Are We One Step Closer to Artificial Life? Genome pioneer Craig Venter and a team of scientists have successfully turned one species of bacteria into another. Venter says the research could mark the first steps toward being able to create artificial life by inserting an entirely synthetic genome into a bacterial cell.
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Are We One Step Closer to Artificial Life?

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Are We One Step Closer to Artificial Life?

Are We One Step Closer to Artificial Life?

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A bit later in the hour, we'll be talking about the latest stem cell research.

But up first, a closer look at a research finding scientists say puts them one step closer to creating artificial life. A team of scientists, led by Craig Venter of genome sequencing fame, has taken the entire set of genes from one bacterium and transferred that set into a related one, essentially transforming the second bacterium into the first, a nifty scientific trick he believes could someday help lead to the creation of artificial life. Venter is not talking about Dr. Frankenstein here, rather artificially creating designer bacteria for the microbe factories to produce products like, well, let's say, eco-friendly fuels. The team's work is published in today's issue of the journal Science.

Craig Venter joins us this hour to tell us about his research, where it's headed, and if all this talk of creating artificial life, even artificial microbial life, leaves you feeling a bit uneasy, you're not alone, bioethicist Mildred Cho is also concerned. Dr. Cho is here to advise us to think about the implications of this work from the introduction of artificial life forms into the environment to metaphysical issues, such as, what constitutes life? And since the odds are that artificial life forms will be patented, who should be able to claim ownership of these noble life forms and the process by which they are created?

If these are things that are on your mind, give us a call. Our number is 1-800-989-8255, 1-800-989-TALK.

FLATOW: Let me introduce my guests. J. Craig Venter is the founder and president of the J. Craig Venture Institute in Rockville, Maryland. His team's synthetic genome research, as I say, is published in today's issue of the journal Science. He joins today by phone from San Diego. Welcome back to the program, Dr. Venter.

Dr. J. CRAIG VENTER (Founder and President, J. Craig Venter Institute): Thank you. It's nice to be back with you.

FLATOW: You're welcome. Mildred Cho is associate director of the Stanford Center for Biomedical Ethics and associate professor of pediatrics at Stanford University Medical Center in Stanford, California. She chaired a panel that examined the ethical issues surrounding Dr. Venter's research into the minimum number of genes needed to sustain life. That panel published its findings in 1999. Dr. Cho joins me today by phone from the Stanford campus. Welcome back to the program.

Dr. MILDRED CHO (Associate Director, Stanford Center for Biomedical Ethics): Thanks, Ira.

FLATOW: Dr. Venter, can you give us a brief thumbnail of what that experiment was? I think you describe it as something like changing a Mac to a PC.

Dr. VENTER: It's - that's certainly a metaphor for it. It's - I think it's much more interesting at the biological level. And we started with two somewhat closely related mycoplasmas - these are very small bacterial genomes. In fact, the reasons we started with them, we sequenced the mycoplasma genome in 1995 as our second genome, and it was and is still is the smallest genome thus far sequenced in history for a self-replicating organism.

So we isolated the chromosome for one mycoplasma, made sure that it was stripped off of all its DNA and other molecules to what we call naked DNA. We wanted to make sure we had just the genetic code molecules and nothing else, because if we're making DNA synthetically that's all we would have. We then inserted that chromosome into another species of mycoplasma, and then used a standard laboratory selection method to select for cells that contain the transplanted chromosome.

And after several days, when the colonies grew up to a visible size, when we looked at them in their molecular biology and biochemistry, they had only the chromosome that we transplanted in and all the characteristics of the cell (audio gap) with the transplanted chromosome. So all the characteristics that we knew this species has before all went away and it completely converted into the new species.

And so, you can look at this at several levels. It certainly validates and proves that it's the genetic material that's certainly transforming all of this information. But the - it was such a complete transformation. It was a very pleasant surprise to us.

FLATOW: Why would you be surprised by it? Did you not expect this to happen?

Dr. VENTER: Well, as one of our reviewers of the Science paper said, this is one of those things that's very simple in concept, extremely complex in delivery.

FLATOW: Mm-hmm.

Dr. VENTER: So we've had to develop a wide range of new techniques and technologies to be able to even manipulate entire chromosome of cells. DNA gets very brittle when it's larger pieces, and to try and keep an intact circular chromosome and have it be in the right supercoiled form, having the right ways to get it across the membrane, all of these things, nobody has known how to do before. So in theory, in a concept that should have worked in practice, there's lots and lots of things, as we try this with different cells, that could potentially block it from happening.

FLATOW: Is the endgame here to create a synthetic chromosome and put that into a cell?

Dr. VENTER: It's certainly one of the goals of our research. And these all emanated from, again, characterizing these first two genomes in history in 1995 and trying to understand what would be a minimal gene complement to have for self-replicating cellular life. For the last decade or so, we've been doing various types of gene knockout experiments, trying to find out which genes were essential and which were not. But you can only take out one gene at a time. There's no way to sequentially take out one, two, 200 genes. And so that's what that led us down to synthetic chromosome path in the first place, just trying to understand basic cellular function.

FLATOW: Mm-hmm.

Dr. VENTER: Out of every genome that's been sequenced - and my team has done now hundreds of them - at least 25 to 40 percent of the genes we discover in each chromosome, in each cell, are of complete unknown function. This is true even for the minimal cell. A hundred out of three to four hundred genes are of unknown function. So our actual knowledge of molecular biology and cell biology is still pretty primitive. We need these techniques to really understand these genes and what constitutes basic biochemistry of a cell.

FLATOW: Why is it not considered - when you do this that you're actually creating new life or creating life?

Dr. VENTER: Well, we're not creating life at all. I mean, we're taking a chromosome from a living species and putting that in another living species and it's converting that second species into the first one. So we're transforming life of that cell. These are all naturally occurring organisms that are widely studied in the lab and in the environment. And even, I think, it's a technical issue as to whether - even with a synthetic chromosome doing the same operation, we don't use that word creating life with it. We're using as a vessel existing cells with existing chromosomes.

What we're doing is creating a new chromosome for it out of chemical synthesized in the lab and booting up that chromosome with the cellular system. I think that's the key thing that we've shown in the Science paper is that it is now possible to take another chromosome and boot it up and have it really take over the cell. I think, ultimately, if you could take all the chemical components in a cell with the chromosome, mix them together in a nice soup and get living self-replicating cells out of it that might someday be viewed as creating life. I think we're developing new life forms out of existing life, as has been the history of biology from the beginning.

FLATOW: Mildred Cho, as an ethicist, how do you view this feat?

Dr. CHO: Well, I think it's a very important technological development. And I agree with Dr. Venter, and I think it's good that he's been very careful to say that what has been done here is not really creating artificial life, but to sort of mix and match different parts of existing naturally occurring species. And also, I think he's been very good to really talk about what we don't understand yet from this work and while it is a significant step forward in creating - being able to manipulate genomes and bacteria, we still don't really understand fully why it works or how it works, and what's happening to the host genome, for example. It seems not to be expressed eventually, but the mechanism of that is still not known.

FLATOW: Do you think the public is uneasy when they hear these kinds of advances?

Dr. CHO: Well, I think so. I think part of it has to do with perhaps the fact that scientists can very easily see what the wonderful applications that this work can lead to, but it's maybe not so obvious to the public generally. And when I look at the title, for example, of the article that was published, it's called, "Genome Transplantation in Bacteria: Changing One Species to Another." And if you look at that as someone who doesn't really know much about microbial genomics, one might just ask the question, why would you want to change one species to another? I mean, what's wrong with the ones we have?

So I think one thing for the scientific community to consider is to really be clear about why they're doing what they're doing and acknowledging that they have the best of intentions, but being more specific about what those intentions are to allay some of the fears that the public might have.

FLATOW: You don't think they're proactive enough in it.

Dr. CHO: Well, I think it could be explained a little bit more clearly, yeah, and proactively what the purposes are and what the potential beneficial applications of this research might be.

FLATOW: Well, we're going to do very much of that. After we take a break, we're going to come back - take a break, come back, and talk with Mildred Cho and Craig Venter who's going to layout for us, hopefully Dr. Venter, what the purposes are? What are the potential benefits? I mentioned something before about bacteria making ecofuels for us, but bacteria - a little factory that can make all kinds of stuff, can't they? So we'll take a short break and come back and talk lot's more.

Our number, 1-800-989-8255, 1-800-989-TALK. If you'd like to talk with J. Craig Venter and Mildred Cho about this experiment, which they were able to transplant chromosomes and create one - change one bacteria into another. We'll talk about your bacterium experience if you have one. If you have some questions for us to answer, give us a call 1-800-989-8255. We'll be right back after this break.

(Soundbite of music)

FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow.

We're talking about some research conducted by Craig Venter and folks in his lab, a team that he led where he has taken an entire set of genes from one bacterium and transferred them into a related one. Essentially, transforming the second bacterium into the first.

Dr. Venter, what can you do now? What is - give us some of the things that Dr. Cho said that scientists need to explain to the public about why you do you do these sorts of things.

Dr. Venter: And I agree with Mildred completely. I think scientists particularly with public funding have a natural obligation to explain their work to the public. And sometimes when we do that too much, we get accused of doing it too much. So it's a delicate balance. But I think this work is exciting in a very basic science level in terms of trying to understand basic cellular physiology. And I think it also helps maybe to understand some key events in evolution.

For example, when we sequenced the color of genome, several scientists thought the color of genome would be indistinguishable basically from E. coli because it had some similar genes in it. When we sequenced it, we found it actually had two chromosomes, one that was, in fact, similar to E. coli and one that was dramatically different. So it's entirely possible what we have done in the lab and the Science paper. Actually, it happens occasionally in nature. You wouldn't see if it completely transformed the species. But when you get the stable chimeras where you have both chromosomes present, you get totally a new species that didn't exist before. Unfortunately, in the case of cholera, it's one that causes human disease. So maybe by understanding how these events took place, we can understand speciation and stuff a little bit better.

I think the other thing that it really does is enable the field of synthetic genomics. We've been trying for sometime, as I think many people know, to try and make a synthetic mycoplasma chromosome in the laboratory. And the big question has been, number one, can we do that and if we were able to chemically make this chromosome, what would we do with it? How do you boot up a chromosome to give a living entity out of it. And we've explored a number of approaches and ideas. Initially, we thought we would have to use a ghost cell, where the chromosomes were removed and try and add a new one in.

And I think it was Hannah Smith who came up with a notion why not just why not just leave the chromosome in and add the new one and use selectable markers to go in this new direction. The fact that we can now know that we can take naked DNA, a pure chromosome, we now know how to manipulate it and deal with it without it being destroyed and transplanted into these cells and that these mechanisms - and Mildred is right, we don't know exactly what happen in the cell. We have a couple of ideas - when cells divide, the chromosomes go in different directions. So maybe, even after the first division, one chromosome goes to one cell and the parent one goes another way.

Also, bacterial cells have unique defense mechanisms and I think this study shows why they would need to have those restriction enzymes - restriction systems were developed in evolution to protect cells from foreign DNA coming in. And you can see if a chromosome can enter your cell and take over your whole existence and your identity, you'd want to have mechanisms to protect against that.

The one cell we used didn't have a restriction enzyme in it. The chromosome we put in, we think, does have one and it's possible that that was expressed and shoot up the parent chromosome on entry. So these events took place in just such a small number of the cells, they're impossible to track right now as to the exact mechanism. But I think this is important to understand as we try this with other cellular systems. You have to overcome the restriction enzymes.

FLATOW: You've said that the earliest application of this work - the earliest applications are likely to be in creating designer fuels from bacterial metabolism? Why would that be the earliest application?

Dr. VENTER: Well, we think it's one of the most important applications. After myself and my colleagues finished sequencing the human genome, we started looking around to where we could apply our technology and know-how. And the biggest problem I think facing humanity is what we're doing to the environment; burning these billions of tons of fuel, where we end up with - on the order of, right now, three and a half billion tons of CO2 going into the atmosphere each year.

We can't keep doing that. And the estimates - that's going to go up to 12 billion tons as population growth changes and developing countries had more and more cars and industry. We're facing potential - the end of life ultimately as we know it on this planet, if we don't change things. Certainly even the predictions of flooding in the near future could be a disaster for major populations.

So I think coming up with alternatives to taking the carbon out of the ground, burning that and putting that in the atmosphere, is our most pressing issue. And I'm a believer that biology can play a key role in that, and that synthetic biology - maybe we can come up with chemical pathways to make fuels that don't currently exists. Our existing repertoire comes from altering properties of oil, we can actually make better designer renewable fuels using bacteria metabolism.

FLATOW: 1-800-989-8255 is our number.

Leslie(ph) in Thomasville, Georgia. Hi, Leslie.

LESLIE (Caller): Hi, Ira. How are you?


LESLIE: My question is - and I've been following the genome project and I know a little bit about molecular biology, but I'm not a molecular biologist - is how, especially since he said that some of those genes - they may not know exactly what they do. How do we know that when we put that gene into that other bacteria that it won't create something that will come back to really bite us? And I'm just reminded of Michael Crichton's book the "Prey," where there was some nano products that took over. And I'll be glad to take my answer off the phone.


LESLIE: Off the air. Thank you.

Dr. VENTER: It's a very good question. In fact, if you're a Michael Crichton fan, you can go back much earlier to "Andromeda Strain," where scientists were manipulating things in the lab. So there are lots of themes in books and movies about the science fiction horrors of science. And it's something obviously that scientists need to be very careful with.

We're working with systems and we've - through a year and a half to two-year long review, along with MIT, you know, a project funded by the Sloan Foundation - trying to look at laboratory practices for laboratories doing synthetic biology, synthetic genomics. One of the rules that we've set is a very absolute rule, nothing should be allowed to be made that could grow outside of the laboratory and outside the laboratory conditions.

And we have 30 years of molecular biology with millions of experiments being done with those kinds of conditions and it's worked quite well. Also, we're working with gene sets from known species. And we do want to understand those unknown genes, but we also understand whether they're expressed or not in their existing cells. I think it's a caution that we need to constantly pay attention to. And I think we certainly, at the Venter Institute, set up elaborate procedures to do that.

FLATOW: Dr. Cho, we're dealing with life forms and products that have never existed before. How do we use our current infrastructure - our current regulatory infrastructures or do we need to set up all new ones?

Dr. CHO: Well, that's a very good question because I think our - the way our laws and regulations go, they don't handle radically new technologies very well. And so if - there isn't really a good set of processes to deal with or to evaluate the kinds of synthetic biology products that will soon be multiplying. Though we may need to rethink the way we regulate or at least evaluate new products, especially if they going to be released into the environment.

Because right now, our regulatory system is very specifically focused on known toxins - like ozone, or mercury, or other hazard pesticide, radioactive materials because of their known hazards - or on things that we want to protect like air, water, wetlands, endangered species, that kind of things. So they're either focused on sort of things you want to protect or known toxins.

And when you go into the area of the unknown, the regulations aren't really built to handle those very well. So we may need to really do think how we might evaluate things that eventually as we want to release bacteria, for example, into the environment, a way to evaluate, you know, what counts as an environmental risk that we want to avoid. Is that just human health? Is it risks to the whole ecosystem? And try to avoid - even if we have the best of intentions, you know, the kind of scenario that has occurred when we release organisms into new kinds of environments that have not seen that organism. And we don't want to have a, sort of, repeat of, a molecular repeat or a microbial repeat of kudzu, for example.

FLATOW: Right. Dr. Venter, have you filed a patent for what you just accomplished?

Dr. VENTER: Our team has filed patents on multiple steps in the process that -the normal methods that we have developed. And I think that, - at the top of the show you've mentioned that there was an issue whether you could patent synthetic life. And I think it's always been an issue even though the Supreme Court ruled that you could patent life forms, and large number of patents have been issued for naturally occurring organisms, something that I've never quiet understood how that happened.

But I think it's pretty clear-cut if we're designing and synthesizing genomes from scratch that these are clearly human designed and human-made processes that should fit in the existence patent law, if naturally occurring organisms (unintelligible) this should be much more clear-cut.

FLATOW: Dr. Cho?

Dr. CHO: Well, it's absolutely true that our patent system does allow patenting of life forms if they have been modified in a way that such - they don't occur that way in nature. So, although a lot of people find that strange, I think that you could patent something that's a living thing. If it's something that wasn't naturally occurring, it's considered an invention, that it's patentable.

I think where the public policy issues do come into play though is in the details of what is claimed in the patent. And so, what you want to try to avoid in a patent is overly broad claims that actually claim something that you haven't actually invented yet or, something that might potentially block new inventions but that are not similar to what was actually done.

So for example, if you patent something that claims that you've made a new car because you've designed new wheels and an engine, what you don't want to do is have that patent be so broad that it excludes somebody else patenting or making something with very new kinds of wheels or a new kind of engines, like, you know, a fuel cell instead of a combustion engine. So the devil is really in the details of how those patents are framed.

FLATOW: Talking about synthetic life forms this hour at TALK OF THE NATION: SCIENCE FRIDAY from NPR News. Dr. Venter, where do you go from here?

Dr. VENTER: Well, the, the next obvious step for us is to - once we have a completely chemically synthesized chromosome, to try these same type of experiments that we've just reported in Science with a synthetic chromosome. And I think based on these experiments we've done, there is no theoretical barriers to that at all. For example, if we made the microdius(ph) chromosome chemically, it would be indistinguishable from the naturally occurring one if we just took the genetic code and copied it.

So I think it's more of a technical issue and proof of a point that you could do this with a chemically synthesized piece of DNA. I think the challenge there is the largest piece of DNA that's been reported in the literatures on the order of 35,000 base pairs. And the smallest genome that we're working with is 560,000. So it's quite a substantial different scale to be working at in terms of DNA synthesis. Once that's done, combining the two, we think, would give us certainly a living entity with a completely synthetic chromosome as it's starter material.

And one of the things you can do when you're designing and making DNA chemically is we can watermark that in all kinds of interesting ways. So with the genetic code, we have four letters in it, but triplet sets of those, three letters code for the range of amino acids that we use, they'd give us ways to spell out all kinds of interesting things in the genome both for fun and for proof of principle.

FLATOW: And at that point, you would be - you would consider what you've created in that case, something living?

Dr. VENTER: Yes. If they …

FLATOW: Something synthetically…

Dr. VENTER: …if it becomes like we've reported in Science, a self-replicating cell based on the synthetic chromosome as its starter material, yes, I think people would agree that it would be a, a living self-replicating entity.

FLATOW: Dr. Cho, how would that - what kind of reaction would that get?

Dr. CHO: Well, again, I think, it raises a lot of the same issues that we've already talked about in terms of- the safety and so forth. And - but also, as we get a greater understanding of how to manipulate species, and if we are able to indeed change one species into another, it does raise a lot of other issues even if they're not technically feasible right now.

But now would be a good time to talk about some of the issues like, for example, what are the implications for human life? What if you could change one species to another? Does that mean you can take a non-human species and make it human? And when does the species become human? What do you have to change about something to make it human? And then, does that entity have human rights and responsibilities, for example? And this is way off in the future if ever possible.

But I think this is one of the reasons why, if people get a little nervous about this kind of research, that they are kind of looking forward to the future and it would be good to have a more broad public discussion about that now rather than later.

FLATOW: Yeah. It's not too…

Dr. VENTER: I think this is one of those cases where the ethicists are willing to go a whole lot further than the scientists. We think talking about transforming or improving humans through these techniques is I think that kind of speculation that they think does make and should make people nervous, and I don't know of any scientists that are actually advocating it.

And I think if we can solve with single-cell bacteria some of the world's, you know, problems with food and fuel and contaminated air, I think those are very worthwhile goals. And it's certainly not our goal to transform or synthesize new humans or to try and, you know, repeat evolution at a much larger scale.

FLATOW: All right. We've run out…

Dr. VENTER: I'm sorry. Go ahead.

FLATOW: We've run out of time, Dr. Venter. But I think you made your point and made it very well.

I want to thank you for talking time to be with us. J. Craig Venter is founder and president of J. Craig Venter Institute in Rockville, Maryland, and Mildred Cho, associate director of the Stanford Center for Biomedical Ethics. Thank you for taking time to be with us. We're going to take a break. Come back and switch gears. Don't go away. We will be right back.


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