cutting edge aspects of genomics.
Eric: This round in fact, we even have a new organizational mantra for our Institute where it's called the forefront of genomics because we recognize that we can no longer be about all the genomics. We have to really focus on the forefront of genomics. But even at the forefront, there's incredible responsibilities and incredible opportunities, incredible challenges. And that's what we described in this new vision that will be published shortly. And it's very exciting and it's across the entire spectrum, still continued important emphasis on understanding basic structure and function of the human genome, getting those last bits, getting all the functional elements, understanding how variation influences function, and then moving into translational opportunities of how variation might play a role in human health and disease really understanding the genomic architecture of human diseases. And then even pushing that into the clinical realm and thinking about how to more broadly apply genomics in the practice of medicine. We've seen genomic medicine be realized over the last decade, but that's only the early instances and early examples. And we think genomics has to become much more mainstream in medicine over the coming decade, but it requires a lot of development, a lot of research, a lot of education, a lot of policies. And, you know, healthcare is complicated. It's complicated in every country. And so genomics has great potential, but it has to find its way in the complicated ecosystem of healthcare delivery.
Kat: So thinking back to those naysayers 30 years ago, who said that there was no future in this for an early career researcher - you've proved them wrong?
Eric: Well, not only have I proved them wrong, I would say probably the most gratifying part of my job now is realizing the promise of genomics that I saw when I got involved in the Human Genome Project, but really saw it as something the next generation would realize. We would lay the foundation in genomics and the next generation, even maybe the generation after that would actually see its way into medicine. I never thought I would see it in my lifetime. I certainly never thought I would see it in my professional career. So the pace at which this is happening is incredibly gratifying.
Kat: I have got one more question to ask you. I'm afraid it's a terribly cheesy question, but, do you have a favourite gene? I can't not ask you!
Eric: Well, I actually do. When I got involved in genomics, even before the Human Genome Project started, I was a young postdoctoral fellow working in the laboratory of Maine, but also was my postdoctoral mentor, working on this brand new cloning technology that had really just been invented actually by graduate school of friends of mine called yeast artificial chromosome cloning, or YAC clones, which allow you to isolate very big pieces of DNA. And my project was to start to figure out how to use YAC clones to actually build maps of human chromosomes. And we picked a number of specific regions of the human genome to try to study and use those as a model. And that model ultimately led to the strategy we used for mapping human chromosomes as part of the early projects in the Human Genome Project. And among the regions I picked, I happened to pick the region of chromosome seven where human geneticists were desperately searching for the cystic fibrosis gene.
And so some of the very first YAC clones that I isolated contained what turned out to be bits and pieces of the cystic fibrosis gene, and that became a model for how to build maps eventually. Then we expanded it to chromosome seven and then others picked it up and mapped other chromosomes. So I've always embraced the cystic fibrosis gene as sort of my favorite gene, because it was where I got my start in genomics. And I got my start developing the approaches for building physical maps of human chromosomes that we ultimately used in the Human Genome Project.
Kat: Thank you very much to Dr Eric Green, director of the National Human Genome Research Institute for sharing his thoughts on the past, present and future of human genomics. And thanks very much to Alyssa Jones at NHGRI for her assistance setting up the interview.
That’s all for now. We’ll be back next time taking a look at the history of one of the most useful genetic techniques ever invented - the polymerase chain reaction. And before that, there’s another bonus episode of Genetics Shambles to fill your ears.
Guests:
Dr Eric Green, director of the US National Human Genome Research Institute
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Genetics Unzipped is written and presented by me, Kat Arney. It is produced by First Create the Media for The Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall, and audio production was by Hannah Varrall. Thanks for listening, and until next time, goodbye.
