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Craig Venter


Craig Venter

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Interview: J.Craig Venter

http://www.frontlinegenomics.com/2328/j-craig-venter-from-sequencing-the-first-human-genome-to-sequencing-all-the-human-genomes/

FLG: You recently told the Graduating class of 2015 at UC San Diego School of Medicine that pretty soon they’ll find that most of what they’ve learned is “just plain wrong”. What would you say is the first thing in our understanding of human medicine that is going to change significantly?

JCV: One of the areas that’s changing the fastest right now is cancer – as we drill down to the genome level we’re getting more information and understanding than has ever been possible before. Every single cancer is a genetic disease. Not necessarily inherited from your parents, but it’s genetic changes which cause cancer. So as we sequence the genomes of tumours and compare those to the sequence of patients, we’re getting down to the fundamental basis of each individual person’s cancer. And that’s truly my definition of my view of precision medicine. For example, at Human Longevity (HLI), we sequence the whole genome of the patient; we sequence the genome of the tumour to a very high, adept, coverage; we sequence the RNA in the tumour to understand which genes in the tumour are being expressed and modified; and we sequence the entire immune system. From that picture we understand the patients susceptibility in the first place for cancer, and why they probably got it, and whether their immune system responded to the cancer – and usually it doesn’t which is why cancer shows up. From the modified proteins that show up from the genetic changes, we get a whole new view of which drugs will work, and will not work, on that tumour. Also, we’re taking that further, developing personalised cancer vaccines for that individual against their specific tumour. So, it’s getting very precise – very data and information driven, versus what standard practise is today; doing surgery and trying to diagnose things using a microscope. It’s a different level resolution. It’s like trying to look through a telescope on Earth at Pluto versus the photos we just saw from that flyby.

FLG: Your new company, Human Longevity, is aiming to play a significant part in changing the human experience. What got you excited enough to buy all those hi-seq machines and set out to build the world’s largest genomic database?

JCV: Well, you might recall that 15 years ago I announced the first human genome that my team sequenced at Celera. The trouble is, that genome cost $100 million and took 9 months to do, with a large dedicated team. That seems extraordinary today, now that we can do thousands a month for little over $1,000 each, but 15 years ago there was a $3 billion 15 year government program to try and do the same thing. So we’ve changed from that 15 year $3 billion dollar effort, down to 9 months and $100 million, and down to thousands a month. It’s always been the dream, but technology didn’t allow it until recently.

FLG: You guys already have some great partnerships out there giving you access to samples to get you to that 1 million genomes mark. Are you still on course to hit your total by 2020? What are you looking for when you approach organisations whose samples you want to sequence and analyse?

JCV: The way it’s starting to look, we may greatly exceed the 1 million! The technology is still changing – we’re exceeding Moore’s Law still with technology change. We have more transistors per unit that change the compute capacity; we’re getting higher and higher throughput per machine; there’s new technologies coming – I’ve never had sequencing machines last more than 3 years in the last 20 years of my career, before they were replaced by a new, faster and better, technology. 5 years from now, this will still look like the end of the dark era.

FLG: From a technology standpoint, what are you hoping to see in the next 5 years that can help you better reach your goal?

JCV: We need a combination of the cost and the throughput of the Illumina sequencers, with the quality and long sequence reads on single molecules that we get with PacBio. Future technologies can still improve substantially on the quality of the data, the percentage of the genome that’s covered, and how well that’s done. In my talk at the Festival of Genomics, I talked about haplotype phasing, where on sequencing your genome we can separate your chromosomes into the parts you got from your mother and the parts you got from your father. We need much better technology to do that routinely, rapidly, and cheaply.

Craig Venter_quote3

FLG: At a personal level, the idea of staying healthy for longer is very appealing. However, we already have some major social and economic factors to deal with as a result of longer life expectancies. Here in the UK, we just had our general election. One of the topics for discussion was how the government was going to address some of the challenges being faced by my generation of 20-30 something year olds. People are living longer, so the government has to pay more for pensions, which in turn are funded by those working today on comparatively lower salaries. People are working further into their life times, so some of those big opportunities for vertical movement can be harder to come by. And then you have the general problems associated with an every increasing population. So, if you’re successful in increasing healthy lifespan for people, what kind of knock-on effect do you think it will have at the population level?

JCV: I’m glad you picked up on our emphasis on healthy lifespan versus just increasing human longevity. Even though that’s our name, our goal is totally focused on the healthy lifespan.

Healthcare is the biggest rising cost, certainly in the US, and in the UK I think as well. So we don’t bankrupt our entire economies, we need to switch to preventative medicine. One of the challenges with a government health system, like in the UK, with all of this data, is that you have a government making decisions on which treatments they’ll pay for and which ones they won’t. That’s a dangerous, dangerous, place to get into society. The UK health system is already there, insurance companies are already there – but countries where that isn’t an issue right now, are where there is good competition and different paying systems. So there’s a lot of reform that’s going to be needed across the board, there. But if we can prevent disease – it solves a lot of the social dilemmas about the government deciding you’re not worthy of getting a new kidney or getting a new treatment.

On the other hand, if we live longer healthier lives – in a few months I turn 69, I have relatives who are younger than me, who have retired already – it would be an incredible thought to me, to even consider stopping what I’m doing. I have a very exciting job and career. But we could solve a lot of these economic problems as well (the US has a bigger problem with this than the UK I think) if we just changed the retirement age to 75. With this notion that you work 20 years and then retire, it’s pretty stunning. My science career has already been close to 40 odd years, and I’m hoping for at least another 20. We need to have opportunities, not just for labourers to labour another decade, but having an education system that helps people move up the economic ladder. Knowing you’re going to be working a much longer period of time, you get incentivised to get retraining and take on something new, rather than assuming the government is going to take care of you at age 65.

FLG: One of the first things that brought your name to public attention was the congressional briefing back in 1991 where you mentioned that the NIH were planning on filing patent applications on thousands of genes based on expressed sequence tags. Amongst the numerous arguments against this plan, was the notion that this would impede the open exchange of information and increase the price of obtaining the sequence of the human genome. Ultimately, the NIH didn’t go ahead with the plan, and you’ve been carrying the ‘egomaniac’ tag ever since. By having that patent and license protection in place so early on, what do you think would be different today if the plan had gone ahead?

JCV: Well, even though the US government abandoned their patents, I think it put the taxpayer at an economic disadvantage. It’s well documented history that as the UK and US public genome labs, with the $5 billion funding, dumped their data nightly – every single pharmaceutical company downloaded that data nightly, and patented it. So it just shifted it from US taxpayers owning it directly, to the worldwide pharmaceutical companies owning that data directly. It’s led to the development of a lot of drugs and tests that are currently available in the market. I’ve said so publically, and am delighted by the recent Supreme Court ruling saying that these naturally occurring DNA sequences are not patentable – like Myriad have done with their breast cancer test.

What we’re doing with whole genome sequencing was going to make them obsolete anyway, because they’re multi thousand dollar tests, while we get the entire genome for a little over a thousand dollars. The patents wouldn’t have allowed them to block us looking at that data. So one way or another, they were going to become obsolete. I think it quite interesting now – some of the biggest critics from 20 years ago, are using the economic models that they criticised me for. In fact the Wellcome Trust, is now charging subscriptions to get access to data. So the world has come around. All this stuff was in the heat of a competition that most academic scientists never expected – that somebody would just come along and take their 15-year project away from them and just do it!

That created a lot more heat than light at the time. Some of the arguments that came out then were the weapons of the rhetoric of the time that had nothing to do with reality. Point to drug after drug, and test after test – even Myriad’s test with breast cancer – that have helped hundreds of thousands of people understand their risk for cancer and have new drugs to treat them. So if it was such an oppressive system, it would have disappeared a long time ago. Academic scientists have never been limited in their access to any of this data, so all of these were political arguments for rhetoric.

One of the things I’ve said several times recently, with these anniversaries of our first genome announcement, is that if you look at all of the rhetoric of the time – Francis Collins calling what we were doing, generating the “Mad Magazine” version and that whole genome shotgunning wasn’t going to work. All you have to do is take a look around the world, and every genome that’s been sequenced by us and what every other group has done with the methods that we published 20 years ago. That’s the nice thing about the field of science – the test of time sorts out the truth. Sometimes it takes the test of time to get away from the emotion and the rhetoric, but the fact that we’re now sequencing 3,000 genomes a month with this technique, and globally millions of genomes of countless different species… Every one of them has been sequenced with the technology we first described with the first genome in 1995.

Craig Venter_quote2

FLG: There’s a worry out there that today’s political and commercial interest in genomics is not always in the best interest of scientific pursuit?

JCV: You’re probably hearing that because you’re in the UK! We don’t hear that so much in the US. But there’s this constant left wing thinking that comes out of academia in the UK, that companies are inherently evil. It’s just bull****. The leading edge of the best science in the world is being driven by private money, and investment money because of the scarcity of government money to do this. It’s not only by far the best and most advanced science, we’re driving the equation at Human Longevity that everyone else is beginning to follow as well. I think those are old world thinkings of academia versus industry versus government, and just has nothing whatsoever to do with reality outside of perhaps a totalitarian communist regime!

FLG: We touched on it before, but, for better or for worse, you do seem to be seen as one of modern science’s greatest egomaniacs. Is there any factual basis to that allegation, or is it just part of being at the top?

JCV: Show me a highly successful person in any field that has gotten there having a weak ego. You have to believe in yourself, and you have to believe in what you’re doing. I think because of all that early rhetoric, and because my teams have been continuously successful at the very leading edge of this field for that last 20 years, it’s easy to label anyone at the front of things. I do have a healthy belief in my teams and the science that we’re doing, and that it’s going to change what’s going on. If I had a weak ego, and doubts about this, the first genome would not yet have been completed with US and UK government funding.

FLG: You’ve already had a pretty storied career in genomics, and it certainly seems far from over. When it does come to an end, is there any one thing in particular you hope people will remember you for? What is it, ultimately, that you’ve been trying to achieve?

JCV: I think you should ask me that in another 20 years! I think I’ve achieved some good things; doing the first genome in history – my team on that was phenomenal and all the things they pulled together; writing the first genome with a synthetic cell; my teams at the Venter Institute, Human Longevity, and before that Celera. These are all team sports. I’m the captain of the team, or the orchestra conductor, but the only reason I’ve been successful is because of having the most extraordinary scientists, mathematicians and engineers excited about working on some of the ideas I put forward. I’m hoping that these next 20 years will show what we did 20 years ago in sequencing the first human genome, was the beginning of the health revolution that will have more positive impact in people’s lives than any other health event in history.

Craig Venter_quoteFLG: In the build up to The Festival of Genomics, we asked people who they were most looking forward to seeing present. Perhaps a little unsurprisingly, your name was almost always mentioned. So we thought it would be a nice idea to have some of our previous interviewees and contributors to the magazine put some questions to you:

Richard Lumb, CEO, Front Line Genomics: One of your partners, Peter Diamandis, talks about the need of businesses to regularly “disrupt their own business model”. The stated purpose of Human Longevity is already differentiating and your approach already appears disruptive [an impressive combination of stem cell technology and genomics in a commercial enterprise]. Is this concept of ‘self-disruption’ something that you recognize in your past work, and how would you anticipate Human Longevity disrupting your own business model over the next few years?

JCV: That’s an excellent, thoughtful, question from somebody who’s obviously put some unique things together. If you ask anybody that works at Human Longevity, and on my other projects, I disrupt things daily. There’s no complacency. We modified our business model, relatively substantially, from 18 months ago when that was first put together. We’re adapting to the data in real-time, and that’s what happens in the best of science. All the things I’ve done are because the data we got has told us what the next direction was going to be, and what was possible, and the kinds of questions to ask. We have new data here on tens of thousands of human genomes. The machine learning team here, headed up by Franz Och whom I hired out of Google (you’re aware of his work if you use Google Translate), have already come up with some amazing associations out of the data. Now we’re trying to predict somebody’s voice from their genetic code, pictures of them, and their precise biological age. If you’d asked me about a year ago if these would be highly probably in the next year or two, I would have said “I’m doubtful!” We have great scientists making real nice breakthroughs, modifying how we think about the data going forward.

Some of the biggest companies of the past have disappeared because they stuck with their technology and have refused to evolve. Our genomes are evolving and changing every single day. I think that is somewhat of a surprise for me. I thought we’d just sequence the genome once and that would be sufficient for most things in people’s lifetimes. Now we’re seeing how changeable and adaptable it is, which is why we’re surviving and evolving as a species. If we don’t adapt and change constantly, then we will become one of the relics of evolution. So it’s not just a nice thing to do for survival, it’s essential in building for the next stage of success.

Jean-Claude Marshall, Director Clinical Pharmacology Laboratory, Pfizer: What are your thoughts around how the FDA could regulate both LDTs (laboratory developed tests) and NGS (next generation sequencing)? Additionally, what do you foresee as the next set of challenges in the field of both companion diagnostics based on genomic analysis of patients, and the challenge of direct to consumer genetic offerings?

JCV: That’s a sophisticated question, and an important one. We have a staff of several people who’s job it is to help work out a good regular trade path. I’ve met personally with the FDA commissioner. This is an area that’s very key to us. We want to help educate the FDA on these changes. We’re working with companies, and Pfizer is one of the ones we’re in discussions with, to use our technology to change how they do clinical trials. We’re working with several pharmaceutical companies on sequencing the genomes of patients from failed phase III clinical trials, to rescue them. In fact, Pfizer is probably more familiar with this than any other company. They did a large clinical trial for one of their drugs to treat lung cancer. The trial failed pretty badly. But then they did retrospective analysis of lung cancer patients with a translocation in the ALK gene. It turns out it’s in around 4-6% of lung cancer patients. Over 60% of those individuals, respond extremely well to the Pfizer drug. And now Pfizer have a blockbuster drug, totally because of that genetic segregation to rescue that failed trial.

As to the question on companion diagnostics; if you measure whether people have the ALK translocation, that’s a companion diagnostic for prescribing the Pfizer ALK targeted drug. To me, it will become the standard of care. Not an unusual abnormality. Pfizer’s path to this helped pave the way for others to see it.

Brian Dougherty, Translational Genomics Lead – Oncology, AstraZeneca: What’s different for you this time around? Sequencing and analysis is more sophisticated. The first human genome is done. Will similar business models work a decade later?

JCV: Well Brian was one of the key contributors back in the early days at TIGR and he participated in the very first human genome. He came in from Ham Smith’s lab, and saw first hand and contributed to the very first stages.

So what’s different today? Well the world has had my genome for 15 years, done with Sanger sequencing. Others have been added to it, Jim Watson was the second one done with the 454 technology. One, or two, or even a few dozen genomes, have proven to give great targets for pharmaceutical analysis. But they don’t give you enough to answer fundamental questions about what’s unique to you, what’s unique to me, and how do we interpret that data? So we concluded that the only route to get to that data, was rather than wait for the academic community to do one genetic study at a time, was to build a very large database so we can comprehensively and globally understand the 3% differences amongst all of us. It’s already starting to pay out. Doing more of the same in a highly homogenous species doesn’t really make sense. When you sequence sperm cells, no two sperm are alike. No two eggs are a like. No two people’s genomes are alike. Even Identical twins have some spontaneous mutations that make their genomes different. So we’re now able to get down to the resolution to start seeing those differences. I’d say that this is actually the most exciting era of genomics!

Anna Middleton, Principal Staff Scientists, Genetic Counsellor, Wellcome Trust Sanger Institute:What hooks do you use to start a conversation about genomics with people who know nothing about genomics, i.e. what, in a nutshell, do you think people want to connect to?

JCV: That’s a very interesting question. What we’re trying to design, with helping to introduce the data to people, is that we’re ultimately trying to describe them at the most comprehensive level. The interpretation of medicine today is ‘do your clinical values fall within a normal range?’ Everything in the globe right now is in the law of averages, which mean absolutely nothing to individuals.

Larry Page told me that even if we cured all cancer, it would only change average human lifespan by a few years. But you can see what a meaningless statistic that is if you’re a 9-month-old child and you die from a neuroblastoma tumour. That doesn’t shift the averages, but it’s a huge individual effect. Genomics are about individuals. It’s about what’s specific to you, not your siblings, not your parents – each of us is totally unique. We will only see that uniqueness by drilling down to the genetic code. Like I said in my talk, we’re a genetically, DNA driven software species. Every parent knows that when they see their children on day zero. We all come out totally unique, and everyone comes out differently. We understand it at an intuitive level, we are now developing the scientific data to help all of us understand what’s unique and different about us, and how we can use that information to have better, healthier lives.

Alka Chaubey, Director Cytogenetics Laboratory, Greenwood Genetic Center: You played the most important role in not only the Human Genome but also getting your diploid genome sequenced and available to the public. With all the human genome information available and the ability to identify rare genetic (constitutional) disorders, what are your thoughts on approaches to reducing the burden and improving the quality of life of individuals with disorders persisting as lifelong disabilities (e.g. Autism, Intellectual disability, etc.)?

JCV: That’s a nice compliment and another important question. It’s going to be the challenges of medicine, and of this technology. Not every disease or disorder is going to be amenable to cure and treatment. Particularly for diseases that result in a dramatic reordering of brain structures and functions. For autism in particular, we’re doing a large cohort where we’re sequencing the entire genome of autistic individuals. It appears that no two are alike. But we classify it as one disease under that name. It doesn’t have a single cause. So if you call any disease the ‘unlucky disease’, you might call that one the unlucky one. It seems to be primarily driven by spontaneous mutations in that individual’s genome. The rate of those spontaneous mutations is accelerated by having older parents. Perhaps that’s why we’re seeing more of it?

Sequencing the genomes of individuals with autism, and trying to find which genes are affected – in some cases will lead to some pharmaceutical therapies that might help them. But it won’t be across the board. So, I am not one to promise that genomics is the savour for all of medicine and all of humanity. That’s why prevention becomes more important than treatment. If we can prevent the miswiring of the brain, either by early screening, or selecting embryonic cells that don’t have mutations, we increase the chance of healthier outcomes for everybody. But there won’t be magic drug treatments for every disorder. But Alzheimer’s disease might be an important exception if it’s treated early enough. We can detect changes through a combination of the RNAi imaging we’re doing here of the brain, and the genome, that indicate a high risk of Alzheimer’s disease 20 years before somebody would experience their first symptoms. If that’s what we target for preventing the development of the disease, it might yield, as some recent trials are beginning to show, a very different outcome compared to trying to treat late stage Alzheimer’s disease where a third of the functioning neurons have already been lost in the brain, and pathways are gone – you can’t just instantly restore those with a magic pill. So prevention is probably the single most important word to come out of the genome era.

Keith Bradnam, Associate Project Scientists, UC Davis: What do you see as the limits of synthetic biology? Could we assemble a functional eukaryotic genome, and what are the practical applications of such technology?

JCV: That’s a great question! The limitations will ultimately be more society limitations, ethical limitations, and standards rather than technology. I think a synthetic single eukaryotic cell would be very straightforward to do today. Various groups of scientists have been trying to build the yeast genome. It’s kind of like rebuilding a house one brick at a time, but they’re making a synthetic version of yeast. That’s not quite the same as writing the genetic code and then booting it up as we did, but that’s just because of the limitations on writing the genetic code now.

I think understanding what makes a multicellular organism, and all the regulation associated with that, are so far away from design that we’re going to have to learn a whole lot more biology before we get to that stage of deliberate design. I think about 10% of the genes in our designed synthetic bacterial cell, are of unknown function. All we know is that you can’t get life without them. That problem expands tremendously with eukaryotic cells. If you extrapolate to the challenge of interpreting the human genome, we only understand a tiny fraction of the human genome today.

Nick McCooke, former CEO of Solexa also asked to remind you that you still owe him for tea at Claridges, in London, back in 2003.

JCV: Ha ha ha! Well it’s interesting…My cofounder at HLI is Peter Diamandis, who is also the CEO of the XPRIZE organization. I started a prize out of the Venter Institute early on, which was a half million dollars to spur on technology development. Today, Solexa would clearly be the winner of that. But things progressed so fast. The economics changed so dramatically, that nobody cared about a half million dollar prize anymore. XPRIZE made it a $10 million prize, but that wasn’t big enough to influence anything that Illumina or Life Technologies was doing. So the economic scale of the field has changed in part due to the tremendous success of Solexa.

FLG: That’s it for the questions, so thank you very much for your time! Is there anything else you’d like to mention?

JCV: No, I think you’ve covered the waterfront pretty nicely! It was fun talking to you and an enjoyable conversation. I was impressed by the quality of questions you guys put together!

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One Response

  1. Larry,

    If we were to use a preventative measures of medical science, instruments of medical science must predict future outcomes based on observable parameters of history….. There are several key issues arising: 1. Despite pinning a difference on genomic scale , say pieces of information, we do not know how to have changed that – that is shift methylome occupying genome surfaces , in a precise manner.. 2. Living systems operational quo DO NOT work as by vector gravity physics of ‘building blocks. That is projecting a delusional concept of a masonry trick, who has not worked by corner stones and ever shifting momenta … Assuming genomic assembling worked, that is dealing with inferences through data mining and annotation, we are not in a position to read future in real time, and we will never be, because of the rtPCR technology self restriction into data -time processing .. We know of existing post translational modalities… 3. We don’t know what we don’t know, and that foundational to future medicine – that is dealing with biological clocks, behavior, and various daily life inputs ranging from radiation to water systems, food quality, drugs…



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