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Expanding life's alphabet

New Scientist

IN AN attempt to go one better than nature, researchers in California are expanding the genetic code that has given rise to just about every form of life. They hope to create artificial DNA capable of producing proteins no one has ever seen before.

Apart from RNA viruses, all organisms carry their genetic information in strings of DNA built from the same 4 bases, adenine, which pairs with thymine, and cytosine, which pairs with guanine. These bases are grouped in units of three called codons, and each codon adds one of 20 naturally occurring amino acids to protein chains.

Researchers at the Scripps Research Institute in La Jolla, California, led by Floyd Romesberg have succeeded in adding new players to the original cast of four DNA bases, increasing the number of ways bases can pair up to produce new codons. These in turn should make artificial amino acids and hence new proteins, they say.

Researchers have experimented with unnatural bases since the 1980s, but no one has been able to incorporate them into DNA without making it unstable. Now Romesberg's and his colleagues have overcome these barriers. They have made 20 unnatural bases which, like natural bases, link with sugars to form nucleosides. "The biggest surprise was there's nothing special about a [natural base]," says Romesberg.

The group then inserted one of these artificial bases into single strands of DNA. During DNA replication, enzymes called polymerases read single-strand templates and then add appropriate bases to form pairs-adenine to thymine, cytosine to guanine and vice versa. An unnatural base has a different shape and binds differently, and in early experiments the team found that several polymerases would add unnatural partners to such bases. The problem was that replication then stopped.

To overcome this, the group tested different polymerases and unnatural bases until they found a combination that worked without shutting the system down. They have now successfully replicated DNA strands beyond the formation of the unnatural pair. The process remains slow, because the researchers are working by trial and error.

The team's ultimate goal is to insert the artificial DNA into bacteria and get the new codons read without disrupting normal cellular operations. "That is not an easy project," says Eric Kool, a chemist at Stanford University in Palo Alto, California. But if successful, bacteria could produce completely unnatural proteins for use in medicine or chemistry.

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Author: Mark Schrope

New Scientist issue: 8th April 2000

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