The Marvels of Telomerase
By Rebecca Skloot
Meet Carol Greider, a geneticist who does handstands on horseback, competes in triathlons and made what may prove to be one of the most significant finding in modern biology.
hen Carol Greider was growing up in Davis, California, they called her The Flier. Her preferred amusement at that point was a sport called vaulting—doing handstands on the back of a speeding horse. As a teenager, she got to be quite an expert at soaring through the air, arms and legs outstretched, as she balanced on the shoulders of two friends, and the horse beneath them cantered in smooth circles.
Those who know Greider, now a 39-year-old professor of molecular biology and genetics at Hopkins, are never surprised when they find out she vaulted competitively. “That is so Carol,” they say—“fast-paced, fun and daring.” Greider, who talks so quickly she often soundslikethis, is famous for never taking the slow and easy route. That goes for her science, too. In the mid-’80s, when she was still working toward her Ph.D. in molecular biology at UC Berkeley, she took on a project most graduate students would have gone out of their way to avoid and ended up making a discovery that has changed her field.
Working in the lab of molecular biologist Elizabeth Blackburn, Greider became interested in telomeres—specialized regions of DNA that protect and stabilize the tips of chromosomes. Researchers knew that a small section of telomeres wasn’t copied as cells divided and chromosomes were replicated. This should have left the resulting cells with shorter telomeres, but it didn’t. Telomeres always maintained their length, and Blackburn wanted to know how. She had a hunch it was because of a yet-undiscovered enzyme that balanced each telomere shortening with a subsequent elongation (by creating telomeric DNA and attaching it to the ends of chromosomes). Blackburn wanted to find that enzyme, but she knew it would be tough. She therefore was impressed when Greider announced she wanted to take on the search.
“I had reason to think the enzyme existed,” remembers Blackburn, now a professor of biochemistry and biophysics at UC San Francisco. “But I had tenure, so I felt brave [enough to persist with the search]. For a student to want to get involved in this project was almost unheard of. Students want to do safe things, and this was not safe. It could have completely crashed and burned. But Carol had a sense of adventure, she said, ‘Hah, this is interesting, I want to do it.’ And she did.”
On Christmas Day 1984, working alone in her Berkeley laboratory, Greider pulled an X-ray film from the developer and felt a rush of adrenalin. She had been searching for the enzyme with autoradiography, a process that uses radioactive markers to find the makeup and location of molecules within cells. There, on the X-ray film, was the exact pattern researchers had anticipated they would see when they found the enzyme. “Okay,” Greider remembers saying to herself, “don’t get excited. It could be an artifact, it could be many things besides what we’re looking for.” But after countless experiments to rule out other possibilities, it was clear that Carol Greider had indeed found the elusive enzyme. That night, she ran home, cranked up Bruce Springsteen’s “Born in the USA,” and “rocked out” in celebration. Greider and her lab group dubbed the enzyme “telomerase.”
“It was a fundamental discovery, right up there with figuring out how DNA is replicated and how cells divide,” says Lea Harrington, an assistant professor of medical biophysics at the University of Toronto. “People had been asking how organisms maintain the genetic material at the ends of their chromosomes since the ’70s. Telomerase was the answer.”
With Greider’s discovery, research on telomeres and telomerase exploded. Greider finished her Ph.D. in 1988 and sped off to take a postdoctoral fellowship at Cold Spring Harbor Laboratory on Long Island so quickly she never picked up her diploma. She’d been recruited to the famous research institute by the director, Nobel laureate James Watson, co-discoverer of the double helix.
Over the next six years, working with a colleague named Cal Harley, Greider came to understand that the role of telomerase in the human body was even more profound than anyone had surmised. The two demonstrated that telomeres shorten progressively in normal cells until the cells either die or enter senescence, a state in which they are alive but not dividing. “They’re just hanging out in culture,” as Greider puts it. She and Harley conjectured that the telomerase enzyme had been active prenatally but had turned off at some point before birth. This they went on to verify in mice. By then, Greider had been promoted twice and was a full-fledged investigator at Cold Spring.
By the mid-’90s, Greider had begun thinking about cancer cells—they divide far more often than average cells. If the telomeres in cancer cells shortened with each division, as they do in other cells, cancerous cells should die in the same way. But they don’t. Greider and Harley hypothesized that telomerase might somehow be reactivated in cancer cells, allowing them to go on lengthening their telomeres and dividing indefinitely. The two researchers began to imagine a treatment for cancer in which telomerase could be inhibited long enough to wipe out the telomeres in the malignant cells. This would trigger death in the cancer cells but not in normal ones with their longer telomeres. No one took the idea seriously.
As it turns out, Greider and Harley were right. More than 90 percent of cancer cells do reactivate their telomerase. Harley demonstrated this a few years after he and Greider had surmised it, and, suddenly, everyone began paying attention to the two researchers’ cancer therapy idea. Greider took one more step in preparation for work on a search for a cancer treatment involving telomerase. She wanted to determine that depriving the body of the enzyme for a limited period of time wouldn’t be harmful. By early 1996, she had created a mouse model in which she’d genetically “knocked out” the telomerase enzyme. The mouse showed no adverse effects.
That winter while at work in her lab, Greider took a telephone call and found Tom Kelly, chairman of Molecular Biology and Genetics at Johns Hopkins, on the other end. He was calling to offer her an associate professorship in his department. For Greider it was the dream job. Her husband, Nathaniel Comfort, had just finished a Ph.D. in history and accepted a faculty position in the history of science at George Washington University. The couple was looking hard for a post for Carol in the D.C. area. Not only was Johns Hopkins less than an hour away, it was also the top-ranked department in her field. She joined the faculty here in July 1997.
Since then, as her telomerase research has expanded, Greider’s science has grown more complex. In 1999, she was promoted to professor. In the meantime, she’s traded her passion for vaulting for competing in the occasional triathlon. The sport requires superb abilities in swimming, biking and running. “Vaulting is just a little different from gymnastics,” she explains. “And being a triathlete is just a little different from running. So far, I’ve only done four triathlons. Maybe a few more … I don’t know.”
This tendency toward understatement accentuates much of what Greider does. But it’s not for lack of conviction. She isn’t soft-spoken; she’s careful-spoken. She’s learned from experience. Soon after she and Cal Harley announced the earliest findings in telomerase research, a reporter pre-empted publication of their work by publishing part of the data. She swore she’d never talk to another member of the press, but Jim Watson convinced her to soften her stance. The results have been mixed.
On the good side, Greider met her husband Nathaniel, in his former career as a science writer for the public affairs office at Cold Spring Harbor Laboratory when he called to interview her in 1992. “I insisted he come to my office instead of doing the interview over the phone,” she says, “and when he walked through the door I said, Oh! I’m glad I insisted.” They married the next year. She’s also found herself in everything from The New Yorker to Esquire, where she shared pages with the likes of Leonardo DiCaprio as one of the 21 most important people for the 21st century. “Me and Leo,” she says with her fingers crossed, “we’re like this.”
On the down side, reporters are fond of referring to telomerase as the immortality enzyme and claiming that researchers like Greider have found the cellular fountain of youth. After publication of her work showing that telomere length helped determine when a cell enters senescence, “suddenly cellular senescence turned into cellular aging,” Greider explains. “Then pretty soon, the ‘cellular’ got dropped, and people were writing that telomere length determines the lifespan of the organism, which we never said.”
Sitting at a small round table in her office, flipping through articles about her work that she’s collected through the years, Greider bounces to the edge of her chair and lets out an I-can’t-believe-this sort of shriek as she waves a Time magazine in the air. A seductive woman with perfectly unwrinkled skin stares from its cover above the headline “Forever Young.”
“Don’t believe it!” Greider yells. “If you put telomerase back in normal cells in culture, you can extend the lifespan of the cells, but extending cell life has nothing to do with the lifespan of an organism.”
Her voice gets faster as she talks. “Journalists don’t call me as much anymore. I think they’re tired of hearing me say, ‘Look guys, the aging thing is not that big a deal.’ On the cancer side I still say there’s great hope for treatments, but telomerase is definitely not going to change human longevity.”
As she speaks, Greider twirls a pen between her middle and ring finger, which is stacked with three rings. Her husband gave them all to her, one for their wedding, and one for the birth of each of their two children—Charles, 4, and Gwendolyn, 1. Greider considered putting the rings for the children on a separate hand, but her husband, Nathaniel insisted she keep the family together. “I can’t have any more kids,” Greider says, “because my finger won’t fit any more rings. But if I do, I’ll just get used to not bending my finger.”
Greider approaches her family with the same gusto she brings to the lab. She spends all her free time with Nathaniel and the children. When her research calls her to a conference, the family goes along. After Gwendolyn was born, she quickly became known as the woman who gave riveting talks, zoomed from the podium to nurse her child between sessions, then rushed back for more science while her husband played nearby with the kids. Several female colleagues admit they’re in awe of the way Greider pulls off being both a mother and a prolific scientist. She responds: “Nathaniel is why it’s possible for me to do this crazy balancing act.”
For Greider, life is all about fun, and that includes digging into telomerase biology. For her fellow researchers, simply being in the lab with her is fun. With her long brown hair bouncing behind her, she’ll charge through the lab in her stretch pants, letting out a laugh as she moves from bench to bench. Her blue eyes sparkle with the kind of mischief that has defined her since childhood. She’s still fond of snowball fights and practical jokes, and is known for announcing suddenly to the entire lab, “Okay, time for a human pyramid.” She’ll then climb to the top of a stack of students, technicians and postdocs, strike a pose reminiscent of her days as a flier atop running horses and remind them all quite seriously that she wouldn’t be where she is without their support.
Meanwhile, if you ask telomerase researchers where they’d be without Greider’s work, they appear dumbfounded. “Well,” says Titia de Lange, professor of cell biology and genetics at the Rockefeller University, “the discovery of telomerase …” She pauses for several moments, then says, “I can’t even begin to describe what an impact it’s had. In the early ’80s when they proposed it, I didn’t believe it was possible. When Carol actually found telomerase, it was an absolutely stunning discovery. As the work continues, telomerase just becomes more and more interesting, and more and more important.”
The telomerase-cancer connection stirs excitement among scientists. From what Greider and others have learned, it now seems that a cancer therapy soon might be possible that doesn’t kill all cells, like many chemotherapies, but targets only cancer cells. The result would mean getting rid of the debilitating side effects of chemotherapy.
“Carol’s work has established that if you remove telomerase, it’s not lethal to animals,” says Toronto’s Lea Harrington. “Her mice that lack telomerase are viable and normal for several generations, and there’s evidence that this lack of telomerase is detrimental to cancer cells. This has turned into a kind of Holy Grail for cancer therapy.”
But Greider is leaving the therapeutic research to the pharmaceutical companies. She herself is pursuing the questions that keep her awake at night, the real cell biological questions, the fun stuff, like what happens when you lose telomere function?
Carol Greider will give the last of the esteemed Dean’s Lectures of this academic year on Monday, May 14.