When Genes "Breed" In The Lab, A Suprising Number Of Their Offspring Are Supergenes

November 18, 1998

SEX at a molecular level is spawning an elite class of proteins. Maxygen, a company in Santa Clara, California, has used a DNA shuffling technique to create interferons that are dramatically more effective against viruses than any produced naturally by the immune system. It has also made ultra-efficient versions of an industrial enzyme.

When organisms reproduce sexually, the offspring end up with a mix-and-match set of genes inherited from both parents. Maxygen's technique is similar, except the parents are a series of related genes. These are cut into pieces, shuffled together and then assembled to form a new genetic generation. Some of these daughter genes can manufacture proteins that are much better at certain tasks than nature's originals. The best ones can be screened out and shuffled to produce whole lineages of superior descendants, in a process mimicking evolution by natural selection.

Maxygen's technique was described earlier this year in Nature (vol 391, p 288). Now its potential is beginning to be realised. The parent genes are first broken into fragments by shattering their DNA with ultrasound, or cutting them up with an enzyme called DNAse. They are reassembled into daughter genes, comprising fragments from several parents, using a variant of the DNA-building polymerase chain reaction. Short template or "primer" sequences ensure that the fragments are stitched together in the correct order to produce a functioning gene. The daughter genes can then be inserted into bacteria or fungi, where they begin making protein.

To make superior versions of an industrial enzyme, the identity of which is still secret, Maxygen's scientists isolated genes from 26 microorganisms which each make their own versions of the enzyme. Using its system of DNA shuffling, Maxygen made 600 new daughter genes, 77 of which produced superior enzymes. Screening showed up variants which functioned better than natural enzymes at high, low or intermediate pH. Others were more resistant to solvents or heat. "They're all highly significant commercially," says Pim Stemmer, Maxygen's vice-president of research.

Maxygen has also shuffled genes that make the 20 known human interferons. This time they made 2000 daughter genes-and once again, the results were spectacular. The best interferon produced by the genes was 285 000 times as potent as interferon alpha-2b, which is marketed as a drug, as measured by its ability to protect cultured cells against a mouse virus. It could prove a major moneyspinner for Maxygen. Sales of interferon alpha-2b, which is used to treat viral diseases and cancer, pull in $600 million each year for Schering-Plough of Berlin.

At present the most popular method of coaxing genes into making new versions of proteins is random mutagenesis, in which ultraviolet light or a DNA-disrupting chemical makes genes mutate. But most of these mutations are damaging, with typically only 1 per cent yielding genes that make improved proteins. By comparison, 13 per cent of the enzymes Maxygen produced through DNA shuffling were superior. "DNA shuffling is a very powerful technology," says Andy Ellington of the University of Texas at Austin, who is currently comparing the technique with random mutagenesis.

It is not even necessary to know the identity of all the genes which might profitably be "mated" with one another, says Stemmer. Fragments of DNA from a known gene can be used to trawl genomes of other species for related genes.

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New Scientist

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