Craig Venter’s Legacy: The Most Influential Geneticist Since Watson and Crick

0:00And now a word from our sponsor, South by Southwest London. Imagine a future where things just make sense. In the 1700s, we had canals. In the 1800s, the railways. Then telecom, fibre optic. And now? In a world that's more unsure than ever before, we need the answers. South by Southwest London presents over 900 speakers, 200 music artists, and 100 films in one location in June. To find out how they merge together and shape the future in person, visit southbysouthwestlondon.com That's s-x-s-w-london.com Today we want to talk about Craig Venter, the geneticist. He's died at the age of 79. Now, Venter's most famous for the leading role he played in sequencing the human genome.

0:44There's a case to be made, I think, that he's the most influential geneticist since Watson and Crick. What do you think? Definitely. There's a case to be. That's what we're getting into today on The World of the Universe and Astronauts. I'm Dr Rowan Hooper.

0:56Craig Venter:And I'm Dr Penny Sarche. Now it is a mark of Craig Venter's influence that we've written so much about his work over the years at New Scientist. So to get into this, we're joined by two former New Scientist journalists. We've got writer Michael Marshall and former editor Roger Highfield, now science director at the Science Museum in London. And Roger, you knew Craig very well. You edited his memoir. That's right. I mean, I interviewed Craig on and off during the 90s. And then I was a bit shocked to get a phone call saying, look, you know, it was Penguin in New York was having a bit of a meltdown because Craig had delivered his genetic autobiography because he was the first to sequence his own genetic code.

1:37and it was basically a quarter of a million words of Californian and it was way too long and they didn't dare touch it. He was kind of revered by the publisher, so I was drafted in. Yeah, to do the dirty work. Yes, that's right. And in fact, we did another, right? I edited another of his books, but obviously got a vivid insight into Craig the man and also worked with him, you know, dealt with him. And I, you know, he's often demonized. He's a very polarizing figure among geneticists. And in fact, if you see official accounts of the race to the human genome, quite often he's not mentioned, which I think is scandalous, actually.

2:17But hugely influential and refused to retire. I mean, only a few months ago, he was, I think he set up another company. So he was kind of serial entrepreneur. He was emailing me about doing another project together. So I was actually really, I knew he'd been diagnosed with yet another cancer, but he just felt like he was going to go on forever. So it's a sad day. The world's definitely got rather grey and boring and beige now as a result.

2:46Craig Venter:I think most of all, he's famous for his role in the race to sequence the human genome. And it's a complicated legacy there, isn't it? Mike, do you want to start us off really by talking about that story, that iconic story of the race to get it done? So it was kind of a two-way race, really. So the official Human Genome Project kicked off in 1990, and that was a publicly funded thing. It was this huge consortium of researchers in the US, the UK, all around the world, working together to read the entire human DNA sequence from beginning to end, which at the time, an absolutely gargantuan endeavor.

3:25I think it cost something like$3 billion by the time they'd finished it. it took them essentially a decade the sort of the first draft of it was published in 2000 but meanwhile venter had been sort of working away at the national institutes of health in the u.s and he had sort of got the idea that the way that they were doing it was just too slow and he was just like no no we need to we need to hurry this the hell up and so he founded his own company celera in 1998 and just said i'm gonna beat them to it and he didn't it was a tie essentially that and that both of them published their draft genomes sort of essentially at the same time.

4:04That's because they sort of came together at the end and made peace. They did, they did. Mike, it's such a complicated story because Craig himself, you know, he tried hard to work with the government-funded program. I think he put in something like four proposals through Jim Watson and was endlessly frustrated. then he came up with this very nifty way to find genes express sequence tags and it was the NIH that wanted to patent them really to get clarity about what it meant for for pharma it wasn't Craig driving this but this got sort of twisted into a narrative that he was a kind of rapacious capitalist and that he was trying to do a kind of cheap and dirty version of the genome when you had to do it the kind of grinding james watson said any monkey could do it well exactly at first they were there was this tension between there was huge tension watson probably thought oh is someone stealing my crown as the young brash up-and-coming american knew all about what craig was up to and it was a bit of grandstanding in front of i can't remember a congressional committee or something like that i think the solera guys actually donned a gorilla suit the next day and pose next to the sequence for a bit of fun.

5:20But actually, it was a useful adjunct. I don't think Craig ever saw anything more than an adjunct to doing the series Genome. And I think what happened was that ultimately, he found that private money could let him do what he wanted to do. And he set up this non-for-profit outfit, Tiger. You know, he did the first genome of a pre-living organism in in the mid-90s and you know as mike said he really felt look i can do the genome much more quickly and more easily than the public guys i think he completely enraged i mean craig would never win diplomat of the year award he would say things like i'll do the human why don't you guys rush off and do the mouse or something like that and then we're not overlapping yeah but you're right rowan that when it came to that white house agreement it had all got completely ridiculous behind the scenes.

6:11I think it was Ari Petrinos who worked with Craig, who kind of acted as a peacemaker. And it was a highly choreographed joint announcement. But I talked to John Sulston, who's always portrayed as the kind of, it was a bit like the anti-matter matter cook and anti-cook. John Sulston, son of a vicar, wore sandals versus this evil Vietnam vet, Craig Fenter. Well, the atheist and Francis Collins of course that's our leader of the on the other side being a devout christian very devout indeed but john had said look craig accelerated the the first draft of the genome by about three years but as i say he is sort of being airbrushed out of genetics history now which is a bit of a shame

6:56Craig Venter:but i'd also suggest that okay he's fed it up by three years isn't the bigger legacy shotgun sequencing because there was this snobbishness about it's quick and dirty but if you look at how we do genetics and biology today, the vast number of genomes we have for all these species that we can now study, that's shotgun sequencing. The ability to cheaply sequence many people's genome, not just one person, that's shotgun sequencing. Would you agree, Mike? Oh yeah, absolutely. Shotgun sequencing, which is where you sort of break up a genome completely at random into all these little chunks and then sequence all them individually and then use a computer to put it all back together.

7:34It's so much faster than the other way, which is to map the genome first. I mean, one of the biggest discoveries of the last couple of decades, I think, is Asgard archaea, which are these single-celled microbes that are probably the ancestors of all animals, plants, and complex cells. They're found by metagenomics, by literally just scooping up some sediment from the bottom of the sea, reading all the DNA in it, and then putting it back together. And that, I'm fairly sure, is shotgun metagenomics done on a massive scale, and it discovered one of the most important biological finds of the 21st century.

8:07There's no way that that would have turned up, I think, by the other method. Yeah, so that's part of his legacy. Yeah, and Craig realised it was really a computational challenge. It wasn't a chemistry challenge. So they put a lot of effort into the software to put all those gazillions of bits back together again. And also, it had been out there, you know, he's got a lovely letter, or he had a lovely letter from Fred Sanger, who he revered, saying he liked shotgun sequencing but his colleagues thought it was a bit off and a bit naff because sanger

8:38Craig Venter:sequencing was the slow careful clean method though yeah yeah yeah yeah and didn't they double check it using sanger eventually they you they did they did the rough draft with mostly shotgun and then it eventually they went through it with this the sort of more thorough sanger sequencing and found yeah basically is that he got it right yeah good enough yeah i mean there was there was huge argument at the time about whose genome was better etc etc but of course the thing is you know Craig went on to do other stuff as well so it wasn't just him and the human genome you know he's hugely influential yeah in loads of other ways well I want to get into some of that in a bit but let's let's rewind because he was a surf bum yeah he went and then he went to Vietnam too he was called up he went to the war in Vietnam and that really changed his life didn't it for the positive, actually.

9:31Yeah, I mean, he, well, he was completely at the end of his tether and he, you know, he described in his autobiography how he just wanted to keep on swimming until he died and then he encountered a shark and that sort of shucked him back into, then he swam furiously in the opposite direction. Not by shark. And I think he was, I think he saw hundreds of men die in the Da Nang medical unit where he worked and was always sort of amazed by things like how some people with impossible injuries seemed to, by sheer power of will, keep on going and others couldn't. And I think he gave him a kind of seize the day attitude, then went back to college, did his doctorate at UC San Diego, and that really set him on the career to get to the NIH and then do some very early sequencing where he was very meticulous about using these dodgy old sequences and a lot of people just couldn't get the things to work and sent them back but Craig you know actually kind of reminded me strangely of Jim Lovelock who say the same thing that he didn't trust lab purity measurements he had to make sure every single chemical going into the sequencer he understood and he'd characterized yeah and he got brilliant results and he you know His lab in the NIH was doing great things in terms of sequencing, and Watson was very impressed.

10:57But then politics got in the way, and the rest is history. Well, you mentioned Lovelock, and I also thought of him in a different way, though, that being an independent scientist, being like Lovelock's income allowed him to basically do what he wanted without having to apply for grants. Craig Venter was also able to do that. It also made me think of Elon Musk, actually, as another sort of independently, well, he can do what he wants. And, you know, you can argue how much science there is. But in the same way, there is these men with big chunks of money that can go off and do what they want. Definitely.

11:31And, you know, people always characterize Craig as this rapacious, buccaneering capitalist. But I think they got it exactly wrong. Well, he wasn't poor, though, was he? He wasn't poor. He made a shed load of money.

11:43Craig Venter:Where did that money come from? Well, it was from his rapacious capitalism. But, you know, his driving force was always the science. That's what really, I mean, okay, maybe sailing as well was his great love of his life. But he wasn't sort of getting out of bed in the morning thinking, hey, I'm going to make$100 million today. It was like, I'm going to transplant a genome between organisms or I'm going to get a bug to make something that's never been made before. Yeah. So he was completely irrepressible. And he just became a serial entrepreneur to do, as you say, the cool stuff he wanted to do.

12:20Craig Venter:But just to revisit that sort of narrative that was around the time of the Human Genome Project, he really was by some painted as like a villain. And if we didn't beat him, then he was going to patent the whole human genome and it wouldn't belong to us anymore. And, you know, if we ever wanted to use genetics for medicine, he'd get a cut. Was that true? Is that, you know, 25 years on, can we look at that narrative with more nuance? Or is that actually what he was trying to do? Well, I mean, Solera did like hold back a chunk of their data, at least at first, so that they could sell it. That is straightforwardly true.

12:54Whereas the Human Genome Project, because it was a publicly funded bit of research, just put everything out freely available online to anyone who wanted it and anyone who could download it. And we can sort of fight about the ethics of that until the clouds come out. I tend to think that the evidence for free and open sharing of data and for the benefits of that is so enormous that I do think that essentially the Human Genome Project guys were right on the sort of practical level that you will get more societal benefit that way. Before I was a journalist, I worked for a few years at the Sanger Centre just outside Cambridge, which is where a chunk of the Human Genome Project was.

13:29There was a room you could go into that just had these arrays of sequencing machines. If that was a really important chunk of the Human Genome Program, yeah. Hugely important. I was there in like 2005, 2006. And if you said the word Venter, you would basically get this sort of kiss and then possibly a sign of a cross. Like he was sort of widely despised as just like profoundly unethical. I sort of go back and forth over it because I do think that he did sort of kick things along. But I do also have a mild annoyance with that whole like testosterone driven style of science, which I think Jim Watson, to be fair, was also incredibly guilty on that sort of sentence.

14:17I'm just going to push ahead and I don't care who I offend or like whose lives I sort of overturn along the way.

14:23Craig Venter:Roger, do you have an idea of how Craig felt about being the villain and the rapacious capitalist? I think he got, well, you know, look, he had a giant ego. But, you know, I think he'd done enough impressive things to sort of earn his giant ego. What I thought was really telling was when I waded through this vast manuscript he'd produced, I said to him, look, Craig, I've got to be at a second source all of this, you know, or whatever I want a second source. And he had no worries about that. And in fact, there's an amazing book by Jamie Shreve, I think The Genome War or something like that, where it almost sounds like he was living in Solera.

15:04I mean, he had like access to everybody. And I think Craig was actually very open and straightforward to deal with. And what I found funny, and actually I wish I could mention them because it makes it a much better story, but I can't really. But there is a major, very well-known organization that was central to the publicly funded genome. And when I said, look, I've got Craig saying there was a key meeting. And in fact, I talked to a press officer who was there and that the whole narrative was get Venter, basically. Can I see your minutes? And this is an organization that, as Mike said, went on and on about it's all going to be publicly available, everything.

15:44They said, fine, you can have all the minutes, everything. And then after six months, they said, oh, terribly sorry, our archives are in disarray. You can have the press releases and the cuttings from the race. I thought that was pretty telling, actually. I mean, I think, as I say, the story about how he became commercial is much more complicated than often portrayed. And it wasn't his motor to make money. It was to do the science. OK, Mike, let's talk about the other major breakthrough. And they do overlap. But the whole synthetic biology thing, they overlap because it was in 95 where he sequenced the first genome of a free living organism.

16:23It was that bacterium. And then he took it from there with all this synthetic biology stuff. Yeah, that's right. So after, you know, within a few years of like the Human Genome Project finishing, Venter decided that what he was going to do was to try to create a sort of synthetic cell. Now, that doesn't mean that he was building an entire living cell completely from scratch, molecule by molecule. What he did was to take an existing bacterium, a relatively simple one. It's like a pathogen that infects goats. It has a relatively small genome, so it was kind of easy to work with. And what they did was to create a completely artificial version of the genome.

17:03So they had read it, and then they built their own version of it in the lab. and then they took a cell of a related species you know another single cell bacterium took all its dna out of it and inserted their synthetic genome into it and the cell lived and did not immediately explode as you might expect yeah as expect what happened it's a weird thing it is a kind of synthetic life for most you know the entire cell is um natural except for the fact that its entire genome has been built by a computer. And in some sense, it doesn't have a biological ancestor. It kind of does, except for this whole chunk of it that's artificial.

17:46Including a watermark, I seem to remember. Yes, about 40-something of the team sort of signed their names in the genome. And then there's also a few quotes. I think there's a quote from James Joyce. And I rather like this, actually, a quote from American Prometheus, the biography of Robert Oppenheimer. which is an apt choice. Yeah, that one is see things not as they are, but as they might be, was what Oppenheimer said. He also had Richard Feynman, what I cannot build, I cannot understand. He liked his sense of grandeur, didn't he? Yeah, he did, he did. And the James Joyce one was to live to err, to fall, to triumph, to recreate life out of life.

18:25Craig Venter:Good eye for a quote. Mike, you know, the big excitement with the synthetic cell is that, OK, you know, you can argue that the scaffolding of it is not synthetic, but you can then program the genome. And I, you know, a few times he said that what he really dreamt of doing was making an organism that could then draw down carbon dioxide. And, you know, and this was a long time ago, but he was already talking about, you know, we need to get CO2 out of the atmosphere and this is going to help us get off fossil fuels. We haven't done that yet. and actually synthetic biology has turned out to be much more complicated.

19:06Is that basically the reason it's much more complicated than we thought? It's partly that it's wildly complicated because the network of interacting things within a cell turns out to be so ferocious, even in something as simple as this little bacterium. So it does prove quite difficult to get them to do what you want. um i think also if you want to you know engineer a bacterium that like draws down co2 or do or you know some other kind of useful thing like make a medicine or something like that you probably don't need to do anything quite as wholesale as what craig was doing you don't need to replace the entire genome you're probably going to be tweaking a few little bits of it like adding a half dozen genes that sort of thing and in some respects i think that it was said at the time that probably some of the biggest benefits of synthetic biology in terms of like like societally useful things will probably come from much simpler experiments than what craig was doing and i think that's probably been borne out um since because we have yeah you can i think there's a there's an anti-malarial drug called artemisinin that's now made by like engineered cells and it's just a i don't think it's very many genes at all that we've messed around with to do that well i think venter's experiments with these cells really sort of get it is more is really kind of fundamental biological questions they're actually not i think very much to do with like cellular engineering or like manufacturing or anything like that they're to do with understanding like the the deeper nature of life and like what what it actually is required for a cell to be alive and how simple it's possible to to get it to be they're much more to do with these sort of deep biological questions than they are to do really with anything that has any kind of immediate practical use.

20:48Yeah, he was really interested in this idea of a minimal genome. What's the least number of genes you can get away with for something to live? And, you know, the way that they develop new techniques to synthesize huge stretches, you know, relatively big chunks of DNA at the time, you know, was a kind of technical tour de force. I mean, people carped a lot about, is it really life? Of course, we can't even define life scientifically. So I think we can park that. But, you know, as Mike says, he saw it not just in terms of the practical applications of synthetic biology and making organisms do really interesting things.

21:28He was driven by these more fundamental issues as well.

21:32Craig Venter:I went to see him speak about 20 years ago. And I was interested because this was this guy that I knew as the villain of the race. And then I was very surprised that he basically just gave a talk about traveling the world in his yachts, collecting seawater and sequencing the DNA. Mike, could you tell us a bit about that work? Yeah, so that was an early bit of metagenomics work. So essentially, a few years after he'd finished his work on the Human Genome Project, he took this yacht, which is called the Sorcerer 2, and he basically spent two or three years circumnavigating. He went to a huge number of places and collected samples of seawater.

22:13And then they would just read all the DNA that was in that seawater from the bacteria and viruses and whatever it was that was in that sample. And they were able to identify huge amounts of new things, millions of new proteins that had just never been detected before. And he wasn't the first person to do that. There had been a study, I think, in 2002, where they just took samples of seawater and identified enormous numbers of new viruses that just had never been even remotely detected before. Completely unlike anything that had been seen, just literally by taking a bit of seawater at random. But Venter sort of really took that and kind of ran with it for two years.

22:55And, you know, huge swathes of data came out of that. And, you know, other groups have followed in his footsteps. And I think as a result of that, you know, we have a much better picture of, you know, the real biodiversity that's actually out there. Because, you know, a huge chunk of biodiversity is just microscopic things that we can't immediately see and therefore are difficult to categorize. And metagenomics has really been the way to actually discover all of that. because you can gather up all of this stuff quickly and kind of dirtily and huge amounts of data will fall out of it. And suddenly the tree of life has an awful lot of additional branches.

23:30And his expedition in the early 2000s is a part of why that's true. It's a holiday I'd like to do myself, actually. Yachting and doing science. He loved yachting, all sorts of hair-raising stories. You've been on his yacht, right? Well, actually, a couple of years ago, it was the last time I saw him in Maine, he invited me on board this amazing 30s racing yacht. And, of course, you know, I don't know one end of a yacht from the other. And what horrified me was within about two minutes, my feet were up in the air. My head was right down at the water level. And this thing was tipping over. So it was almost at 90 degrees.

24:12I mean, the power. This is when he'd lost his death wish, though, right? He was just having fun. I kind of got off rather shaken at the end of this experience. But no, he combined in the Sorcerer two expeditions absolutely his two loves of genomics and sailing. And I do remember he studied like the Sargasso Sea, which is always portrayed as a kind of a lifeless sea and just found it teeming with viral diversity. So as Mike said, it wasn't the first metagenomics, but it was probably the first large scale application of metagenomics. So I think we're happy to agree that he's the most influential, certainly geneticist, since Watson and Crick.

24:55Yeah, I think so. But he's also the most hated. That's the thing. So you might find establishment figures won't agree with us on that. I might make a push for the CRISPR people like Jennifer Dutner. Yes. Good shout. Good shout. Well, we're not here to have that argument now, but I think we've done a good job of settling and showing his legacy. Reviewing his legacy, yeah.

25:18Craig Venter:We'll leave it there then. Thanks so much for your thoughts, Roger Highfield, Mike Marshall, and thanks to you for listening. And do subscribe and follow wherever you get your podcasts. Bye for now. Bye.

25:35You can't reason with the sun. Trust us, we've tried. This summer, it's time to put that angry ball of fire on mute. Columbia's OmniShade technology is engineered to protect you from the sun's harsh rays that can burn and damage your skin. The sun is relentless, but so is our gear. Level up your summer at Columbia.com to spend more time outside and less time slathering on aloe lotion. You're welcome. Columbia. Engineered for whatever.