To understand biological processes, it’s necessary to understand the chemistry underpinning them. This is why when biologists discover a new biological phenomenon, chemists are right behind, seeking to explain that phenomenon through chemical principles. “As a chemist who works at the interface of chemistry and biology, I have always been fascinated by and admire the discoveries biologists make,” says Hening Lin, Chemistry and Chemical Biology. “Our work follows on their discoveries. But the research I’ve been doing recently has turned that around in a sense. Our findings are now helping biologists understand biology. And it’s helped me to understand that at the molecular level, biology is chemistry.”
Lin’s research that focuses on a family of seven proteins called sirtuin enzymes has broken new ground in a number of ways. His work follows on that of other researchers studying aging who linked some of these enzymes to longevity. Sirtuins act on various proteins, including histones, which are important for organizing the DNA in cells. Three sirtuins—SIRT1, SIRT2, and SIRT3—remove a two-carbon modification called acetylation from histone. When calories are restricted, the sirtuins become more active, changing gene expression and metabolic pathways, thus increasing the health and lifespan of the organism.
Orphan Enzymes and Anticancer Activity
This was well and good, Lin says, but what were the other four enzymes in the sirtuin family doing? “I called them orphan enzymes because no one knew what enzymatic activity they had,” he explains. “They showed either a very weak ability to remove acetylation or none at all.”
Lin and his lab eventually discovered the activity of SIRT5, which removes a negatively charged four-carbon modification called succinyl, and of SIRT6, which removes long chain fatty acyl groups from proteins. “Finding these activities for the orphan sirtuins helped us to understand their biology better,” says Lin. “Before our discoveries, no one could say what these sirtuins were doing to achieve their physiological function. Now we can explain the biological function of these enzymes much better by looking at these newly discovered activities. That’s very satisfying for me as a chemist.”
Based on this new understanding of sirtuin activity, Lin further developed prototype drug molecules that can inhibit the activity of sirtuins potently and selectively. He collaborated with Cornell researchers Robert S. Weiss, Biomedical Sciences, and Richard A. Cerione, Chemistry and Chemical Biology/Molecular Medicine, to demonstrate that these molecules have excellent anticancer activity.
In fact, when tested on mouse models, one experimental drug stopped tumors from growing. The research showed that the experimental drug promoted the degradation of a very important oncoprotein that is necessary for the growth of many human cancers. “They’ve been trying to target that oncoprotein for a long time without success,” Lin says. “It’s a pretty exciting development.”
Lin’s research brings with it great potential for the development of anticancer drugs.
Lin’s research brings with it great potential for the development of anticancer drugs, but it will take many years of improvements and testing before any drug can go to clinical trials, he explains. In the meantime, while further developing the prototype anticancer drugs, he continues to work on the orphan sirtuins. The activity of SIRT4, in particular, is still a mystery. Lin also points out that almost every family of enzymes has some orphans for which no activity has been identified. “It will be important to understand them, too,” he says.
Inspired to Push the Boundaries
Lin’s research on sirtuins helped him to win a prestigious Howard Hughes Medical Institute (HHMI) Investigatorship. The award is good for five years, covers Lin’s salary and equipment needs, and requires him to spend at least 75 percent of his effort on research. There are no restrictions on what that research can be. Lin is already reveling in the freedom to pursue ideas that push the boundaries of what is known or expected.
“Normally it’s hard to get funding for the kind of research we want to do, to find novel activity or function for a presumed enzyme that has no known activity,” Lin explains. “The HHMI support will fund early work on the enzymes. Once we’ve found activity, we can apply for other grants to fund further research.”
As a scientist working in academia, Lin is quite used to continually showing research results and publishing in peer-reviewed journals, but the Howard Hughes Investigatorship brings a new kind of pressure. “It’s really pushing me to do better than ever,” he says. “The investigatorship has to be renewed every five years, and to be renewed you have to do excellent research. It’s great because it forces me to think bigger, not to just make incremental progress.”