Vicki Lundblad
In junior high school, Vicki Lundblad threw herself into science fair projects. Once she tested whether skin substances repel mosquitoes—and mistakenly released more than 100 insects into her house. Despite her initial enthusiasm for experimental work, she backed off from the pursuit in high school and immersed herself in music. She played the cello for hours each day, relishing the demands and creative opportunities. Lundblad holds a similar attitude toward research.
After college, where she vacillated between mathematics and biology, she decided to enter graduate school in biology. There, she heard a talk by Jack Szostak about his studies with Elizabeth Blackburn on telomeres, the caps that protect chromosome tips. Szostak and Blackburn had proposed the existence of an enzyme that adds DNA sequences to chromosome ends, thus enabling their maintenance, given that the cell-division process whittles down these termini. A year later, in 1983, Lundblad joined Szostak’s lab as a postdoc and strategized how to find this hypothetical molecular machine. She reasoned that telomeres of yeast with a faulty version of the enzyme, now called telomerase, would gradually shorten over many generations. Eventually this erosion would eat into sequences that signal DNA health; without that indicator of well-being, the cells would stop duplicating. By identifying yeast with those properties, she would unearth genes for constituents of the enzyme or its assistants.
In 1989, Lundblad found one such gene, which she named EST1 (for ever shorter telomeres), and we now know that the Est1 protein is a telomerase subunit that regulates its activity. Subsequent work extended Lundblad’s idea about the connection between short telomeres and cell-division capacity to mammals. Like yeast, many human cells fizzle in culture dishes when their telomeres have shrunk too far. This phenomenon underlies the body’s inability to rejuvenate particular tissues after injury or as we age.
Lundblad had noticed that a small proportion of yeast with flawed EST1 escape its lethal consequences. She and Blackburn discovered that these cells—despite inadequate Est1—rebuilt withering chromosome ends. They thus unveiled a telomere-replenishing system that did not rely on telomerase and predicted that similar schemes exist in mammalian cells. This idea proved correct. Some human cancers employ the telomerase-independent mechanism to refurbish telomeres, thus fostering unbridled proliferation.
Fueled by her success at identifying EST1, Lundblad sought additional genes involved in the chromosome-end reconstructing process when she established her own lab. She designed an approach that would expose not only participants in the bare-bones test-tube reaction, but also elements that govern telomerase’s behavior in living cells. This ambitious and painstaking project—as part of it, her team individually transferred 35,000 yeast colonies from petri dishes into culture broth—uncovered three additional genes involved in the telomerase pathway.
In parallel with Tom Cech, Lundblad found that the product of one of these genes resembles enzymes that copy RNA to make DNA—a hallmark of telomerase. The scientists had pinpointed the enzyme’s core.
As predicted, Est proteins also control telomerase’s conduct. For instance, Est1 recruits the enzyme to chromosome extremities. Lundblad is uncloaking additional essential roles the Est proteins play as she discerns how cells revitalize the crucial structures at their chromosome ends.
Author: Evelyn Strauss, Ph.D.