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Szostak's telomere transplant experiment contributed to that buzz. As he stood waiting in the hallway outside the darkroom that day, the x-ray film emerged, dropping from the developer into his hands. “All the DNA was in a single band, which meant that it had to be replicating as a linear piece of DNA,” Szostak recalls. He showed the film to everyone in the lab, including Orr-Weaver. In those days, Szostak was very slender, with a long ponytail and a scraggly beard, and quiet, Orr-Weaver recalls. “I can't imagine him ever raising his voice. But when something worked, his face beamed with excitement.”
Once Szostak knew that Tetrahymena telomeres functioned in yeast, there were loads of experiments to do. He excised one of the two Tetrahymena tips from the linear DNA, for example, and then fished for pieces of yeast DNA that stabilized it—and isolated yeast telomeres. Janis Shampay, a graduate student in Blackburn's lab compared the sequences of Tetrahymena and yeast telomeres that had been maintained in yeast and learned that yeast cells were adding a characteristic DNA sequence of their own to the transplanted Tetrahymena telomeres. This finding suggested an enzyme existed in the cell that built up telomeres—an enzyme that Carol Greider, as a graduate student in Blackburn's laboratory, would later isolate and name telomerase. Greider is now at the Johns Hopkins University School of Medicine.
A graduate student in Szostak's lab, Andrew Murray, now a professor at Harvard University, combined yeast telomeres with several other essential pieces of chromosomes, thereby creating yeast artificial chromosomes, which would be used to map and clone human genes for the human genome project.
Vicki Lundblad, then a postdoc in Szostak's lab and now a professor at the Salk Institute, identified a yeast mutant in which telomeres grew shorter with each generation. After more than 50 generations, the cells sickened, lost chromosomes, and died. “That made us think that perhaps what happened in aging was that the telomeres were getting too short,” Szostak says. This turned out to be true in cultured human cells, though the jury's still out about the role telomere shortening plays in human aging.
Other intriguing results followed. In cells from normal adult tissues, telomerase is repressed. A therapeutic door opened when Bill Hahn's team at the Dana-Farber Cancer Institute showed that expressing telomerase can help make normal adult cells cancerous, and drug companies have pursued telomerase inhibitors for use in cancer chemotherapy. “Jack didn't work on telomeres all that long,” says Hahn. But his ideas about telomeres “were the seminal ideas, at the beginning of the field.”
Although important questions remained about telomeres in the late 1980s, Szostak was ready to move on. He knew that scientists streaming into the telomere field would follow up. Says Szostak: “My approach is to find something off the beaten path.”
In the mid-1980s, that meant RNA. Tom Cech, who later became president of HHMI, and Sidney Altman had just discovered that RNA could catalyze chemical reactions inside cells, just like today's protein-based enzymes. Biologists proposed that the earth's earliest life forms lived in a so-called “RNA world,” in which RNA was both a carrier of hereditary information—a role played today by DNA—and a ribozyme, or catalyst of chemical reactions. “What made the whole ribozyme field so exciting is that it provided a new model of the origin of life,” Szostak recalls.