Imagine that this scientist kept a to-do list: On it would be a cure for cancer and, further down, understanding the diseases associated with aging. Elizabeth Blackburn is the 59-year-old Tasmanian-born scientist responsible for launching one of the hottest fields in the life sciences, the study of telomeres. These tiny strips of DNA cap the ends of chromosomes, and her research promises to yield potent therapeutics for many of the scourges that plague humanity.
The Cambridge-educated biochemist’s work has been honored with just about every major award in science—the Lasker, the Gruber, and the Gairdner prizes—and she recently made the list of Time magazine’s 100 most influential people. Telomeres drew her attention because of their crucial role in preventing the tips of chromosomes from fraying when a cell divides. Usually, when a cell makes a copy of itself, the telomeres shorten, which may explain why cells age and die. In the mid-1980s, Blackburn and her graduate student, Carol Greider, discovered telomerase, an enzyme she has likened to Dr. Jekyll and Mr. Hyde. Sometimes telomerase is a good guy because it helps produce immune cells and stops telomeres from shortening, but it can also make cells immortal, which prompts them to turn malignant. Because of the enzyme’s properties, it may eventually be the basis for therapies to combat cancer, heart disease, and diabetes—perhaps even halt the ravages of age.
Despite her accolades, Blackburn is warm and accessible, with traces of the shy science nerd who would serenade creatures as a child. In her comfortably cluttered office at the University of California at San Francisco, she talked with DISCOVER about how she became beguiled by bits of DNA.
You grew up in Launceston, a small city on the island of Tasmania. Did you feel cut off from the world?
It felt very remote, but Melbourne was an hour’s flight away, and I felt there was a big world out there.
Both your parents were physicians. Did that influence your career choice?
I just liked science. I liked animals. No one ever said “be a doctor.” But because so many members of my extended family—aunts, uncles—were doctors, there was this expectation that I’d probably be a physician. It never occurred to me that as a woman I wouldn’t have gone into science. I’m sure that’s just the example of having a mother who was doing some kind of career.
You left Australia in 1971 to get your Ph.D. at Cambridge in England. At that time, molecular biology was undergoing tremendous intellectual ferment. Did that attract you to the field?
The way I got into the field was very straightforward. I decided I wanted to go to Cambridge, and then I got introduced to Fred Sanger. I was very conscientious, and I asked him when I first got there if I should start reading up on things. But he said, “No, I think you can just start these experiments,” so I plunged right in.
Sanger was already a Nobel Prize winner for his work in sequencing insulin. Was working in his lab daunting?
At Cambridge, there was a completely unintimidating culture, and there were no class divisions among the students. I remember I referred to him as “Dr. Sanger” to the man who was in charge of the lab supply storeroom. And he said, “Who? We all call him Fred.” Sanger was on the cusp of devising methods for DNA sequencing [for which he won a second(pdf) Nobel]. But what he had gotten working was sequencing RNA by using the same essential principle as he’d used for sequencing insulin. He had little blocks of overlapping pieces of the puzzle, and basically, he fit the pieces together. And that just struck me as being really interesting.
John Sedat, another graduate student, who later became my husband, had studied bacteriophages [viruses that infect bacteria] that had a little single strand of DNA. John suggested to Fred that he use the phage as the training wheels for learning how to sequence DNA. It was only one strand. How simple could you get? So Fred and a number of people in the lab, including me, were all using different methods to try and sequence it.
Fred is the one who actually invented the methodology to sequence DNA. But we were all trying different ways, and the ones I learned turned out to be totally appropriate for telomeres.
You began telomere research in 1975 as a postdoctoral student at Yale. You’ve said, “Telomeres just grabbed me and kept leading me on.” Why were you so intrigued?
Studying organisms at a molecular level was totally compelling because it was moving from being a naturalist, which was the 19th-century kind of science, to being very focused and really getting to the heart of these molecules.
We knew they carried genetic material and that the ends of chromosomes were protected in special ways. But what did that mean? You have no clue. It was like you were trying to look at something from 400,000 miles up. You could see a speck on Earth, but you had no idea that if you homed in on it, it was a cat.
I discovered what telomeric DNA consisted of and that it was a special form of DNA. It looked different from anything anybody had seen because of the way it was structured, and analyzing it allowed us to see things that were new. Molecularly speaking, this was uncharted territory. What beguiled me was the excitement of figuring out what it means.
What led you to the discovery of telomerase enzyme?
Scientists in the Netherlands observed that the telomeric DNA fragment would get longer and longer. This was in 1983. So I suspected there must be an enzyme. When I got tenure at the University of California at Berkeley in 1983, I got brave and started thinking about entering a whole new era of research, and so began the hunt for that enzyme activity.
Experiments confirmed that there was an enzyme, which we called telomerase, and that it is actually doing something inside cells that matters. We tracked the enzyme over time and saw it going up and down at the right time, and the pattern was right, so we know the enzyme was influencing telomere production.
What conclusions have you drawn about telomeres and their impact on human health?
In terms of human health, there was a study in 2001 about patients who had progressive bone marrow failure. Researchers chased the gene down and found it was a mutant telomerase RNA gene component, and patients had about half the normal amount of telomerase, which meant their telomeres shorten prematurely.
Even though bone marrow failure is a very rare disease, what it showed was that if you have a defective gene for this essential telomerase component, you will never live to be old [sufferers die in their twenties and thirties]. That was a very exciting paper because it just nailed the proof of all sorts of hints that had been hovering around for a number of years.
You also discovered that there was a relationship between telomerase and stress.
Recently, we did a collaborative study where we looked at the levels of telomerase in white blood cells of women who had a child with a chronic illness. We think that chronic stress is causally related to lower levels of telomerase. The number of years a person was under this stress was related to lower telomerase.
Is there a relationship between telomerase and aging?
The enzyme telomerase seems to accelerate certain diseases of aging, which include the biggies—cancer, heart disease, and diabetes. If you say that a part and parcel of aging is susceptibility to these common age-related diseases, then the telomerase-telomere length maintenance and telomere protection is tying in more and more intimately with that aspect of aging.
But aging has multiple aspects. There’s a great genealogical study that was done in Europe, looking at data from 5,000 daughters of royal and noble families. They lived well.
Researchers found that when the father lived up to about 75 years, or 85 for the mother, there was very little relationship to how long the daughter lived. However, if the parents had a longer life span beyond these years, there was a very close relationship [between how long the parents and the daughter lived]. In other words, genes tracked for the high longevity. If you can get past what kills most of us—get through what I call the hail of bullets—then your genes can do you some good.
I was just at an aging conference and talked with people studying centenarians. Their families included long-lived relatives or parents. Nothing else is in common. Some smoke, some eat, some are obese. I mean, look at Jean Calment [who died at age 122]—didn’t she smoke like a chimney? People who have extreme longevity got to that age free of the big killers. What good genes have helped them avoid those?
But telomere maintenance is tied to the reasons why most people die—cancer, heart disease, diabetes. So in that way, they’re related to aging and health as you age.
But the media hype is that somehow telomerase can increase our life span by circumventing the limit on cell replication and halting the aging process.
The more telomerase you have within the normal range, the less of a risk you have for age-related diseases. But making cells immortal won’t make humans immortal. Things like aging have been such a fertile field for charlatanism. I’m an uncomfortable speculator and I’m hype allergic. I’m put off by quasi science that has these grandiose ideas that turn out not to be right.
What about the relation between telomerase and cancer?
Ten years ago, scientists thought that blocking the action of telomerase might cure cancer. The old way is, we knew that if telomerase was messed up, then the cells would eventually run down. So if cancer cells clearly had lots of telomerase, then you could just turn it off, right? It’s a simplistic approach, but biology is much more interesting.
We used chemicals, like the AIDS drug AZT, that interfere with the activity of reverse transcriptase enzymes like telomerase. And it did run down the telomeres. But while throwing on AZT shortened the telomeres, it didn’t kill the cancer cells. We discovered that the cells kept adjusting. If the telomeres get shorter, cells get more and more friendly to telomerase.
Someone suggested that we start working with breast cancer; it’s a really complex cancer. I thought if you could kill the cells—not just let them run down, but kill them—that might work. So we did this jujitsu where you turn the power of telomerase against the cancer cells, and they committed suicide. The other weird thing was when we dampened down the level of telomerase, the cells didn’t run out of telomeres. But what happened was—and this was a complete surprise—the cells became less cancerous, less malignant, and less metastatic.
Why a surprise?
Because when Carol [Greider] and I first discovered this enzyme in 1985, we thought of it as being a humble bricklayer that ploddingly puts nucleotides together and builds up this little wall of telomeres. But now we found that if you change the level of telomerase, you change the cell program. Now telomerase puts on a coat and tie and becomes a manager.
Will this research eventually help in the treatment of cancer?
We hope so. We’re working with animal hosts where we put human cancers in and we try to attack the telomerase. In one published study, where we put melanoma cells into mice, we published it with mouse melanoma cells, but we repeated it with human cells. We used liposomes—which are almost like tiny soap bubbles in the bloodstream—to deliver a gene that knocks the telomerase RNA down. We then looked at the cells and found they become less invasive just by knocking the telomerase down. Just lowering it, not even killing it off, was enough to make these cells less metastatic. So that’s pretty good because metastasis is what kills you in cancer, not the primary tumor. If you can get anything that lessens the metastasis, that’s good.
So I’m very hopeful. If we can deliver this promptly, it’s worth it.
What do you think about the new cancer drugs that cut off a tumor’s blood supply? They’re really saving lives now.
For five whole months. I know it’s wonderful, it buys some time, and I shouldn’t be so cynical. But the problem is not solved, because cancer is really smart. You know what the cancer cells do? They go hunting for new blood vessels.
Was it luck that you ended up researching telomeres?
Luck and chance played a huge role. But now I’m old enough to say, dammit, I really did have the smarts to take advantage when I saw certain things and move on it. And I worked like a dog—very, very hard. I still do, but I try to be less frantic about it. Luck is part of it, but I could have blown all those opportunities.
And sometimes you hit dead ends.
Well, it depends on what you want. If your goal is very defined and you’re developing a certain product, then of course, you’re going to be subject to these outcomes. Look at fen-phen [the diet-drug combo that turned out to cause heart valve defects]. You’d think that would be a great idea and take care of obesity. Wouldn’t that be wonderful? It’s a great example, because it seemed like such a good idea at the time. People got thin, but then they developed these cardiac conditions.
The huge luck of being in academic research is that you can let yourself learn from the results you get. If you’re on a freewheeling ride like I am, there are no dead ends, because there’s always something new to investigate. I don’t have dead ends. Isn’t it wonderful?