Aging, Cancer and Stress

Elizabeth Blackburn's work on telomeres led to new research and discoveries

From McClintock's era on, biologists had simply accepted the idea that telomeres somehow cap the end of a chromosome, just as plastic caps the ends of a shoelace and protects it from becoming unraveled. The cell is normally vigilant about detecting and repairing breaks in its chromosomes. In so doing, though, the cell could mistake an unprotected chromosome end for a break and attempt to fuse it to another chromosome end. The telomeres prevent that from happening. Blackburn was determined to find out how, but it would be many more years before she would have enough clues to sketch the process, and much about it remains unknown.

"We now think that there's something that hides the chromosome ends in plain sight," Blackburn says. "The cell sees the ends, but instead of hiding—and we still don't understand how they do this—the cell turns the recognition of the ends into a response appropriate to the telomeres. It's a very dynamic process, not like a passive shoelace end, and that was not expected at all."

Another cellular enigma was how telomeres manage to maintain their length and, hence, their functionality. By the early 1970s, biochemists realized that the normal process of DNA replication could not copy a chromosome all the way to its end. Consequently, with every chromosome replication and cell division, the telomeres should theoretically get shorter. Eventually, without anything to arrest the process, the telomeres would get so short that any further chromosome replication would cut into the genes themselves, and the cell would die. Because bacterial cell lines can live and divide for thousands of generations, chromosome shortening became a paradox known as the "end-replication problem."

There was much speculation about how the cells might solve the problem, but no empirical explanation. "In biology you can wave your hands and make up all these paper schemes" Blackburn says. "But the key thing was to show in the test tube that there really was a tangible mechanism." So in the mid-1980s Blackburn, who was running a laboratory at the University of California, Berkeley, and an especially determined graduate student named Carol W. Greider went back to Tetrahymena to figure out how cells preserve their telomeres. "We normally think of genetic material as sacred," Blackburn says. "But [Tetrahymena] chop up their somatic [non-germ line] chromosomes and add new repeat DNA [sequences] to the ends."

Blackburn had hypothesized that an undescribed enzyme within Tetrahymena cells was building new telomeric sequences. Another enzyme that assembles strands of DNA, called DNA polymerase, was already known. But DNA polymerase builds a new strand of DNA by using a single strand of the double helix that forms a chromosome as a copy template. The new strand is a complementary copy of the original. (Nucleic acids that make up DNA always pair with their complement: adenine with thymine, and cytosine with guanine.)

Unlike DNA polymerase, Blackburn and Greider's mystery enzyme, which they called telomerase, would have to build telomere sequences from scratch, with no template. To find the enzyme, Greider mixed synthetic telomeres, created in the laboratory, with extracts of Tetrahymena cells. The synthetic telomeres, Greider and Blackburn had reasoned, would be extended only if the Tetrahymena extracts contained the hypothesized telomerase enzyme. To their delight, the synthetic telomeric DNA grew longer, proving the existence of telomerase.

Their newly discovered enzyme turned out to be a remarkable molecular complex. Like most enzymes, telomerase contains protein. But the telomerase complex also includes a single molecule of RNA, a chemical cousin to DNA. "Telomerase is a collaboration between RNA and a protein" Blackburn explains. No one understands exactly how the two work together, but what is known is that the RNA codes for short segments of DNA that are added piece by piece to the ends of telomeres. Thus telomerase restores bits of telomere lost during cell division

The finding came as a surprise, Blackburn recalls, because "people had thought that only bad things, like the HIV virus, did this conversion of RNA to DNA. But here is a molecule that does this, not for evil, but for a critical function necessary for continued life." She now suspects that telomerase is an ancient molecule, a relic from a prebiotic world dominated by RNA reactions, rather than by proteins and DNA.