Structural biologist Ming Lei was a graduate student at Harvard University when he happened to read an article in the Boston Globe about a recent discovery that would change the course of his career.
The article described the research of Nobel laureate and HHMI investigator Thomas Cech who was studying the telomere, the specialized region of DNA that acts as a cap at the ends of chromosomes to keep genetic information from being lost during cell division. An enzyme known as telomerase maintains telomere length—an important role since telomeres shorten with each cell division. Cells without telomeres can stop dividing and become dormant, leading researchers to begin thinking about the role of telomeres in aging.
The newspaper reported that Cech’s lab had cloned and sequenced the gene for a component of telomerase. “It was very big news,” Lei recalls, because telomerase is crucial for maintaining cancer cells’ immortality. In about 90 percent of cancer types, cancer cells recruit telomerase to keep telomeres long so that they can divide and replicate indefinitely. Scientists now had a better understanding of the structure of telomerase, opening the door for blocking its function in cancer cells. “So if you can inhibit telomerase, ideally you can kill cancer cells,” Lei explains.
Intrigued by the discovery, Lei decided to focus his research on telomeres. After completing his Ph.D. at Harvard, he took a postdoctoral position in Cech's lab at the University of Colorado at Boulder. “I was fortunate to be there at the beginning of this fantastic field,” says Lei, “when not much information was available about the structure of telomeres.” During this time, Lei added to that information by describing the structure of the human POT1 (Protection of Telomeres 1) protein, which, among other functions, covers and protects the very end of human genome.
Because telomeres that are too short can accelerate aging, while telomeres that remain long can aid the survival of cancer cells, “you need a very subtle balance,” Lei says. The detailed molecular mechanisms that regulate telomere length are not fully understood, however, and investigating these mechanisms is one of the major goals of Lei’s lab at the University of Michigan.
This research has important therapeutic implications, he says. Cancer cells exploit telomerase so they can multiply and spread. Understanding how cancer cells activate telomerase could help identify new cancer drugs. “If we understood how cancer cell telomeres are maintained and the differences in maintenance between cancer cells and normal cells, we might be able to design small molecules that block certain processes that are specific only to cancer cell telomere maintenance.”
While most labs that study telomeres take a genetic approach to understanding these regions of DNA, Lei’s lab studies telomeres on a structural and biochemical level to reveal the protein interactions. “That has become the central dogma in my lab,” Lei says. “We’re searching for important interaction surfaces at telomeres.” Identifying these points of interaction is critical, he says, because it can uncover potential drug targets. By interrupting these interactions, researchers may discover a way to thwart cancer cells.
In one study, Lei revealed that two telomere proteins, TRF1 and TRF2, interact with a wide variety of proteins that are involved in DNA processing and repair. Before Lei’s study, very little was known about how these two telomere proteins can interact with such an unusually large number of other proteins. He showed that despite the very similar structures of TRF1 and TRF2, they each recruit different proteins to the telomere. For example, Lei’s investigations revealed that a telomerase inhibitor, PinX1, interacts with TRF1 to prevent the telomere’s lengthening.
Lei did not originally set out to study telomeres. In fact, he never even planned to be a biomedical researcher. As an undergraduate student at Beijing’s Tsinghua University, he studied condensed-matter physics. But while pursuing his master’s degree in physics at McGill University, he realized he was in the wrong field. “I came to believe that biomedical science was the science for the new century,” Lei says. After graduating from McGill, he studied biophysics at Harvard, where he read the newspaper article that would change his course again. His timing couldn’t have been better. “As a structure biologist, I basically witnessed the development of the telomere field.”