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Chemists Chris Chang and Wilfred van der Donk say biologists and chemists have begun to understand what each can bring to the table to explore how the body works and to synthesize more efficient and cheaper drugs.
Each of the dozens of types of GAGs has a different function. At a molecular level, their distinction lies in the sulfate clusters—groups of sulfur atoms—that decorate the carbohydrate strings. For biologists trying to study each molecule’s effect on the brain, the sulfate groups were frustratingly similar. There was no way to isolate only one type of GAG at a time. Moreover, biologists couldn’t use genetics to study the sulfate clusters because DNA doesn’t directly encode carbohydrates. And blocking the addition of all the sulfates at once caused such chaos that it was hard to tell what was what.
“And so here’s where my chemistry background became very important,” says Hsieh-Wilson. “We needed to be able to synthesize and study the different GAGs one at a time. So, we used organic chemistry to design and synthesize these very complex molecules from the ground up.”
Hsieh-Wilson’s group synthesized different GAG molecules and devised ways to block each one individually. Then, they added the synthetic molecules to cells to study the effect of specific sulfate clusters. By experimenting with blocking and unblocking different combinations of GAGs, the researchers began to decipher how the position of the sulfates offered molecular instructions, telling the GAGs what functions to perform in the cell.
“What I think is cool about being an organic chemist is that you can create molecules that are entirely new, that no one has ever dreamed of, or molecules that only exist in minute amounts in Nature,” says Hsieh-Wilson. “And then you can use these molecules to discover something new and exciting about biology.”
Although Hsieh-Wilson still has lots more to discover about GAGs, she’s already found that the carbohydrates are involved in the growth and regeneration of nerve cells after injury. With this fundamental insight, she and her team are working to create a therapeutic approach to help treat spinal cord injuries.
Every organ in the human body functions through a constant interplay of chemicals. By modifying those chemicals—to block them, track them, or isolate them—chemists can add to the knowledge of how the body works.
Among the molecules constantly moving within cells is a large group of signaling molecules called protein kinases. There are more than 500 of them—and, like GAGs in the brain, they have widely varying functions but very similar chemical structures. To figure out which kinases do what, HHMI investigator Kevan Shokat developed a strategy similar to Hsieh-Wilson’s approach to looking at GAGs.
Protein kinases work by binding ATP—a cellular source of energy—and then using it to add phosphates to proteins, a modification that changes the function of those proteins. Biologists know how to block kinases from binding to ATP, which shuts the enzymes down. But the action shuts down many different types of protein kinases in a cell at once.
“After six months of scrambling my brain on how I could tackle this problem through chemistry, I realized that I could chemically engineer the ATP pocket of one kinase at a time so that enzyme could be blocked specifically,” says Shokat, at the University of California, San Francisco. First, the genes for kinases are removed from a human cell grown in a lab dish. Then, the newly engineered kinases can be added.
His method paid off: labs using his technique have discovered the function of more than 70 kinases. His own lab is now focusing on the role of some of these kinases in cancer development.
“I call the whole thing ‘chemical genetics,’” says Shokat, “because neither chemistry nor genetics could have solved this problem on its own. You take the best of both worlds.”
Photos: Chang: Noah Berger / AP, ©HHMI; van der Donk: Darell Hoemann / AP, ©HHMI