Molecular and Cell Biology Laboratory
Ralph S. and Becky O'Connor Chair
Vicki Lundblad, a Professor in the Molecular and Cell Biology Laboratory, seeks to understand the unique properties of telomeres, the specialized structures found at the ends of linear chromosomes. Telomere function relies on a dedicated enzyme called telomerase, which is responsible for keeping chromosome ends fully elongated. In human cells in which telomerase has been experimental manipulated, the resulting loss of DNA from chromosome ends results in a gradual loss in cell proliferation. Most human tissues have very low levels of telomerase, whereas in cancer cells, telomerase is dramatically up-regulated. Scientists believe that this up-regulation is an essential step in tumor development, and thus, drugs that target telomerase could provide a highly specific anti-cancer therapeutic. Conversely, telomere maintenance may also be a crucial determinant that influences the proliferation of certain tissues during the aging process. Even within the normal human population, variations in telomere length correlate with the onset of certain age-related diseases.
Past work in Lundblad's laboratory pioneered the discovery of genes that encode protein subunits of the telomerase enzyme, using baker's yeast as an experimental model system. Her group has also elucidated a regulatory mechanism for telomerase, by demonstrating that a telomere-bound protein called Cdc13 is responsible for recruiting telomerase to chromosome ends. Lundblad is currently expanding on these studies, through detailed mechanistic analysis of telomerase and Cdc13, as well as the identification and characterization of new genes that make important contributions to telomere biology.
During our lifespan, our bodies rely on cell division to replenish our lungs, skin, liver and other organs. However, most human cells cannot proliferate indefinitely. Instead, cells have a "clock" that counts down the number of cell divisions. Once cells in a tissue can no longer divide, the ability to withstand the degenerative aspects of aging declines.
Vicki Lundblad discovered that the molecular basis for this clock resides at the very ends of our chromosomes. These chromosome ends — called telomeres — get nibbled away with each cell division, until they become so short that cells are prevented from dividing further. Although Lundblad first uncovered this process in a simple single-celled organism, subsequent studies by clinicians have shown that whether this telomere clock counts down faster or slower is a contributing factor to age-dependent diseases such as bone marrow failure, pulmonary fibrosis and late-onset diabetes.
However, this clock can be re-set by a telomere-dedicated machine called telomerase which re-elongates telomeres, thereby rescuing them from oblivion. Lundblad's group pioneered the discovery of the components of telomerase, once again using a single-celled organism (baker's yeast). Because the process of cell division is basically the same in baker's yeast and human cells, her laboratory's findings provided the tools for uncovering the components of human telomerase. With telomerase components in hand, this has allowed experiments to determine why the telomere clock might count down faster in some cells. Lundblad postulated that these variations are likely due to be how telomerase finds its way to chromosome ends in order to re-set telomere length. In support of this, her laboratory has made a series of discoveries showing that the surface of telomerase has multiple docking sites that ensure its efficient delivery to chromosome ends. This provides an unexpected insight into how telomerase might be manipulated to promote healthy aging.