A conversation with the Johns Hopkins University molecular biologist and co-winner of the 2009 Nobel Prize in Medicine.

Question: Have you encountered any gender-specific obstacles as a scientist?

Carol Greider: I think that that's a very complicated kind of question, because although I really feel like I never had a particular obstacle that I had to overcome as a female scientist—I never felt that I was singled out or had anything done against me—I do see that when one looks at where women are in science that there is a very large discrepancy, and that there does seem to be an inability for women to get to higher echelons in the scientific hierarchy or in academia. So I think that although I didn't feel like I had anything done personally to me, I think that there may be more subtle social interactions at play in the scientific world that does have a little bit of a negative effect on women advancing in their careers.

Question: What can be done to remove these obstacles?

Carol Greider: I think that as more women get into higher levels of science, and as it's very clear to younger women coming into the field that yes, it is possible to get to the higher ranks, that will help. And also I think that the way that women run meetings, and when the power structure is such that you have a larger representation of women at higher levels, that the conversation may change somewhat. And so that could also be helpful moving forward.

Question: What is your advice to female scientists starting out today?

Carol Greider: Just follow what you're excited about. I would say the same thing to female scientists as to male scientists, to all young people, really: the fun thing is to be able to do something that excites you. A lot of times what we do is a lot of hard work, but hard work is actually okay if you really are engaged in it. And so that really, I think, is the main thing, is find something that you're passionate about and be able to follow that.

Question: How did it feel to win the Nobel Prize?

Carol Greider: That was very exciting. It was a tremendous honor to get a phone call from Stockholm and to share it with Elizabeth Blackburn, who I've worked with for many years, as well as Jack Szostak. So I was very excited, and I was very happy that I got to share the day with my children. I was able to wake them up at five o'clock in the morning after I got this phone call and to have them there with me to share and to celebrate.

Question: What role did you and your co-winners each play in the prizewinning research?

Carol Greider: Yeah, Liz Blackburn and Jack Szostak had a collaboration in the early 1980s where they were interested in trying to understand the function of telomeres. And they had a collaboration which was a cross-country collaboration with one in Berkeley and the other one in Boston. And they would call each other up on the phone and explain experiments and send materials back and forth. And that collaboration resulted in this idea that there may be some way that the cells have of maintaining their chromosome ends. It was known that chromosome ends would shorten every time a cell divided, and in doing a collaboration to try and understand the functional components that make up the telomeres they proposed that there may be an enzyme that lengthens telomeres. And so then when I went to graduate school at U.C. Berkeley and I met Liz Blackburn, that was the project—after I had worked on a smaller project in her lab—that was the project that I thought was the most exciting to follow up on and find out, is there really going to be this hypothesized enzyme which can lengthen telomeres? So that's when I started to work with Liz Blackburn, and it was together in her laboratory that we discovered the enzyme telomerase.

Question: How do you think the prize will affect your work?

Carol Greider: I don't think I can anticipate the kinds of changes. Again, I never have been one to sort of think 10, 15 years out. I really just sort of try to follow what's exciting at the time. And it certainly is an honor, not just to me, but really to everybody working in the field of telomeres, because of course the prize is given to a person for a particular discovery, but the prize wouldn't be given unless there were many, many, many different people working in various laboratories that made it clear that that discovery was going to be important and has implications to it. So I really think that I'm sort of sharing this with the telomere field in general and many of my colleagues.

Question: Is your research highly targeted or guided by curiosity?

Carol Greider: Well, I've always been somebody that likes to follow interesting questions, and that initial work in Liz's lab was really a curiosity-driven question: how can the cell maintain its chromosome ends when we know that they should be getting shorter? So it was a puzzle that we needed to solve. But it was an important puzzle because all cells need to solve this problem of replicating the chromosome ends. But I feel like I've been really fortunate because at every step then along the way I've been able to follow my curiosity and see where the next step led. So, for instance, I started off working on this enzyme telomerase and trying to understand how the enzyme actually functions. What are the different components? Can we find out the mechanism by which this enzyme operates? And then the question came up about cells, and if the telomeres are shortening every time, what would happen to cells? And I got then into this field of cellular senescence, which is that cells can divide a certain number of times and then they stop dividing. And it turns out that the short telomeres play a role in that. So that was a very interesting discovery, and that then led to the next question, which is: if the cells normally stop dividing, why don't cancer cells stop dividing? That's a cell type that has to divide many times. So then our interest went into the area of cancer research, and I was able to follow that because it's very nice to be able to be in this kind of environment where you can just do science, and as long as you're learning something interesting and you can get funded—and I've been funded continuously by the National Institutes of Health, and so that's been very nice—to then be able to follow the next steps along the way in terms of what the most interesting question was to me.

Question: Did you ever doubt that you were on the right track with your telomere hypothesis? 

Carol Greider: Well, at the time there were really two main hypotheses for how telomeres may be elongated: that there could be a recombination-based model or this hypothetical enzyme. And I just thought it was like an exciting puzzle to see which might be true. And so I chose one because I was working with Liz, which was to look for an enzyme which might lengthen telomeres. And it was really just fun to be part of solving that puzzle.

Question: Do scientists fear chasing false hypotheses?

Carol Greider: Of course it could have been possible that there was another mechanism that lengthened telomeres, and it's not clear how long one would then keep looking for something without any success. Luckily, in my case it was about nine months of trying various things, and then I had some success. But yes, there are a number of dead ends in science, and you may be doing experiments along one track, and either technically the experiments don't work, or you get something slightly wrong. And that's what's really important about the whole scientific process, is that it's really about what the results are. And either you or somebody else will be able to determine whether or not the result of your research are correct. And so being able to let go of ideas and move forward I think is just as important as having good new ideas.

Question: What was the telomere problem and how did you solve it?

Carol Greider: Well, at the basic level it has to do with how cells can divide many times. What was known in the late 1970s was that when you copy a chromosome, the way that the mechanism copies a chromosome, every time a cell divides, the very, very end bit can't be completely copied. And so then the idea was that the chromosomes, or the telomeres, which are the chromosome ends, would get shorter and shorter and shorter every time a cell divides. And that can't happen indefinitely; there has to be some mechanism which will balance that shortening. And that's where the discovery of telomerase comes in. And so for any cell that has to divide many times, they need to have a way to balance so that there's some shortening and some lengthening and some shortening and some lengthening, and an equilibrium is then maintained so that the cells can then go on and divide.

Question: What was your methodology in making the discovery?

Carol Greider: We were very interested in, as I said, telomeres and chromosomes and how they functioned. And so we really went to the source where there are a lot of telomeres. And this was something that Liz Blackburn had done a number of years before, when she had discovered the DNA sequence that telomeres is made up of. And it's a very, very simple repeated DNA sequence that is sort of a monotonous many, many, many repeats. And she had discovered the telomere DNA sequence in this organism called tetrahymena; it's a single-celled organism very much like the paramecium that high school students might go out to a pond and bring back some pond water and see the paramecium floating around. The thing about tetrahymena is that they have 40,000 chromosomes. And so it was a very good source to be able to understand what the ends of the chromosomes were. So when we set out to ask, is there an enzyme that can lengthen the chromosomes to balance the shortening, we went again to tetrahymena, and you can just get these organisms and grow them up in the laboratory. So we would grow up a large batch of the cells, and then you spin the cells down in a centrifuge so you make a very compact collection of them, and then break them open to get the insides of the cells out so that you can understand what is going on inside the cells.

Question: Was the 25-year delay in recognizing your discovery unusual?

Carol Greider: I think it's more that the discovery was made in 1984, and it was clear that it was important at the time. But it was important as a very basic cellular mechanism. And there wasn't a lot of questions; I didn't get a lot of people doubting what the conclusion was. But instead, it wasn't clear what the implications were. In the 25 years that have intervened, my lab and Liz's lab and a number of other labs throughout the world have contributed all kinds of different ideas from different avenues that have made it very clear now what the medical implications are. And so there are clear medical implications that we didn't know at all at the beginning. We were just solving a puzzle because we were curious about how cells worked, although we knew that it was a fundamental mechanism. We weren't just doing experiments just to find out anything, but rather to really understand how a cell works. And the 25 years in between really has allowed it to be clear what the implications of that discovery were.

Question: What are some practical applications of your telomere discovery?

Carol Greider: Well, it turns out that there are really two different areas in which the ability of cells to divide have medical implications. And one is in cancer, where a cancer cell has to divide many, many more times than any of the normal tissue surrounding it. And so the cancer cells have to solve this telomere problem, or the telomeres will shorten and the cells won't divide. And the other area is normal cells in the body which have to do with tissue renewal. So tissue-specific stem cells where—for instance, in your blood the cells need to be able to divide every day to provide new blood cells, because the blood cells only have a very short lifespan. And so it turns out that there are a number of degenerative diseases that are typically associated with aging because the cells have gone through so many rounds of cell division. If they have short telomeres, then there are problems with tissue renewal. So the degenerative diseases of aging and cancer really are the same kind of question of how many times cells can divide.

Question: Will the discovery have anti-aging applications even for healthy patients?

Carol Greider: Yeah, I think that the interest in this age-related disease isn't just limited to certain families where they have short telomeres due to mutations in telomerase. That's where they have been studied, as well as we've studied them in mice which we create that have short telomeres. But the implication is that all individuals, when the telomeres get short, will have a certain risk associated of these age-related degenerative diseases. And it's not limited to just a subset of patients with particular mutations, but rather pointing out a general risk of these degenerative diseases in the whole population.

Question: What other medical mysteries might your research illuminate?

Carol Greider: Well, I think that we're just really trying to understand the role of telomeres in these diseases, and the spectrum of the different kinds of diseases that short telomeres may play a role in, and down the road whether or not there would be some way to have a therapeutic intervention in these diseases. They're really devastating diseases: bone marrow failure and lung diseases. And so if there were some way to intervene and change the process so that the telomeres don't shorten progressively or don't shorten as rapidly, then perhaps there would be therapeutic approaches for these diseases. So going in that direction in terms of the therapeutics, but also I think the work that has been done has opened up many more questions than it really has answered. The number of questions that have to do with how telomere length equilibrium is maintained is greater today than when we started back in the 1980s. What we discovered was the enzyme telomerase that has to provide the raw material to make telomeres longer. But how is that process regulated? There is a very, very tight equilibrium of shortening and lengthening and shortening and lengthening, and it's maintained at a very precise spot in the cell. And we would like to know, what are the molecular details that go into that? Because those molecular details will then tell us about any potential diseases in the future where the changes might lie that have to do with telomere length.

Question: How do you suspect telomere length equilibrium is maintained?

Carol Greider: I think that there are going to be multiple different layers of regulation. When the cell really cares about a process, there are always multiple different inputs and several backup mechanisms. So people are working now on the actual proteins that bind along the length of the telomere, and how those proteins then tell telomerase to elongate the telomere, and how those proteins are modified by other proteins, and I think that it's going to be a fairly complex interactive network that will take some time to tease out. But it's exciting to find out even a few of the little pieces of the puzzle. 

Question: Are we on the cusp of a genetics revolution?

Carol Greider: I think that we're in the middle of the age of genetics; I don't think that we're on the cusp of a revolution. I mean, I think with the sequencing of the human genome and now sequencing of many, many different genomes from a variety of organisms have given researchers such powerful tools to find out new associations. Being able to compare whole genome sequences from many, many different organisms, one can see what is conserved and therefore what is very important. So I think that the tools that we've been given just in the last 10 years are tremendous, and people are just now learning to be able to take advantage of those. And yes, there are of course ethical implications in terms of issues having to do with insurance and genetic privacy issues. If whole genomes are going to be sequenced, who will have that information? And I think that there are a lot of processes going on. There's a bill that was passed a number of years ago, the Genetic Information Privacy Act, which will limit the use that can be made of some of this. But I think it's an ongoing process that people need to be discussing more widely, that the more people in general in the population understand about genetics, the more they'll be able to have an informed discussion about these issues when they come up. So I think that scientific literacy is going to be really important as these things are disseminated more into the public in terms of the possibility of people having their own DNA sequenced, and what does it mean? And what does it mean to them, and what does it mean to family members who might not want to know that? Those are privacy issues. And the only way to move forward with that is to really have an informed discussion and to talk about it. So that's why I think that general education in terms of genetics is really essential.

Question: Are you worried or excited about the changes genetics research will bring?

Carol Greider: I'm excited about what's to come, but I think that along with the actual scientific changes there's a certain responsibility of scientists and educated people in general to talk about these things, because I think that with knowledge comes power. And so the more that the lay public understands about what we're learning in genetics, the more they can then understand how it would be useful to them. So I think it's a very, very exciting time, but I think that there's also a responsibility to be able to discuss things in a very open way that makes clear what the implications are and what the implications aren't.

Question: What will be the technical and ethical limits to genetic manipulation?

Carol Greider: It depends on what you mean by genetic manipulation, in the sense that we do genetic manipulation in the laboratory all the time to try and test ideas about how genes work. So we will take cells and we will change the genes in those cells and then be able to ask what is the consequence of that change. That's basically doing an experiment. We do that with mice as well. If we want to understand—for instance, we wanted to understand what would happen if a cancer cell didn't have telomerase. Could it still grow? So we generated a mouse, and the whole mouse doesn't have telomerase. So that's a genetic manipulation of the mice, but it was an important question to know the answer what would happen if you could completely get rid of telomerase. So I think that in that sense, those kinds of genetic manipulations are very powerful tools that scientists have. Now, if you're talking about things like human genetic engineering and those kinds of things, there are certainly ideas about gene therapy that people have put out there to solve various diseases, and some of the ones that people have been looking at are diseases that are in the blood, because blood cells are very accessible to changes. And those kinds of things don't worry me so much except for the technical aspects of—in some cases when you try and put genes back into cells, people have found that then those genes can cause other changes, which in some cases can lead to cancer. So there are clear technical hurdles which have to be overcome in that realm. And in terms of germline gene therapy, where you may change something permanently in the human germline, I think that basically that is something that's out of the question and shouldn't really be on the table. I don't think that anybody's really discussing changing the human genetic germline.

[Question: For technical or ethical reasons?]

Carol Greider: For ethical reasons. Technical as well, if we can't even get it right right now. If the science today—we can't do a bone marrow transplant; that is, take some bone marrow cells and correct a defect of a single gene in the blood, put that back in and know that the correction is going to happen. And instead, these children developed tumors because of unknown consequences in doing that. So if we can't even do this to blood cells, we are very, very far technically from being able to do anything without having many unintended consequences in the germline. So for technical reasons I would say it should be completely out of bounds, and then there are the ethical issues, which again would need to be discussed in a broader context. And I don't know of anyone that seriously thinks that that is something that one should be changing.

Question: What has been your biggest mistake as a scientist?

Carol Greider: Well, I've made a number of mistakes along the way. When you make—I feel like if there's a scientific mistake—so when I publish something and it turns out that the conclusion that was drawn wasn't completely correct, then it's the responsibility of the scientist to then do the experiments and publish the correct answer. But in that sense, science is very self-correcting, because if something is published and it's important, and it's wrong, then a number of other people will find out that it's wrong, although that may take a number of years, and some people may be led astray. So I think that the real importance is to not be necessarily attached to a particular idea, with the idea that telomere shortening plays some role in cell death, say. The thing that we would like to do is to test that idea. And one thing that I think creeps into people's thinking sometimes is that they want to prove a hypothesis. And I never think about proving a hypothesis, but rather think about different ways to test the hypothesis. And this was something that I think I learned very early on in Liz Blackburn's lab when we first had discovered something that looked like it was elongating telomeres. And then a period of about nine months went by where we set up to ask ourselves, is it really true that we've discovered a new enzyme? And we came up with a variety of methods to shoot down our own hypothesis. Maybe we're being fooled because it's a normal DNA polymerase that's just making this, and it looks like it's something new. Or maybe we're being fooled in a different direction. And then after the discovery withstood the test of nine months of attacks from our own standpoint about how could we shoot ourselves down, then I started to really believe that it was true. And so that really taught me that it's most important to be critical of your own hypothesis rather than to be a cheerleader for it. And I have a little bit of a fear against people just cheerleading for ideas, rather—I think it's more important to test them because that's how you then move forward, because many ideas are going to be wrong. And if you test an idea and find out it's wrong, you can go in another direction. But if you're a cheerleader for an idea, it may last for a longer period of time even if it's not correct.

Question: What was your opinion of President Obama’s Nobel win? 

Carol Greider: Oh, I was very excited when I heard that he had won the Nobel Peace Prize, and I really saw it as a promise of something for the future. And he's been such a supporter of science, and science in the public eye, that I really felt like that was a very good thing. And I do see it as a hope for the future for the direction that he is going in terms of world peace.

Question: Can science promote peace?

Carol Greider: Science can promote an understanding between people at a really fundamental level. So yes, I think that science can promote peace by bringing people together to work on problems and to realize that there are problems that everybody faces that can be best approached by people working together in different directions.

Recorded November 10th, 2009
Interviewed by Austin Allen