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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 24, 2002

A New Form of Hype, uh, Life?

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Posted by Derek

Craig Venter and his wife Claire Fraser had a controversial effort going a few years ago, known as the "minimal life" project. The question was: what's the smallest number of genes an organism can have and still function? They got reasonably far along with it, then shelved it for a number of reasons. I'd seen interviews with Venter recently where he was mentioning it again, so the news that the project is underway again didn't come as a shock.

You wouldn't want to look for a minimal gene set starting from something as complex as a mammal - or any decent-sized organism, for that matter. They picked a really small single-celled creature called a Mycoplasma. It's a good choice, because they're pretty minimal organisms to start with - they're so small (and can be so hard to detect) that over the years they've been a major pain in the neck as a contaminant in cell culture labs. The species that they chose, for example, has only 517 genes. The plan is to knock them out systematically, one at a time, and see if the resulting organism can survive (and if it can, what its limitations might be.) It's a large project, but not a prohibitive one - before they project was mothballed in 1999, they'd already narrowed the list down to about 300 genes.

There could be some complications: for example, depending on the order in which things get knocked out, you could end up assuming that a particular function is non-removable when in fact it could be part of a system that has to be taken out all-or-none. These patterns will probably become apparent as the work goes on, and should provide some interesting information.

Once they get down to the minimal instruction set, we get into the territory that unnerves people. The amount of DNA that we're talking about is still going to be long, but in relative terms it might well be short enough to produce in a DNA synthesizer. If you do that, and toss it into a cell that's had all its genetic material stripped out, you could bootstrap your own organism. That'll be weird in two ways: it'll be a new species, made up on the spot, and it'll have been made, to some extent, from reagents on the shelf.

There shouldn't be anything unsettling about that, but to many people there is. It's true that a virus has been recently been produced in the same way, but most people (including me) don't really think of viruses as being living organisms. This experiment doesn't bother me, partly because they're still relying on all the already-built cellular machinery to accept the new genetic material. Building a whole cell from scratch would be a much greater effort, one that I really don't think anyone can swing yet. But they will, at some point. . .vitalism dies hard: it's going to be interesting to see the press coverage when it finally bites the dust in wide-screen stereo sound.

Editorials are already appearing - the link takes you to the Washington Post, which seems not to have been keeping up with the pace of molecular biology. It's a little late to worry about "a living thing that is at least partly a human creation," guys. The bacteria that have been engineered into making interferon and insulin for us for years now are partly a human creation, you know, as are uncounted recombinant cell lines throughout academia and industry. If you want to get picky about it, chihuahuas and sweet corn are partly human creations, too: we just took longer to make those because we didn't have very good tools.

Some of that coverage is going to be breathless what-if-the-new-life-form-escapes stuff, no doubt. I think the answer should be clear to anyone who's thought about the biology: what will happen is, the organism will be outcompeted very quickly and die out. Think about it - if it were easy for an organism to survive in the wild with such a small genetic code, there'd be some critters out there doing it. Perhaps when life was just getting going it was possible to get away with it, but not now, after billions of years of fine-tuning. As Neal Stephenson colorfully puts it near the beginning of his Cryptonomicon:

Like every other creature on the face of the earth, (he) was, by birthright, a stupendous badass, albeit in the somewhat narrow technical sense that he could trace his ancestry back up a long line of slightly less highly evolved stupendous badasses to that first self-replicating gizmo - which, given the number and variety of its descendants, might justifiably be described as the most stupendous badass of all time. Everyone and everything that wasn't a stupendous badass was dead.

No, this is going to be one finicky creature, able to survive only where everything is built for its pleasure. For that reason, I'm not sure about its usefulness, either, as a platform for adding new functions. Venter's been talking about using this to engineer an organism that will be able to make hydrogen for fuel cells, or take up carbon dioxide to ameliorate greenhouse warming. I'd have to classify both those reasons as, well, hooey. There are already plenty of organisms that will take up carbon dioxide. You probably have some big ones growing in your back yard, and they're a lot more robust than this organism will be. It'll still be frail enough to be a tremendous headache to culture and keep happy, unless you start adding stuff back into it to make it more robust and free-living. And if you're going to do that, why not start off with something that's already been optimized for being robust and free-living? Don't get me wrong: there are a lot of good scientific reasons to do this work. I just worry that the explanations offered for the general public are - at the very least - inadequate.

The whole project could be explained in terms of cars and trucks: what we have here is an attempt to disassemble a small car down to the most primitive conveyance possible, by removing parts one by one until nothing extraneous remains. This stripped-down go-cart will indeed be a new vehicle, one that's so simple that it could be built from things lying around the house, stuff that you wouldn't normally associate with cars at all. People that think that you need a huge factory to build a car will be amazed. But this thing won't stand a chance on the open road, and will probably barely make it around your back yard on a warm day. You'll be able to turn it into any sort of motorized thing you want, by adding stuff back on to it - but you might be better taking one of the more complicated, capable cars that zip around on the main roads and work on them instead. (It's been a while since I came across a metaphor I could, uh, ride that far. . .)

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