Geneticist Dr Kat Arney brings 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. They discuss the past, present and future of human genomics in the latest episode of the Genetics Society’s Genetics Unzipped podcast.
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. 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.
Dr Eric Green has seen the Human Genome Project 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. Arney interviewed him up 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.
“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.”
“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 organised project. 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, counselled young scientists like me to stay away from it, that this was no place for somebody who wants to be a successful biomedical researcher.
“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. 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 believed 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 favour of it.”
Eric remembers how, at the start of the Human Genome Project, whose genome would actually be sequenced wasn’t really a question that was focussed upon:
“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.”
“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.”
Though everyone in the project initially expected a revolutionary new sequencing technology to make a fully sequenced human genome a reality, Eric describes it as more like an evolution of existing sequencing techniques rather than a sudden step-change:
“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.”
Eric notes that being part of such a major international project was, at times, quite daunting, but hugely rewarding:
“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.”
“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.”
Finally, Eric answers the question we’ve all been burning to ask – which is his favourite gene?
“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, 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 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 favourite gene, because it was where I got my start in genomics.”
The team would like to thank Dr Eric Green for sharing his thoughts on the past, present and future of human genomics, and also Alyssa Jones at NHGRI for her assistance with setting up the interview.
Full show notes, transcript, music credits and references online at GeneticsUnzipped.com.
Genetics Unzipped is the podcast from the UK Genetics Society, presented by award-winning science communicator and biologist Kat Arney and produced by First Create the Media. Follow Kat on Twitter @Kat_Arney, Genetics Unzipped @geneticsunzip, and the Genetics Society at @GenSocUK
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