How Low Can You Go?

Like a refrain they can't silence, there's a question that's simple for scientists to pose but maddeningly difficult to answer: what is life? Yes, biologists can list the qualities of being alive--the basic ability to reproduce and to derive energy from the world outside, the rudimentary ability to grow and to excrete waste. But that dry recitation is deeply unsatisfying, so much so that many people--even a few scientists--cling to the romantic idea that there must be a vital spark, something that cannot be reduced to mere biochemicals, that imbues inanimate matter with the breath of life. That notion, however, may be doomed. Researchers are on the brink of determining the minimum number of genes that life needs to live. And to really prove their case, the scientists from The Institute for Genomic Research (TIGR) might have to do what many researchers have envisioned, what some have warned about, but what only science fiction has dared: they might have to create life in a test tube.

It isn't called ""tiger'' for nothing. TIGR, in Rockville, Md., has hunted down more genomes than anyone else, and once it catches sight of its prey it is relentless in pursuit. TIGR founder J. Craig Venter figured out, in the mid-1990s, a speedy way to discover the entire genetic repertoire--called the genome--of a bacterium, and last year he vowed to beat an army of government-funded scientists to the biggest quarry ever: the human genome. In the meantime, TIGR has sequenced the genomes of 11 microorganisms, including bacteria that cause syphilis, ulcers and Lyme disease. ""The question that came out of this,'' says TIGR president Claire Fraser, ""is, are all these genes essential?'' Or are some the biological equivalent of magazine blow-in cards, superfluous bits that can be pulled out without crippling the main product?

To answer how many genes are enough for the most stripped-down form of life, Fraser and her team set to work on a parasite called Mycoplasma genitalium. With 470 genes, it has the smallest genome known (humans have an estimated 80,000 genes). The TIGR scientists started knocking out mycoplasma's genes: the researchers slipped, into the parasite, bits of DNA that act like a toddler sneaking onto your word processor. The rogue DNA messes up a gene so badly--inserting ""gaga'' into ""ta-ta'' to produce the incomprehensible ""tagagata,'' for instance--that the gene, like the document after the tot gets a hold of it, is destroyed. Then the scientists observed which knockouts mycoplasma survived. Under ideal lab conditions, in which mycoplasma is kept warm and well fed, TIGR discovered that about 170 of the bug's genes are superfluous. Knock 'em out, and the little guy lives on.

But just because the bug can survive without one gene doesn't mean it can live without all 170. To discover a truly ""minimal gene set'' for life, the researchers would have to string genes together, one by one. Eventually, they would reach a tipping point, where adding one more gene would turn nonliving chemicals into life itself. Struck by the prospect of venturing into ""dangerous territory,'' Venter says, ""we stopped our experiment. We thought we should have ethical input before creating life in the lab.''

They got in touch with bioethicist Arthur Caplan of the University of Pennsylvania. Caplan assembled 20 theologians, philosophers, lawyers and ethicists to ""get out in front of the science.'' They expect to issue their verdict in a few months. ""We are trying to answer whether creating life in a test tube would violate religious prohibitions, and whether it could be misused,'' Caplan says. There will likely be many minimal genomes--sets of genes that produce life--so it's not as if TIGR will uncover the formula of life. But it will probably find one formula that works. ""I think what they discover will be a threat to the view that there is some magic, secret, outside force creating this thing called life,'' Caplan says. One day a TIGR scientist will drop gene number 297 into a test tube, then number 298, then 299 . . . and presto: what was not alive a moment ago will be alive now. The creature will be as simple as life can be. But it will still be life. And humans will have made it, in an ordinary glass tube, from off-the-shelf chemicals. There will be no going back.

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