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Decoding the DNA decoder

Image: Venter
J. Craig Venter tells his story inViking

It's been almost seven years since dueling teams of scientists unveiled the first draft of the human genetic code, but the implications of that achievement are only now beginning to kick in. And it's also been only recently that the most colorful players in the great genome race have had their stories told, in more ways than one.

One one side, there's James Watson, the co-discoverer of DNA's double helix, who got the ball rolling for the Human Genome Project in the early '90s. On the other, there's J. Craig Venter, who turned the quest into a real race with his privately backed DNA decoding effort.

Watson had his full genome deciphered this year, as did Venter. Both scientists published their memoirs this year as well. Watson's life may have had more drama lately, thanks to his comments about race and intelligence. But when it comes to dramatic life stories, it's hard to top the tale Venter tells in "A Life Decoded."

Can you name any other world-famous scientist who started out as a surfer dude and self-confessed slacker, faced death in the Vietnam War and came close to literally drowning himself in despair - then returned to the States, went back to college and eventually climbed his way up to the highest echelons of genetic science and commerce?

What's more, Venter is not one to rest on his genetic laurels: He has mounted a years-long expedition on his 100-foot sailing ship, called Sorcerer II, to catalog new species in the world's oceans. His gene-cracking operation is registering growth on a geometric scale. And oh, by the way, he's working to create synthetic life in the lab.

Venter's brand of bio-hacking could lead to next-generation biofuels and pharmaceuticals, produced by custom-made microbes. The idea has already touched off an international patent dispute as well as a deep ethical debate.

During a recent interview, Venter talked about his work with genomics (natural as well as synthetic) and about the implications of the genetic revolution for future health and social trends. He also reflected on Watson's recent troubles - and revisited the tale of a deadly sea snake he killed long ago in Vietnam with his bare hands. Here's the edited Q&A:

Cosmic Log: OK, so you’ve decoded the human genome. What have you done for us lately?

Venter: Heh, heh. Well, we re-decoded the human genome, which is perhaps the most important thing right now. We just published the first complete version of the human genome, the diploid genome - in contrast to half the genome being done at the turn of the decade. People thought doing the 3 billion base pairs would be sufficient, but it turned out that it grossly underestimated human genomic structure and diversity. So we just had now the complete one - which includes the sets of chromosomes from, in my case, both my parents. It totally changes our view of what’s out there, in the sense that we look like we're 1 to 2 percent different from each other instead of 0.1 percent. That’s a huge change.

Now we understand that not all the variations are the simple single nucleotide polymorphisms that people thought represented human variation. These were roughly 1 in 1,000. The assumption was that we all had the same human genes, and that we just differed from each other in one letter out of a thousand. Now we know that we in fact don't all have the same gene sets, and that we differ quite substantially in those genes. Forty-four percent of my genes had what we call heterozygote variations. The two chromosomes differed from each other in terms of the gene structure. So there's a huge degree of human variation if we all have two different versions of genes to that same extent. You can imagine that there could be billions and billions of variations.

Does this variation have implications for diseases? I know that you’ve looked pretty thoroughly at your own genome. What are some of the things in your genome that explained characteristics that you do or do not have? You sprinkled examples of this liberally throughout your book.

Well, the point of that is to show the complexity of interpreting the human genome, based on a sample size of one - or a sample size of two, because in fact we have both my parental chromosomes, at least one of them [for each]. Our goal is to get 10,000 or more human genomes over the next decade and really try to understand what all these variants mean.

I certainly list some risk factors that I have for cardiovascular disease in some genes. With the gene Apo E, for example, I have a heterozygote mutation, which means one of my parents gave me a heightened risk, and the other one didn't, for heart disease and perhaps Alzheimer's disease. But there are literally hundreds and hundreds of genes that contribute to heart disease.

I also have positive alleles for some of the genes. For example, there’s a gene that's associated with caffeine metabolism. Caffeine can definitely cause arrhythmia in some people that can lead to heart attacks. There are some variants of this gene that can result in very slow caffeine metabolism. I have two copies of the gene that actually lead to very fast caffeine metabolism, so I can drink far more caffeine than the average person, with a much lower risk.

Aha, did you find that to be the case in reality?

Absolutely. It’s an experiment I do every day.

Is there such a thing as too much information? Are there some people who don’t want to know what’s in their genes?

In my experience, there are two groups of people: those who really want to know, and those who are afraid to know. I haven't heard of any people who want to go halfway and see just some of their genes. Some of the same people who are afraid to know are also afraid to go to the doctor's office, because they might get bad news by being diagnosed with a disease. But one of the major things that I'm trying to teach people is that knowledge is power. If you know this information early enough, you have a chance actually to make a change that’s meaningful to you. If you get the information too late because you waited to go to your physician, you're in a different category.

You’ve made some changes because of what you saw in your genes, isn’t that correct?

Yes. Some of these changes are just the common-sense everyday advice we're all given about improving your diet and getting more exercise. But even though I knew through my father's early death from heart disease that I have a family history of this, when you see it in your own genetic code, that takes it away from testimonials and likelihoods – and affects you very differently.

And you’re taking a cholesterol-lowering drug?

I’m taking a statin to lower cholesterol and blood lipids. ...

In the near future, the information [on genetic risk factors] will be changing exponentially as we get multiple human genomes and can understand variation across the genome, and how it affects disease outcomes. Only then will we truly know how to interpret that information. It will also tell us how important environmental factors are. The reason I’m not at all afraid to have my genome out there is because I know that, at best, it’s only half the picture. The environment is equally as important, and perhaps the best way to get at the environmental component is to understand what’s genetic. Therefore, we’ll know everything else is environmental.

When the human genome project and your efforts first came to fruition, a lot of people had expectations that this would really revolutionize in the short term how medicine worked. It seems as if it's taking longer than perhaps the hype had advertised. But it sounds as if the long-term revolution is still building up steam, at least from your point of view.

Well, it’s an unfortunate aspect of things. We’re seeing that a little bit with stem cells as well. It’s a similar kind of effort, convincing Congress and government funders to fund things. Things get hyped and promises get made that science can’t possibly in the short run deliver on.

I kept saying that the human genome race was a race to the starting line, not a race to the finish line. But if you’re part of a large bureaucracy with a large budget, you see hitting that milestone as your finish line. So unfortunately, it did get hyped. And we have to worry that things like gene therapy and stem cell therapy have been equally hyped.

Understanding stem cells in the long run is going to be critically important for understanding our physiology and disease - almost equivalent to the genome, perhaps. But I'm not expecting or suggesting that anybody should be promising short-term cures.

It's interesting that you mention gene therapy and stem cells. The recent advance with induced pluripotent cells appears to have relied on some of the techniques that have been used in gene therapy. Do you think that hints at a convergence of all these different technologies, rather than seeing this as genetics vs. cell-based therapies?

Well, it wasn’t gene therapy, it was just transferring genes into those cells. I think gene therapy is one of those simplistic notions that sounded really good to everybody, because if something was broken, and you knew what it was, you could go in and fix it. I think the real issue is that we have 100 trillion cells, and it's hard to get the right genes under the right regulation into the right cells for the effects we’re looking for.

Gene therapy would be great if you're dealing with individual cells outside the body - so-called ex vivo gene therapy. Or if we were a giant amoeba with only one cell, it would probably be pretty effective. But that’s not the case.

The scientific community is as capable as the rest of the world of coming up with naïve ideas. I think that was clearly one of them.

Talking about one-celled organisms, toward the latter part of the book you talk about the quest for the synthetic genome. Maybe you can bring us up to date on where that is, and where you hope to go with the synthetic genome.

All this work actually started in 1995 when my team and I sequenced the first two genomes in history from living organisms, and we were trying to understand the differences in operating systems for cells. One cell required 560 genes, the other around 1,800 genes. We just asked questions like: Is there a minimal operating system? Was that it? Is there a basic system that would help us understand basic cell biology?

Another question was, is gene order important? If we had the same genes in the genome, only they were shuffled in a different order, would we still get the same species? The only way to answer these questions would be to chemically make the chromosome in the lab so we could make all the variants.

That’s what started the field of synthetic genomics, and we’ve been spending the last several years trying to perfect ways to accurately make DNA in the laboratory to go down this route. There are two aspects to it: One is, can we make large molecules of DNA? And we seem to be progressing well in that fashion. The second question is, what do you do with it? DNA is an inert chemical that needs to be booted up in a cell system. It was easy to do that with viral DNA. We could just inject that into E. coli, and the bacteria started making phage particles based on the DNA that we injected.

Earlier this year we published a paper on gene transplant, which I think is going to be the enabling step to go to this next stage. We purified a chromosome from one bacterial species, eliminated by digestion all the proteins associated with it, so we’re down to just naked DNA. And we transplanted that chromosome into another bacterial species, and then selected for cells with the new chromosome.

What happened is, the original chromosome got digested by enzymes and the new chromosome took over the cell. All the characteristics of one species completely went away, and the species got transformed into the new one based on the chromosome we put in. So it’s the ultimate in identity theft.

That showed that we could transplant a chromosome. We’re now trying to get it to work with a chromosome we’ve made in the laboratory; to see if we can boot up a cell with it. There are a lot of barriers to this, a lot of technical and other hurdles to overcome. But now that we know we can both make chromosomes and transplant them, it’s more of a question of when, not if, this will be possible.

Along the route to doing this, we saw that there were possibly additional benefits to society other than answering basic science questions. We decided these same approaches could perhaps be useful for reprogramming cells to do much more what we’d like them to do. For example, making large amounts of biofuels, the same kinds of fuels used in our gas tanks and diesel tanks now, but derived synthetically by bacteria from sugar as a starting point.

You could do this instead of taking the carbon from the ground and burning it – something that is contributing to what many of us are worried is the biggest threat to long-term stable societies and humanity. That is, possibly dramatic climate change from the continued placement of carbon in our atmosphere from burning fossil fuels.

Are there other applications that you are eyeing for this technology, or would you say the possibility of synthesizing alternative fuels is a big enough bite for you to take?

It’s certainly a grandiose challenge. Fundamentally, anything that comes from the petrochemical industry is fair game for this technology. DuPont is already having some success with extensively modified bacteria that they are using, starting with sugar as their raw material, to make propanediol, one of the key components of their new Sorona polymer.

DuPont argues that Sorona is going to be the first billion-dollar biotech product other than a pharmaceutical. It's got pretty interesting properties. They claim it produces carpets that are completely stain-resistant, and also clothing that will be stainproof as well, because nothing will bind to this chemical. When you spill something on there, you can just wash it away. Certainly every male over 50 has to be excited about that.

Anything we make in terms of pharmaceutical chemicals, plastics, bioremediation … we’ll be limited more by our imagination going forward than we will be by the types of metabolism that we’ve been discovering during the Sorcerer II expedition out there in the oceans, for example. We know only a tiny fraction of the biology on our own planet, and I think this is going to be the century of harnessing that knowledge, that new information.

You've mentioned how many new strains of microbes were harvested during those voyages in your book. Are there more scientific findings yet to come out of that project?

It's ongoing even as we speak. Earlier this year, we doubled the number of all known genes that have been sequenced. We hope to double that number again in 2008. We're at the early part of the discovery curve.

One of the biggest surprises is how little actual biology we know on our own planet. Discoveries are there, even for students just taking a cupful of seawater or soil and examining what's in it. We've been finding new microbes in the air. Here it is, 2007, and scientific discoveries are easier to make than ever before in history.

I wanted to touch upon this issue of genetic determinism, and the trouble that another pioneer in the field, James Watson, got into recently. I feel that you and Watson sometimes live almost parallel lives, just in terms of how you both can be outspoken - and you both tend to create controversy, whether you like it or not. It all caught up with Jim a few weeks ago. Have you drawn any lessons from Watson's experience, watching it from outside?

Well, one of the jokes I've made is that people are comparing our genomes - and I said recently that I applauded him for also making his genome publicly available. It helps to overcome this notion on the part of some government researchers that this information has to be locked up and seen only by a few people. We're trying to demystify it and make it so it's not so fearful.

People wanted to know what my concerns are about comparing my genome with his, and I've joked that it might be too similar.

You know, I don't think he personally believed what he was saying [about race and intelligence], but to some extent it doesn't matter. There is not going to be a genetic or skin color association with intelligence, or with disease. People find that some populations have a 63 vs. 52 percent incidence of hypertension or prostate cancer or other diseases, and claim that there's now a race-based determination. It's simply not the case.

Race is a social concept, it's not a scientific one. Our genomes - all 6.5 billion of us, soon to be 9 billion - are all going to be based on the same group of Africans that we all evolved from in very recent history. We'll see that continue. Anyplace you find populations that have been isolated - we call those ethnogeographic differences - anytime that there's inbreeding, you'll see certain traits that tend to get more emphasized in those populations vs. others. That's why people in certain regions start to look more alike after several generations.

We're all part of a continuum. I am 100 percent certain that if we could determine the genome of everybody on this planet, there would be no bright line that distinguished this social concept of one race vs. another.

What's one of the lessons that you think people will draw from your own book?

... It shows that I have a very unusual history for a scientist. I've been told my story gives a lot of hope to parents about their own kids, when those kids don't know where they want to go at an early stage of their life. I think I've shown that can have a positive effect.

I was particularly taken by the story about the snakeskin - the snake that you killed and skinned while you were stationed in Vietnam. Do you still keep that snakeskin around, and is there anything that it tells you about what the road ahead is going to be like?

It is certainly framed and in my office. It's a constant reminder, perhaps, that things can come up and bite you from any source.