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NEWS&ANALYSIS

weedy lamentous algae are displacing an array of larger, ashier shell-building species. That could be bad news for tourism if acidifying waters spark similar changes elsewhere, she says: People are going to be much less likely to pay to go see a bunch of eshy seaweeds. A third emerging approach is to study the evolutionary implications of acidication by pursuing longer and larger experiments. Several teams, for instance, have launched years-long rapid evolution experiments to evaluate how organisms adapt to acidied conditions. In one, a team led by David Hutchins of the University of Southern California in Los Angeles spent nearly 4 years raising about 600 generations of an important marine nitrogen-f ixing bacterium, Trichodesmium, in either current or more
C H E M I ST RY

DAVID MALAKOFF

Awesome Synthesis Could Boost Protein-Based Drugs


Like mountain climbers always on the lookout for a higher, more dramatic ascent, synthetic chemists constantly strive to make larger, more complex molecules. The challenge forces them to invent novel chemical techniques, and the moleculesonce in handcan spur further studies that lead to broad insights in biology and medicine. When you climb a mountain, you dont know whats on the other side. But at least you can nd out, says Samuel Danishefsky, a synthetic chemist at the Memorial SloanKettering Cancer Center (MSKCC) in New York City and Columbia University. Now Danishefsky and colleagues have scaled a peak that offers a good view of not only their latest molecular targeta protein known as erythropoietin (EPO)but a host of other molecular landmarks as well. Last week, the MSKCC-Columbia team reported online in Angewandte Chemie that for the rst time they had synthesized EPO with a uniform coating of sugar chains that decorate the outside of the natural molecule. EPO is a hormone produced by the kidneys that stimulates the production of red blood cells. Its also administered as a drug, sometimes called a biologic, to anemia patients, as well as those with cancer who have undergone radiation and chemotherapy treatments that can damage red blood cells. EPO is the most complex biologic synthesized to date, says Laura Kiessling, a chemist at the University of Wisconsin, Madison, who calls the accomplishment remarkable. Peng George Wang, a synthetic chemist at Georgia State University in Atlanta, agrees that the new synthetic ascent is an awesome achievement, because the researchers not only synthesized a complex protein but also decorated it with a uniform set of sugarsa feat that has long been out of reach. A decade ago, we could not imagine it could be a target. It was just too complicated, Wang says. Danishefsky notes that the feat rests on a decade of advances in fabthesis of EPO has a broader signicance. Medicinal chemists have long synthesized small druglike molecules and then tweaked their structures and watched to see whether these changes reduced the compounds toxicity, improved the amount of time it circulated in the body, or changed other hallmarks of a good drug. But this tweakand-peek strategy has largely been impossible with complex biologics. Take EPO, for example. When harvested from cell cultures for use as a drug, it forms a mixture of molecules in which three of the four sugar chains differ widely. Researchers have long known that EPOs sugars are essential to its function. But it has been difcult to tease out the precise role of all the different sugars in the various chains. Now, because the new synthetic techniques make it possible to create single glycoforms of the protein, researchers can synthesize different versions and systematically test them to see how the proteins function changes. That opens up an enormous opportunity to take the chemistry and use it to probe a biologics secrets, Danishefsky says. His group is now doing just that, he says. Wang predicts that chemists will soon extend the new synthetic sophistication far beyond EPO, with repercussions including illuminating how glycoproteins function and designing novel medicines. I think the implications for biomedical research are enormous, he says.
ROBERT F. SERVICE

ricating portions of the protein, linking them together, and then coming up with novel chemical techniques to tie sugar chains on at precise locations. Although the version of EPO the group made has shorter sugar chains than those typically found in organisms, biochemical studies showed that it carried out the same function of stimulating the production of red blood cells. But Peng and others argue that the synVOL 338 SCIENCE

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5 OCTOBER 2012

www.sciencemag.org

Published by AAAS

CREDIT: MEMORIAL SLOAN-KETTERING CANCER CENTER

New feat. Synthesis of proteins with uniform sugar chains (colored shapes) should aid drug development.

Downloaded from www.sciencemag.org on November 1, 2012

acidic conditions. Bacteria in the acidied tanks greatly stepped up their nitrogenxing activity over time, he reported. And, surprisingly, they didnt revert back to lower activity when moved back into the less acidic tanks, suggesting true adaptive changes, he says. Genetic studies backed up that idea, he reported: Acidication could have major implications for the future of the marine nitrogen cycle by altering bacterial populations. Other researchers are taking to the eld to nd wild populations that have already adapted to acidic waters, which occur naturally in some parts of the ocean. Basically, space is substituted for time, and we just go see if Mother Nature has already created populations that are ne-tuned, says Hofmann, who is helping organize one such

collaboration, the Ocean Margin Ecosystems Group for Acidication Studies (OMEGAS). It is studying sea urchins and mussels along North Americas West Coast, where waters tend to get more acidic along a southto-north gradient from California to Canada. As a result of natural upwelling, the waters off Oregon are like it is already 2100, says Hofmann. She reported preliminary studies showing that sea urchin larvae there tolerate acidic water better than their California cousins. That early picture from OMEGASs crystal ball is good news, Hofmann says, because it suggests that the thorny urchins have the resilience and genetic variation sufcient to tolerate global acidication. Still, she says, thats an experiment shed rather not run.

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