September 25, 2006

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HMS Researcher Takes Lasker Award

Jack Szostak, a Howard Hughes investigator and HMS professor of genetics at Massachusetts General Hospital, has received the 2006 Lasker Award for Basic Medical Research. Szostak, along with collaborators Elizabeth Blackburn of the University of California at San Francisco and Carol Greider of Johns Hopkins University, is being honored for the prediction and discovery of telomerase, an enzyme that builds and maintains telomeres, the protective caps on the ends of chromosomes.

The Lasker Awards recognize outstanding contributions in medical research. In addition to the award for basic medical research, prizes are awarded in the categories of clinical medical research and special achievement in medical science. Nicknamed “America’s Nobels,” the Lasker Awards are considered one of the greatest honors for medical researchers. With more than 70 recipients going on to receive the Nobel Prize, the Lasker Awards are seen as a forecast for future winners of the Nobel Prize in Medicine.

In the 1930s, scientists hypothesized the existence of telomeres based on observations that chromosomes had protective caps that prevented them from fusing to one another inappropriately, but no one had figured out a way to test the idea. Blackburn and Szostak met at a research conference in 1980, where Blackburn had given a presentation on her work determining that the telomeres of a single-cell protozoan, Tetrahymena, were made up of sequences of DNA. She discovered a repeated sequence of six nucleotides, but did not know if this feature appeared in the telomeres of other organisms. After her talk, she and Szostak, a yeast geneticist, decided to see if the sequence would work as a telomere in yeast.

Experiments showed that the Tetrahymena sequence did act as a yeast telomere, and further study revealed that yeast chromosomes had a distantly related structure. The researchers discovered that the telomeres grew in length when placed in yeast, which led Szostak and Blackburn to believe that a novel enzyme was adding protective sequences to the chromosome tips.

Blackburn and Greider, then a graduate student, went on to detect and isolate telomerase, the predicted enzyme. Meanwhile, Szostak and his postdoctoral fellow, Victoria Lundblad, established that an inability to replenish telomeres spells trouble for a cell. Their work showed that without the ability to restore telomeres, the protective caps diminish after multiple divisions, eventually resulting in cellular senescence, in which a cell is alive but unable to reproduce or perform normal functions. Using yeast mutants that could not elongate telomeres, they found the responsible gene and named it EST1. They also identified proteins essential for maintaining telomere stability in yeast, one of which was telomerase’s core protein.

Szostak and his collaborators did not know it would become applicable to human disease while they were carrying out their work, but many years later, researchers found telomeres and telomerase in human cells and determined that they play an important role in cancer and age-related illness. Today, telomerase is widely studied.

In the early 1990s, Szostak took his lab in a different direction and began investigating the molecular origins of life in order to understand how chemicals combined to form the first living organisms on primitive Earth. Inspired by Tom Cech and Sidney Altman’s discovery that RNA could, like DNA, catalyze chemical reactions inside cells, Szostak began to explore RNA’s ability to catalyze its own reproduction. Using a technique he developed called in vitro selection, Szostak evolved RNAs that have the potential for a variety of applications in disease diagnosis and treatment. His lab also used in vitro selection to evolve catalytic RNAs called ribozymes. These artificial ribozymes can catalyze a wider range of chemistries than those found in natural cells, suggesting that RNA and ribozymes may have played a larger role in earlier organisms than they do today.

Another part of Szostak’s work involves creating an artificial cell that can grow and divide and adapt to a changing environment. He and his colleagues are attempting to develop a cell-like structure that incorporates a nucleic acid—such as RNA—and a fatty acid membrane. Both the membrane and its contents must be able to self-replicate and must do so at the same rate. Szostak has found that the nucleic acid reproduction can drive the growth of the membrane, meaning that nucleic acids that reproduce more quickly make for faster-growing cells. When these cells compete, the fast-growing cells are more likely to survive.

Some of his work with RNA has received mainstream media attention. Building on earlier work by other scientists, Szostak and colleagues began experimenting with a clay mixture common on early Earth called montmorillonite, which was found to catalyze the chemical reactions needed to make RNA. The researchers found that the clay also helped expedite the process by which fatty acids form vesicles that could serve as cell membranes. When RNA and fatty acids were mixed with the montmorillonite, the clay seemed to help transport the RNA inside the vesicles, forming a cell-like structure. Szostak and his team surmised that a similar process could possibly have lead to the creation of the first cell. This suggestion that life was formed from clay brought widespread attention to the study.

Copyright 2006 by the President and Fellows of Harvard College