Building Synthetic Genomes: Life from Scratch? Scientists in the lab of genome pioneer Craig Venter have built an artificial copy of a bacterium's genome. The new work, reported in the journal Science, marks another step toward being able to create artificial life by inserting an entirely synthetic genome into a bacterial cell.
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Building Synthetic Genomes: Life from Scratch?

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Building Synthetic Genomes: Life from Scratch?

Building Synthetic Genomes: Life from Scratch?

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JOE PALCA, host:

This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Joe Palca. Ira Flatow is away.

Later in this hour, global warming news. But 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 built an entire custom-made bacterial genome in the laboratory. This feat gets Dr. Venter and his team even closer to creating the first artificial organism. The team's work is published in today's issue of the journal Science. And Craig Venter joins us now from the World Economic Forum in Davos, Switzerland, to talk about it.

Welcome back to the program, Dr. Venter.

Doctor CRAIG VENTER (Founder and President, J. Craig Venter Institute): Hello. Thank you, Joe.

PALCA: So, tell me, did I say that right? Have - is that what you've done here, is you've created this entire genome of this bacteria not exactly from scratch, but from building blocks that are very small?

Dr. VENTER: We started with four bottles of chemicals, one for each letter of the genetic code, and built all 380,000 base pairs in a synthetic way in the laboratories. So, it's the largest man-made molecule of a defined structure to date.

PALCA: Now, if you - I mean - so it's a string of letters on a backbone - on the DNA backbone. How does it exist in a cell? Or - I mean, where does it get made after you make it in the lab?

Dr. VENTER: So the first parts of the stages and it was, sort of, looks like a final for a basketball diagram in terms of how we started with smaller pieces, combining them to make sets of larger ones. At each stage, we grew up those pieces in E. coli to make a lot of that DNA.

PALCA: E. coli is this bacteria that you guys use all the time.

Dr. VENTER: Yes, it's a workhorse that we use for making copies of DNA. So we can make a lot of it, and we use that for DNA sequencing to validate that we have the right structure. And then we kept growing bigger and bigger pieces so it would no longer grow on the bacteria E. coli until we switched to yeast. The people know that for making bread and beer. And larger pieces grew in yeast, but more importantly, yeast was able to do the tedious task of combining the pieces to make the entire chromosome from the design piece, smaller pieces that we put in.

PALCA: So this is now a bacterial chromosome that's sitting inside a yeast cell. Does this get the yeast confused about what it is?

Dr. VENTER: Well, fortunately, it doesn't or it probably would have deleted it. So, it grows basically as an extra chromosome inside the yeast and then we can grow up large amounts of it and isolate it. The genetic code for the cell we're using, Mycoplasma genitalium, is a little bit different than what would be used in E. coli or yeast. So if yeast tried to translate the chromosome, it would have frequent stop code on. So, Mycoplasma genitalium uses a slightly different reading of the genetic code. And so, that probably helps to keep it from confusing the yeast cell.

PALCA: So the genes in the - the bacterial genes in the yeast aren't doing what they normally do, but the reproductive - the machinery for reproducing the DNA is working properly, so it makes more copies of itself.

Dr. VENTER: Precisely.

PALCA: Got it. Okay. So what - okay, so what's the next step in terms of getting to your goal of an artificial organism?

Dr. VENTER: So the big challenge now - and that's why we've described this as the second of three steps. So there are two challenges: One, could the chemistry be done to make molecules as large? And this is over 20 times the next largest piece of DNA or any chemical molecule that's been made. And so, it was a complete unknown and DNA gets very brittle. These species don't like for you to take big chunks of DNA necessarily, so we had to develop a lot of new methods and tricks to make this happen. But it would just be a chemistry exercise if we didn't have a way to boot up the chromosome in the cell. So last year, we did the preliminary experiments on this where we isolated a chromosome from one Mycoplasma species and transplanted it into another one, and then selected further cells with the new chromosome. And we saw that we had a complete transformation of one species into another based on the new chromosome. So we know now that we should have the ability to combine the two approaches. And that's what we're working on now. We're now trying to boot up this chemically made chromosome in a bacterial cell.

PALCA: Now, I guess that - well, the question is - I mean, if - as I've heard you say, if it were easy, you would have done it already. But it seems a little confusing that if you can take one chromosome from a yeast and transplant it into another yeast and then you can make a chromosome - you've done the first two steps. Is there something different about your artificial chromosome that makes it harder to transfer into the related species, the Mycoplasma species?

Dr. VENTER: Well, some cells have protective mechanisms against similar DNA coming into their cells. It's what my colleague Ham Smith received a Nobel Prize for in 1978, discovering the restriction enzymes. These are the molecular scissors that cut DNA. And bacteria, sort of, used these as their immune system, so a piece of foreign DNA comes in, they can cut it up. The one that we did a successful transplant in, the recipient cell's genome was missing the restriction enzyme, and the genome we put in had one. So in fact, the genome we put in expressed the restriction enzyme and it recognized the chromosome in the cell is foreign and chewed it up.


Dr. VENTER: So we have to trick the cells and overcome numerous mechanisms to make this work.

PALCA: I got it.

Dr. VENTER: The other problem we found is that when we try to just take the DNA and put it back into Mycoplasma genitalium, when it's the same cell, the DNA is too close in identical structure, and you get recombination of the parent chromosome with the transplanted one.

PALCA: I see. So it's, sort of, your artificial chromosome merges with the one that's already there and, you know, you don't have a pure strain of your artificial one, which is what you're aiming for.

Dr. VENTER: Exactly. So we're having - there's numerous barriers that we're having to work around to make sure that we have truly the complete chemical genome that's run in the cell. But we know what the problems are and we're trying to find good workarounds for them.

PALCA: Right.

Dr. VENTER: So, I'm confident it will happen and it's - these are just slow, tedious experiments. Each experiment takes about six weeks before you even see enough cells to know what you have.

PALCA: Okay. Well, let me just - the final question I want to ask you and then I'll let you go back to the economic forum, which I gather is a pretty interesting place to be, a lot of people to - but, well, I guess I'm curious. Are you able to explain to people in Switzerland and to your colleagues what it is that - I mean, scientifically, this is interesting. Is there something broader and maybe financially important about doing something like this?

Dr. VENTER: And the answer is that, I think, yes to both. Our original motivation for doing these experiments was just to truly understand a minimal operating system for a cell, to understand cell structure. What do genes do? What's involved in life? What's involved in replication? And we've been talking about and working on various aspects of this since 1995 when we sequenced the first two genomes, and they were very different from one another.

But over that time, we've realized that these techniques could be very powerful for taking us to the next stages of applying biology to solve some of the world's problems. And that's what we're trying to do. We're trying to engineer cells to produce biofuels, seeing if we can get off the dependency on nonrenewable fuels, like oil and coal, to ones that we could make, starting with carbon dioxide, or if not that immediately, at least sugars. And we've made a lot of progress down that road. Now, these aren't completely synthetic chromosomes now because we don't have our proof of concept yet.

But I suspect in 10 years, these are the techniques that are going to be widely used to rapidly develop new chemicals in some places whether it's for pharmaceuticals, for plastics and hopefully for major sources of fuel.

PALCA: Excellent. All right, well, I wish you luck with that. Sounds like a fascinating project.

Mr. VENTER: Well, thank you, Joe. Nice to be with you.

PALCA: Okay. Thanks very much for talking with us today. That was Craig Venter. He is the president and founder of the J. Craig Venter Institute in Rockville, Maryland.

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