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gifrf ftmttghm Star Page 4A Sunday. October 29. 2000 HARP TO FIT? Scientists direct evolution to make better products All Sweaters 40 Off Suits Sporteoats 40-50 Off Sport Shirts 20-30 Off QMiBM H0MW-1O56 EASTWOOD MM! different amino acids at any given position. The drawback is that changes can only be made in one or two positions before the numbers get astronomical. In a typical 300-amino-acid protein, there are 5,700 ways to change just one amino acid, but 16 million ways to change two amino acids and 30 billion ways to change three.

9SS-31S1 OUTSOEBWM S1-7406 CGfitiai pigs and mice. Nor is molecular sex restricted to two parents. Maxygen improved subtilisin, an enzyme used in detergents, by shuffling 26 different subtilisin genes, each from a different type of bacterium. Maxygen pioneered the recombination approach, which it calls DNA shuffling. A similar approach is used by Enchira Biotechnology, a directed-evolution company in a Houston suburb.

Diversa and Applied Molecular Evolution tend to use mutations in a single gene. A drawback of the sexual approach is that some changes are not possible. Proteins are chains of amino acids, and if all the parent genes have the same amino acid in a given position in the chain, then all the offspring will as well. The mutation approach, in contrast, can systematically try out all 20 1 IMPORTANT TAiesday October 31, 2000 DEADLINE 4 i ft In Loving Memory improvement in two years. That enzyme, as well as two developed by rival Novo Nordisk, are being used in detergents.

Still, the market for industrial enzymes is less than $2 billion a year. That's why some directed-evolution companies are turning to pharmaceuticals, a much bigger market Maxygen is developing improved versions of proteins that are already being sold as drugs by other companies, posing a potential threat to other biotech companies. Maxygen, based in Redwood City, published a paper showing that it could improve the anti-viral activity of interferon alpha which is now used to treat hepatitis and other diseases, by as much as a factor of 285,000. Maxygen has licensed one such improved protein, which it will not identify, to H. Lundbeck, a Dutch drug company, which has not yet begun clinical trials.

Russell J. Howard, president and chief executive of Maxygen, said patents on human proteins or genes held by other companies would not stop Maxygen, because evolutionary techniques can be performed on the equivalent animal genes, which usually are not patented. There are two basic approaches to directed evolution, and they can be used separately or in combination. One is to create numerous mutations in a single gene. This is often done by deliberately introducing errors into a technique used to copy DNA.

One way organisms evolve in nature is tlirough chance mutations. The second way is to mimic another powerful method of evolution "sexual reproduction. Twoparents mix their genes and a different combination is given to each child. No child is exactly like either parent, and some children have traits not evident in either parent. In molecular sex, two or more similar genes are broken into pieces, which are then recombined in new configurations.

Unlike natural sex, molecular sex is not restricted to the same species. Scientists trying to improve a hormone might cut and paste the genes for that hormone from humans, cows, i By Andrew Pollack Y. Times News Service Novo Nordisk is designing better enzymes for laundry detergents. Dow Chemical is trying to cut the cost of food processing. Pioneer Hi-Bred is aiming for better crops, and Medlmmune is seeking a stronger version of its main drug.

What these works-in-progress have in common is their reliance on a new version of a process that is almost as old as life itself evolution. The process, known as directed molecular evolution, aims to harness the principle of survival of the fittest but at a microscopic level in a test tube rather than in the jungle, and in weeks rather than in millenniums. The result, proponents say, could be a whole panoply of improved drugs and industrial chemicals, and the creation of a new business sector. Three companies that specialize in directed molecular evolution Maxygen, Diversa and Applied Molecular Evolution have gone public in the last year. So has Genencor International, an enzyme company that uses directed evolution as one of its tools.

Directed evolution works by making numerous mutations in a gene that produces a particular protein. These mutated genes are put into bacteria to make the mutated proteins, which are then tested to see how well they perform a given task. The genes for the best proteins can be mutated again and again in hopes of evolving an even better protein. This is somewhat similar to the breeding of crops and livestock, but in this case it is molecules, not whole organisms, that are bred. "You can do better than nature," said James Young, executive vice president for research and development at Medlmmune, a biotechnology company in Gaithersburg, Md.

Medlmmune is one company benefiting from directed evolution, which is also called molecular breeding. The company's 2-year-old drug, Synagis, is an antibody used to prevent a serious infection in infants from respiratory syncytial virus. But treatment requires five injections over five months at a cost of $5,000, limiting Synagis' use to those most at risk mainly premature infants. If the drug could be made more potent, reducing the cost and number of injections, the market could be expanded to other infants. So Medlmmune turned to Applied Molecular Evolution, which evolved several improved versions, the best of which is 30 times stronger than Synagis.

Medlmmune expects to begin clinical trials to test the safety and effectiveness of one of the new antibodies next year. For all its promise, however, directed evolution remains largely unproved. Only three products all laundry-detergent enzymes have reached the market so far. Some say the technique might be too costly and complex for some applications. Shares of Maxygen and which have been public the longest, have declined steadily from their peaks in March, even as many other biotech stocks have risen.

Until now. scientists have improved natural proteins by making specific changes to them, a process called protein engineering. But scientists usually do not know enough to predict the best changes to make. Directed evolution removes the need to understand the protein in order to improve it. "Nature's been doing this for millions of years and nature has very little theory," said William D.

Huse, founder and chief executive of Applied Molecular Evolution. Of course, if natural evolution has honed proteins for millions of years, one could reasonably ask if there is much room left for improvement. The answer is yes, because evolution selects proteins that help an organism survive and reproduce. It does not select for a protein that is good at, say, doing the wash. One use of directed evolution is to improve enzymes, which are proteins that speed chemical reactions inside cells.

Genencor used directed evolution to achieve a fivefold improvement in the stain-removing ability of a bacterial enzyme in a year. Using the older technique of protein engineering, the company could make only a twofold S- Peggy Brannon Arnold si For the renewal of all Calhoun County business and professional licenses. After that date, 15 penalty and interest, will be added to the price of the license. 102544-21200 HOME AT LAST We are all God's children, From the morning hour of birth He lets us live laugh love. And have our day on earth.

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