Crock Pots Get Smart

Lab robots have been knitting together short chains of DNA or proteins for years, allowing scientists to test novel variations as drugs and gene probes. Now these machines could soon be routinely pumping out a third class of compounds--notoriously complex biomolecules called oligosaccharides, branching sugar chains involved in everything from immune cell recognition to the spread of cancer. New tools described in today's Journal of the American Chemical Society should help chemists concoct their own easy-to-follow recipes for synthesizing oligosaccharides in one simple step.

Cooking up DNA and other straight-chain biomolecules is pretty easy--just link together their molecular building blocks like boxcars in a train. But the sugars that form oligosaccharides are more like a child's Lego bricks that snap together into a myriad of shapes. The conventional solution for synthesizing oligosaccharides has been to cover up each sugar's reactive groups with "protecting" groups until only one is free to react. But this chemistry is still so complex that Ph.D. students can spend a year just learning how to link two or three sugars together.

Previous work had shown that researchers could create a simple oligosaccharide by throwing together the right blend of predesigned sugar building blocks capped with protecting groups. By timing how fast various sugars react, the researchers could control the order in which differently masked blocks will attach together. The speediest blocks latch onto one another first, while slower ones amble up to the remaining available reaction sites.

Now Chi-Huey Wong and his colleagues at The Scripps Research Institute in La Jolla, California, have expanded the pool of ingredients by building 50 masked blocks and clocking their reaction rates. The team used this information to design a computer program in which users type in the sequence of a desired oligosaccharide. The computer churns out a recipe of exactly which masked building blocks must be dunked in the reaction stew. So far, Wong and his colleagues have made two- and three-sugar oligosaccharides in minutes.

"It is very important work," says Samuel Danishefsky, an organic chemist and oligosaccharide expert at the Sloan-Kettering Institute for Cancer Research and Columbia University in New York City. "It helps set the stage for what will be automated synthesis for complex oligosaccharides." But it may take years, the scientists acknowledge, before robots can turn out oligosaccharides like those in the body, which consist of well over 100 sugars.