Dr. Blackburn, how did you become interested in this field of telomeres? Why do you think they’re so significant?
Elizabeth Blackburn: I was trained with somebody called Fred Sanger, who won a Nobel Prize, first for sequencing proteins, and he was working on the sequencing of nucleic acids, DNA and RNA, but then DNA when I was a Ph.D. student with him. And so there was very few ways of sequencing DNA then, and one of the things you could do was sequence DNA at the very ends of the long DNA molecules that make up genomes, and so I saw that there would be a feasibility, a way of looking at the ends of DNA, whereas perhaps in those days you couldn’t look at the middle of DNA so well. And I went to Joe Gall’s lab, and was interested in pursuing this, and Joe Gall, who I mentioned before was a really good mentor, is also an extremely good biologist in recognizing there are good biological systems for asking certain questions. And he was the one who said, “There is this system that has very small short chromosomes,” and lots of them, meaning lots of ends, so that this would be something that — you know, this would be a system. And I was excited because I wanted to look at the ends of things, the ends of DNA, which nobody really had been able to look at in eukaryotes, organisms like us that had nuclei in their cells. And so it was partly that it was doable, and partly because there was a good system to do it in.
As soon as I started looking at the molecular behavior, there was something unusual about the way the DNA was behaving, and then subsequent experiments by us and by others, over the next few years said, “Ah, there’s something going on here which is different.” So now, why are they important? So now, fast forwarding and jump ahead now to much more what we know. We know that the genetic material is in long thread-like molecules, DNA molecules, and they have — each DNA molecule has two ends, and the ends have to be protected. Otherwise they kind of chemically fray away every time the cells multiply. So it turned out to be particularly important to cells that they protect the ends, and furthermore that they replenish the ends of DNA. It was that replenishment that was going on and giving rise to the strange behavior of the DNA that made us first suspicious. And then Carol and I then, you know, we’ll look for telomerase. So we didn’t stumble over telomerase. It was something that, there was some reason to think might exist, but it would take some real digging to get it.
Why did you think it might exist? What function did you think it would perform?
Elizabeth Blackburn: If you put in a certain kind of telomere into a cell of a different species, then you could see telomeric DNA being added directly on to the end of the DNA that it was put in, and that was something that was not predicted. There were also a few other little hints. There was the behavior of telomeres. As you watched the behavior of telomeres, as cells continued to multiply, then the telomeres would get longer and shorter sometimes, so that was odd behavior. And there was a genetic argument in corn, which — you know, none of this is proof positive. These were all interesting things that came together into one idea. There was genetic evidence in corn that was suggestive that there might be a real function for doing something at the ends of chromosomes, and that could have been lots of things, but it happened that this idea that was coming together from these different kinds of observations — it was fitting into one kind of possibility, and that was that there was something new there. So those are the things that led into thinking that there might be such an activity, a set of experimental observations that did not fit into the previously known facts, and that is because nobody had looked at telomeres before. It wasn’t as if people had been looking at them before and not seeing it. It really was something relatively new to even be looking at the telomeric DNA.
Could you define a telomere for a lay audience?
Elizabeth Blackburn: Yes. It’s the protective end of the chromosome, and the chromosome is this thread-like body, there’s lots of them in our cells, and each chromosome carries some of our genetic blueprint. So together, all the chromosomes add up to our total genetic blueprint, but it’s packaged in the form of lots of chromosomes and each chromosome has to have its end protected, and that’s because essentially, things in the cell attack DNA ends unless they have special protective mechanisms.
You undertook your study of telomeres in an organism called tetrahymena. How did you happen upon that particular organism?
Elizabeth Blackburn: As a postdoctoral fellow I’d gone to Joe Gall’s lab, and he had suggested — he had found small linear molecules, short DNAs in high copy number, and that gave an unusual opportunity to look at the ends of the molecules, because if you have very few, very long molecules, you don’t have too many ends, but if you have lots and lots of very short linear molecules, you have lots of ends. So he knew that biological system, and had found these molecules, and so the two came together. So it was just a little pond scum organism, you know. It doesn’t do anybody any harm. It swims in ponds and happens to have lots of chromosomes, so that was the way I had got into looking at the DNA. And then it seemed reasonable, and luckily it was true, that if there was lots of DNA ends then, as we were going to embark on the hunt for this new enzyme, that there might be lots of the enzyme that made this extra DNA. So I stayed with tetrahymena, and you can grow buckets and buckets of it, and get lots of material to work with, not too expensively.
And how did you begin working with Dr. Greider, looking for this unknown enzyme?
Elizabeth Blackburn: I was a professor at the University of California, Berkeley, and we have a graduate research program. A graduate program, students come to the program to do their Ph.D. work, which means doing research in molecular biology. So the program attracts terrific students, and one of them was Carol, and then the students choose a lab and a project that they’ll do research in, and I had the great good fortune that Carol chose to work in my lab.
Carol Greider: I remember the day that we actually met. It was during the interviews when I was interviewing for graduate schools, and I guess at Berkeley I had actually been accepted, and then I went around to talk to professors, just to decide whether I wanted to go there or not. And I had a great time in my conversation with Liz, and she was just very excited about what she was doing, and I was having such a great time talking to her, that the time went by so fast and I really wanted to know more. I remember I asked you if I could come back and talk a little bit more, because I was staying just up the road in Davis. And then, between when I came back and when I’d left, my father had a heart attack and ended up in the hospital, but I did everything I could to come down, because I was going to go back and talk to you some more. And that was sort of the thing that clinched for me that what I wanted to do was to go to Berkeley and to work in Liz’s lab. Typically, one goes to a university and then chooses a lab once you go there, but that was my goal after meeting her.
Elizabeth Blackburn: Carol is not your typical person. I think you see things and you say, “I’m going to go for it!” And you go for it.
Carol Greider: It was guaranteed, the way the program was set up. You had to do three lab rotations, so I did a little project in three different labs. Officially, you’re not allowed to make any agreements about where you’re going to go until the end of those rotations. I don’t know if it was because everyone else in my class knew that what I wanted to do was to go back and work for Liz, or how it worked out but…
Elizabeth Blackburn: It worked.
Carol Greider: I do remember, at the very end of the third rotation, when I came in and said, “I’d like to come back,” and she said, “Sure.” I was quite happy about that.
So there was sort of a chemistry, if you’ll pardon the expression, between the two of you?
Elizabeth Blackburn: Yes. Yes, I could tell Carol was terrific.
How long after that did you make the big discovery of telomerase?
Carol Greider: The first piece of evidence that we had telomerase was Christmas Day of ’84. December 25th. And then another year until our first publication.
Elizabeth Blackburn: Right. But you jumped right in right from the start, knowing what you wanted to do. Sometimes people sort of cast around a little bit here and there for a project, but Carol knew that this was one she wanted to get involved in.
Carol Greider: I remember asking you, when I first came: (a) could I work in your lab, and (b) could I do this project. You said yes to both.
Elizabeth Blackburn: Yes. I was so happy to have someone to agree to do this project, which was a daring thing, because the idea was, “Maybe there’s something that hadn’t been described before.” To look for something new is not something that wise people — prudent people — would normally do.
Carol Greider: Young and naive!
Elizabeth Blackburn: Yeah. So being young and hopeful — I had just got tenure and I had research money — and that gave me a lot of mental freedom to say, okay, I can do something which, if I had written it as a planned research project, funding agencies would have said, “Is this even feasible?” Of course, you don’t know. If there’s something that’s new, you don’t know if it’s feasible. I had the confidence to go ahead and have the lab and have our energies go into something new.
So after that initial discovery on Christmas Day, were there setbacks along the way that caused you to doubt yourself?
Carol Greider: I wouldn’t call them setbacks. Like I said, we took about six months from the first hint that the enzyme existed before I was pretty much convinced that it really was what it was. So all along I kept trying to think of how could this data be fooling me. How could it be some other kind of activity that just looks like this, because I think I want it to look like this. How could I be fooling myself? And then thinking, “Well, maybe it’s this other process,” finding a way to test that. So there were points along the way when I thought, “Oh well, maybe it’s not telomerase at all, but a DNA polymerase that’s copying repetitive DNA.” So there are little bits of doubt along the way, but that was part of the process of verifying. We ended up jumping through the hoops, and every hoop you always worry about what was going to be on the other side of the hoop, but by jumping through them all, at the end we were fairly convinced.
In university laboratories, it’s often the professor who gets the credit for the discovery. It seems like Dr. Blackburn was very open to letting you do a lot of the good stuff.
Carol Greider: Yeah. That’s the way it ended up working out. A lot of labs work this way. I’m also to the point now where I don’t do a lot of experiments on my own in the lab, although that’s what I like to do and that’s why I got into science. You end up going into slightly different positions. So I’m more of a manager and a data analyst for the people that are working for me. At that point, Liz was probably working in the lab more than I am now. I was there, ready to do the experiment, so I was the one doing all of the actual hands-on experiments, and she and I would talk about them. As it evolved over the course of the four-and-a-half years that I was in her lab, I did all of the actual hands-on experiments, and she was very gracious in letting me continue to do that, even when it was clearly as exciting as it was. I started it and I got to finish it, and maybe it was slightly unusual.
Is it unusual, in this field, for two women working together to make this kind of discovery?
Carol Greider: It depends on what “this field” is. This field is telomeres.
Elizabeth Blackburn: And telomerase. It is relatively unusual. Women coming into degrees has become very usual. Women coming into assistant professorships was pretty unusual. I’m going to turn your question around a little bit. I think it did make a difference that there were two women in the field. A lot of people say, “Gosh, there’s so many women in the field of telomeres and telomerase. My first thought is, “Of course there aren’t so many. It’s just a reasonable number of people.” And then I realize, of course, compared with most other fields, it is a lot of women. So I think that that has made some difference, and I think it’s terrific.
Carol Greider: In part, women feel more comfortable working in women’s labs. I think that’s some amount of it. And seeing the role models that are there. For a long time my lab at Cold Spring Harbor, when I was there, was filled entirely with women. There were eight people and they were all women. So I think that there’s a certain amount of people seeking to work in the lab of role models. And then, of course, the people that then graduate from the lab go on and populate the field, so it’s a self-fulfilling prophecy that a particular field might be founded by women. Actually, I think in this case it might be founded by Joe Gall, a man who was very supportive of women.
Elizabeth Blackburn: That’s right, a good mentor of women.
Carol Greider: Because of that, there were a large number of women that came into the field, as I would say a jackpot event.
Elizabeth Blackburn: Not such a large number, but significant. The absolute numbers were not huge but…
Carol Greider: But relative to other fields.
Elizabeth Blackburn: Yes, that’s right. Right. But it is great. You know, we co-organized a scientific conference last year, about 250 people came. Many of them happened to be women scientists and it is great. It’s a real sort of terrific sense to see an area of research in which it’s not the usual sort of demographics of relatively few women there, among the speakers, and among the invited participants and attendees and so forth. Because what happens is that even though women come into Ph.D.s at about equal numbers to men, more and more, as you look at what happens as careers progress — and this is no surprise, accepting the numbers — get much, much sparser as one advances in the career. And the old argument used to be it was the pipeline. We used to say, “Well, there were very few women in the pipeline.” Can’t hide behind that any more. It’s not true. Lots of women are coming in, and have been coming in for a few decades in large numbers into these sorts of scientific fields.
Carol Greider: I had the good fortune to be involved in writing the grant that we put together to fund this meeting that we did on telomeres two years ago. And typically, when one writes a grant for funds for a meeting there are certain boiler plate clauses that have to go in, and a lot of the funding agencies make sure that you want to invite women, minorities, and you have to state in there that you are going to go out of your way to invite these people. So I had a little fun, and I wrote the little boiler plate paragraph and changed it around to say, “Well, there are so many women in the telomere field that we will try to go out of our way and invite some men,” and this got past the people at Cold Spring Harbor that had to vet the grant. So I was quite pleased that actually went to the funding agency.
Elizabeth Blackburn: Yes. I hope it is sort of a model, an encouragement. There can be fields where great science gets done. It doesn’t have to be one group, one gender or another, who particularly dominate it. It wasn’t like it was planned, but it has clearly evolved in that direction. So in answer to your question it is a little unusual and I hope it will be less unusual.
Dr. Blackburn, we’d like to hear about your childhood and how you first became interested in becoming a scientist.
Elizabeth Blackburn: I think I was very lucky, because I knew I was interested in living things from — very, very young. I grew up in Australia and I would — my mother tells me this, you know, I have no direct recollection — but I remember I would pick up little poisonous ants and poisonous jellyfish. There are a lot of poisonous creatures in Australia, and I would pick them up and sort of pet them, and I’d really like them. I was interested in them, and of course this was horrifying for my mother, who was a physician who could see the stinging and the potential biting that would take place, but I seemed to have lucked out. I never got bit by any of these. And I think I have just known for a long time I was fascinated by living things, so I loved animals. And then in high school, as I started learning about what’s in living things, I got very fascinated by what was then called biochemistry. Protein chemistry was something that was the field then, and I got fascinated by — what are the building blocks of living things — cells and molecules.
I feel very fortunate, because even in high school I kind of knew it was biology. I knew that was what fascinated me, and I pretty much knew that it was going to be something, as I saw it, looking deep into how these things really work — which then was called biochemistry, and then became more molecular and more cell biology with the years. So I went through high school knowing fairly much that this would be where I would go, perhaps not even thinking about it all that much. I just kind of fortunately knew, but in Australia, socially, there was very much a strong sense that women didn’t do certain kinds of careers. I was in high school once when somebody said — this was an adult, not my teacher but some other teacher — said, “What’s a nice girl like you doing going into science?” I just remember that vividly. I didn’t lash out at this person, because I kind of socially didn’t know how to do that, but I just remember thinking, “That’s interesting, and I’m not going to basically have any interaction with that person anymore.” Because this person didn’t seem to get that this was something that I cared about.
So then I moved on to a degree, and then the training. Again, as I say, I was so fortunate that I knew pretty much what kinds of things interested me, and I feel very lucky also, because I was in a system unlike the system in the U.S., where students have much more access to a broad undergraduate degree. We had to pretty much make our decision a lot earlier about the kind of degree we were going to take. At one point I had decided I wanted to look for a history and philosophy of science class. I thought I would love to take a class like that, and my schedule wouldn’t allow it, but in going around to all the professors and trying to find out if I could make a schedule where I could take these classes, I was met with such surprise. Why would you want to do this? So for somebody who didn’t know what they were interested in, this could have been a very bad situation, because you would get sucked into an undergraduate degree, and perhaps specialize much earlier. So I think the system in the U.S. that I see — when I was teaching at Berkeley — the undergraduates all take much, much more breadth of courses than we did. So I think that’s a good system, because not everybody is going to have the good luck to know pretty early what kinds of things are interesting to them.
Dr. Blackburn, was there a teacher who was particularly influential as you were growing up?
Elizabeth Blackburn: I think that there were various teachers throughout. I had a good math teacher who — just by getting me to do something in front of the class, show some problem solving in front of the class — kind of let me see, “Oh yes, I can do that.” Not that math was my greatest, strongest subject, but he let me see, “Yes, I’ve got this ability. I can do things that I hadn’t really thought I could do.” And especially, when I was doing high school, my sense is there was much less awareness, compared to the way there is now, about the way women relate to science and math, and how in a mixed group of girls and boys, the boys tended to be more outgoing and so forth. Now I look back at him, and I think he was an extraordinary teacher, because he drew me out, and he did this and made me realize in a way that perhaps most other teachers wouldn’t have taken the time to.
What was his name and where was he?
Elizabeth Blackburn: This was at University High School in Melbourne, Australia. Mr. Stoddard was his name — we always called our teachers “Mister” — Len Stoddard. A good teacher. A good math teacher. My Ph.D. was done in Cambridge in England, and I had a couple of professors in Australia when I was an undergraduate, where I was doing some research, and they had been to two different places. One had been to Rockefeller University, one had been to Cambridge, England, and they both said, “You really should think of going and doing your further training at one of these places.” And the Rockefeller one, he said, “Well, the books used to get so dirty with all the pollution.” I thought, “Oh, well. I better not go to New York.” So you know, I’m really shocked at the triviality of the things that make you make decisions. But they encouraged me.
Who were these teachers?
Elizabeth Blackburn: This was Barry Davidson and Theo Dopheide. They were two professors at the University of Melbourne where I was doing undergraduate research. This was right around the time of the moon shot.
We went across the street to the apartment of somebody who had a TV — not everybody had a TV — so we could watch this (the moon landing). We had this great — we watched this, you know, amazing thing. We all came back, and then I was doing my little biochemical analyses and nothing had fallen into place, and I lost a whole lot of the sample, and I thought, “This is not a good day for my science.” But then very soon after — the same samples — I had analyzed them, and I suddenly thought about them in a different way, and suddenly everything fell into place. And ah, yes! Now I understood what was going on. So I remember that very well, because there was a sort of juxtaposition of the moon’s triumph, my technical failure, and then, very quickly after, somehow things just kind of fell into place. You know, it was a very trivial problem now, but at the time, that process of going through it was something that I suddenly realized, the addiction to science. That “Ah!” You’ve suddenly seen a way through. You’ve seen how something is. You’ve understood how something works.
That was important, to have that opportunity to be doing research. Joe Gall is a professor at Yale University with whom I did my postdoctoral research. He was a very important mentor, because he gave people who came and worked with him a kind of self-respect, and made them feel very safe, such that they could blossom as scientists. Both men and women were, I think, very positively influenced, but for women it did particularly, I think, make a difference. The way a mentor can work in science is very important. I found it was very important in influencing how I felt about my going on to do science.
You mentioned the moon landing. Were there other events or experiences that had an impact on you growing up?
Elizabeth Blackburn: I haven’t thought through this very much, but when I was an undergraduate, I remember there were certain kinds of science-related things that were important to me, because they would keep opening my eyes to certain things that I had never thought about before. I’ll probably think of all the good stories when we leave the interview.
What about books? Was there any book you read when you were young that had a particular impact?
Elizabeth Blackburn: Books? Oh, great question. There was. There was one by a guy called (George) Gamow, and I got this book from the Melbourne Library. Melbourne has a very hot summer. This is a city built in the 19th Century, as though it was Britain. So there was this huge sort of classical arcade library. So in the summer — no air conditioning — so I would go into this library, partly because you could cool off a little. So I went into this library and there was this book by Gamow, and he was just writing this imaginative sort of interesting, provocative science. It was a popular book, and it was about, “What is life about?” and the codes and so forth. I was very intrigued and captured by that book. I can’t remember the title. I racked my brains, because I remember the book and I remember the author, but I can’t remember the title. I couldn’t even tell you terribly much now about the detailed content, but I think there was something about the imaginative way he was approaching the science, and not this sort of very stolid, heavy-handed writing that a lot of scientific writing has.
You mentioned some teachers. Were there other people in your life growing up who inspired you or encouraged you?
Elizabeth Blackburn: My parents were both physicians. The family physician type, not fancy researchers or anything like that. I picked up a sense of this idea that you do serve, you serve people actually. It’s an interesting thing. I don’t think they ever said that in any explicit term, but you could just see in terms of how — individual patients weren’t discussed — but just certain things were discussed, and you could see that that was important that you were doing something bigger than yourself. You were doing something for society. For some reason I was able to pick up on that, so I think that influenced. Especially my mother, who was a physician, who spent a lot of her hours in the office talking to her patients, and she would say talking was so important for many of her patients. Sometimes there weren’t even obvious things that a physician could do something about, but she said it meant a lot to them. I remember that was interesting. I could see what a broad sort of field medicine was, and I also kind of knew that it wasn’t my field either, you know. I knew science was something that I would be much more interested in doing.
Did you think you’d prefer working in a laboratory to working with humans face-to-face?
Elizabeth Blackburn: I think there’s a great irony in this, because in some ways, working in the laboratory, you really have to work with humans so much. Because who does the science? How do things advance, right? It’s people. It’s people thinking and being committed to doing work and so forth. Much more of science than anyone ever tells you, or that you suspect, is to do with people. In some ways the doctor-patient relationship is almost more remote. In science, you are very much dealing with people: your colleagues, your students. They are all very, very important to you, because their success and your success is all bound up together, because the science is difficult, so you have to work in a very integrated way.
Did you have siblings?
Elizabeth Blackburn: Yes. Lots of siblings. I have four sisters and two brothers. I’m the second of our family of seven. I read somewhere about the psychology of second siblings, and I hate to say, but all those things, it seemed like I could check them all off. It all sounded like me.
What, for example?
Elizabeth Blackburn: Oh, some of the things about needing to find your place and your independence and things like that. I’m very, very close to my older sister. Now she went into the medical side of things. She’s a physician and a hematologist. We had a very close relationship and I greatly admired her, but that might have been partly related to the fact I didn’t want to try and just emulate and do exactly the same thing as she did. Perhaps I wanted to find my own niche, and perhaps that’s why I went into science. I don’t know if that played into it, but I noticed that all seven of us, we each chose something as different as possible from the others.
We have the hematologist, me the scientist, my next sister is a kindergarten teacher and very talented at little kids. I never realized what a talent that takes until I had our own son and saw what insights she had. Then my brother who’s a mining production engineer. My other brother who is a musician. And a sister who was a high school science teacher and still is. Then my youngest sister who went into pottery and now is running a computer graphics firm. It’s like we all took everything as different as possible from the others, and kind of made our own little sort of niche, or our own little areas, even though nobody ever stated that explicitly in our family. Nobody ever specifically said, “I’m going to do something different from somebody else,” but here we all did.
Dr. Blackburn, did your parents encourage your going into science?
Elizabeth Blackburn: Yeah. Encouraging. Particularly my mother. I think she encouraged me in things that gave me a sense of self-worth, such that I knew what I chose would be respected. I used to play the piano a lot. There was some piano competition, some local thing, and she drove me, and not long ago I looked on the map and realized this distance she had driven me. Way across the state. It was the State of Tasmania, which is the smallest state in Australia, but still she had driven me this huge long way, just for me to play this piece of music and come back. So I remember just feeling that whatever I chose, I knew would feel relatively validated.
It’s interesting, my mother once — I think she was trying to tell me, you know, there are certain — you can do things in certain ways, it doesn’t have to be all one way. I remember at one stage she said — when I was a teenager — she said, “You know, you don’t have to go to university,” meaning, you know, to college. And I think she was responding to the fact that I was putting myself under all this pressure, right. I remember feeling really mad at that. I didn’t say to her, “What do you mean about this?” I just kind of listened to it. But I remember kind of a little resolve hardening in me. And then I look back at it, not so long after it had happened, and realized what the dynamic was. That she was saying, “Stop killing yourself here.” There are different ways to do different things, but at the time I had a typical teenager’s response, which is to feel very rebellious at the suggestion. But I did feel kind of validated.
Your mother must have been quite an amazing person to have seven children and work as a physician as well.
Elizabeth Blackburn: Yes, she was. And it did take a toll. When I was in late teenagerhood she (my mother) started to have some signs of clinical depression, and for us, as the kids, we actually didn’t really understand for a while what was going on. It was hard, because we didn’t really have people to talk to about it. People didn’t really talk about these things a whole lot. So I remember, we kind of each dealt with it in our own kind of individual way, but now I look back and I think it’s interesting that perhaps society was in this way that even friends didn’t sort of discuss it with us and say, “Well, you know, we see what’s going on. We understand what’s going on.” So yeah, it was tough, and she suffered on and off all through her adult life. She has done basically fine, and I think in a way it sort of made our family — especially us kids — we are very supportive of each other and of her. My father is now deceased, but I think there has been a sort of — it’s been a very strengthening thing, but it was tough at the time. And especially, as I say, people didn’t talk about it a whole lot. That just wasn’t what people then felt they talked about, or didn’t understand or something.
Was she ever hospitalized for depression?
Elizabeth Blackburn: At some stage she was, when I was in college. She was, a couple of times. It wasn’t something that people comfortably talked about. We had some relatives in Melbourne, and people like that in the family, they talked with us about it, and were very supportive of us. But it wasn’t something that you talked to your friends about. I think now it is better, because I think people do speak much more openly about it. When somebody is dealing with this they talk about it.
Did your father live to see your achievements as a scientist?
Elizabeth Blackburn: Yes. I think they were pleased.
Turning to you, Dr. Greider, Where were you born?
Carol Greider: I was born in San Diego, California. I grew up in Davis, California.
How would you describe your family situation? Was it a big family?
Carol Greider: My brother and I.
What did your parents do?
Carol Greider: My father was a physicist at UC Davis, an academic physicist, and my mother was a biologist, although she died when I was six, so I didn’t really know her. So my getting into biology, I think, is more of my own thing rather than necessarily following what she was doing. They were both Ph.D.s from UC Berkeley. So it’s a family thing, since I also got my degree there.
You said you have a brother? Is he a scientist, too?
Carol Greider: He’s not. He’s a year and a half older than me and he’s in computer programming. He worked for a long time for Martin Marietta, a big defense firm, and then went off on his own. He’s a freelance. He writes programs.
You’re close in age. Are you close to each other?
Carol Greider: I think we’ve always been pretty close. We don’t probably see each other as much as one would think, but I think of us as close, and we’re always on the same wavelength. We probably see each other once a year, or once every two years or something like that, but I would consider it fairly close.
What happened to your mother?
Carol Greider: She died when I was six. She actually committed suicide.
Was there a history of depression?
Carol Greider: Yeah. I don’t really know much from my own standpoint, although I’ve been told that there was. She had been in and out of the hospital when I was young.
That’s a little too young to remember the trauma. Do you remember anything?
Carol Greider: I don’t really remember much before I was six. Now that I have a three-and-a-half-year-old myself, it’s amazing to me that one cannot remember anything before six. I remember a few things right around the time that she died, but I really don’t have much detailed recollection before that.
Did your father raise the two of you alone, or did he remarry?
Carol Greider: Both. He raised the two of us for a while, and then remarried. I had a stepmother and a stepsister for a certain amount of time, and then that broke down and they got divorced. By that time I was off at college anyway, so I was sort of on my own.
Did your father encourage you to be a scientist?
Carol Greider: He didn’t encourage me to be a scientist. One of the things I remember most from my father was that he was very clear that it didn’t matter what we did, as long as we loved what we did. Just do whatever you want and make sure it’s what you love doing. Retroactively, I look back on the conversations that we had with him, and realize that probably that’s where my very strong ideal has come from. I think of it more in terms of academia. I have a strong penchant in that direction. Basically, to be able to have the freedom to do whatever you want is the most important thing.
Carol Greider: It’s more important to do what you want than it is to make money. Making money was never an issue. Never valued in any way, aside that you could put food on the table. And all throughout high school, he would always tell us that the important thing is to do what you want for yourself. We would never get five dollars for getting an A or anything like that. We had other school friends that would get paid for getting good grades, and my father said, “You do it for yourself. And basically, you don’t want to shut any doors. All the doors are open to you now. If you do well, they’ll keep the doors open.” And he convinced us somehow to go ahead that way.
Were you a good student when you were young?
Carol Greider: Yeah, I was. In high school I was pretty much up there. I wasn’t a straight A student. I actually got a B in typing.
Did you always know you wanted to go into science?
Carol Greider: No, I didn’t. I did well in science, and I enjoyed it in high school, and somewhere late in high school I got very interested in biology. So when I chose my major, which was to go to Santa Barbara as a biology major, I thought that I might be interested in ecology or something like that. It was sort of a vague idea when it started out. I grew up in a university town in Davis and everybody from my high school either went to UC Davis or UC Berkeley, and I wasn’t going to do that. I was going to go somewhere else, but I still stayed within the UC system. I chose to go to UC Santa Barbara as an undergraduate.
In your early years, Dr. Greider, were there any books that particularly inspired you? What did you like to read?
Carol Greider: I can’t think of any particular books. There were later on. I can remember things that we were assigned in high school, and stuff like that, but I don’t recall anything in particular. I have a hard time remembering what I liked reading back then. I think I sort of project what I like reading now on to what I must have liked reading then. I think I spent a lot of the time in high school just trying to keep focused, and be able to set my goals and go somewhere, and keep doors open that I wanted to keep open.
Was there any stigma attached to a woman going into science when you were growing up?
Carol Greider: I do recall that when I was in seventh and eighth grade, getting straight A’s in science, that I was teased a fair amount. “What are you going to do, become a scientist? Why did you get another A?” And I remember vehemently denying that. “No, it was easy, so I got an A because it was easy. I’m not going to become a scientist.” When you’re teased, you deny it, but it didn’t stop me from really doing what I wanted in the end, but I do recall having that reaction.
Why was it such a horrible idea to become a scientist? Where was that coming from?
Carol Greider: I think it was a social reaction. I remember a group of students teasing me about the fact that I had gotten A’s all semester in this, and therefore, “She must want to be a scientist.” I said, “No, no,” I was just — you know.
Did they think it was too serious? Too brainy or something like that?
Carol Greider: I don’t know if I specifically thought it was too brainy. I think it was more of a social reaction to being teased, just to deny that that was my end goal.
But you did go on to major in biology in college. Was there a particular teacher, or someone else, who inspired or influenced you in that direction?
I have been influenced at a number of different points along the way by people that were very interesting. When I got to Santa Barbara there was a woman I met, Bea Sweeney, who was a biologist there, and I was very much captivated by her. My father and my mother had actually known her from their own scientific travels, so I was set up with her, to get a tour of the campus when I was touring campuses during high school. She was a very captivating person. So I pretty much went to Santa Barbara because I wanted to work with her in some capacity. They had a special college that she was involved with there, and it was through my interactions with her that I then began to learn what I was really interested in.
And what was that?
Carol Greider: I tried a lot of different things actually. I thought that I might be interested in ecology, and so she (Beatrice Sweeney) set me up in a lab with an ecologist. The most important thing that she did for me was to emphasize how important it was to get into a lab early on. She got me into a lab as a freshman, so as a result I was able to try out a whole bunch of different labs. I worked in maybe four or five different labs as an undergraduate, and then it was pretty clear to me what I liked doing, because it’s easy to tell when you’re in — at least for me, when I’m in doing something — what it is that I’m good at and what I enjoy, which I think are mutually reinforcing. It wasn’t until I got into a biochemistry lab — I worked in Wes Wilson’s lab on microtubule dynamics — that I really knew that that’s what I liked. So I didn’t really have any concept of biochemistry or molecular biology before I went to college.
Tell us more about meeting Dr. Blackburn and how you ended up working in her lab.
Carol Greider: There have been a number of instances when I’ve made choices having to do with people that I like to interact with. So I think of one, my choice to go to Santa Barbara, because I had met Bea Sweeney, and I really liked my interaction with her, and she ended up being my advisor there. And then, when I was interviewing to go to graduate school, I interviewed at Caltech and at Berkeley. And I did the Caltech interviews, about ten interviews with different professors, and then a couple of weeks later went to Berkeley. So by then I had a sense of talking to people, what it was like doing these interviews for graduate school, and I was just very struck by my interactions with Liz and was really excited about science. So again, I made up my mind then that I was going to go to Berkeley, and not go to Caltech, and that what I wanted to do was to work in her lab. But again, that wasn’t necessarily a guarantee that I was going to be able to do that. It wasn’t like we had some agreement. It wasn’t for many months later that that worked out.
What attracted you about what she was doing and who she was?
Carol Greider: I think both the science and my interaction with her. My interest in the science when we would discuss things. I could see connections being made in my mind about what was going on. It’s probably a combination of what she was describing in her research, and who she was, and who I was. I thought I wanted to be in that environment, so I did what I could to get there.
Dr. Blackburn, when the two of you discovered the enzyme telomerase, did you imagine that this could have huge applications in medicine?
Elizabeth Blackburn: I didn’t really think to the medical applications. The excitement was more, “Ah, this is understanding how something is working,” but I think it has always been true in biology. You always know, in a corner of your mind, that certain things in basic sciences are going to end up with unexpected ramifications, but it wasn’t consciously a situation of saying, “Well, we are going to set out and study aging. We are going to set out and study cancer.” And I think this is very typical of how much science happens, because when you are trying to be innovative, and trying to kind of push back what we understand, you know that there is going to be an unpredictable nature to how things will work out. We still don’t know how this will work out in terms of medical applications, but I think it’s something that’s caught the imagination of people, and it’s certainly something that should definitely be looked at more, because we have very blunt weapons against cancer these days. We don’t have great weapons against cancer. Anything that looks promising should be tried, and there are certain aspects of telomeres and telomerase that are very, very germane to cancer, for example, or any situation where cells keep on multiplying.
Could you explain the connection between telomerase and the aging process? There’s been a lot of excitement about that.
Elizabeth Blackburn: A lot of interest. I think it attracted interest, partly, because things looked much simpler than of course they were. The basic observation is that without telomerase, then the DNA of chromosomes kind of wears down a little bit each time cells multiply. What telomerase does is replenish that DNA, and adds it back on again so that there’s no overall continuous loss, and cells continue multiplying. And then eventually, as they continue multiplying and start losing DNA a little bit too much, then this “talking to the cells” that I mentioned goes on, where a cell will get a message from its telomeres that says, “I’m not being replenished. Hey, stop multiplying!” to put it in anthropomorphic terms. And that’s partly because the cells have to protect their genetic material, and they say, this DNA sends a signal, “Stop everything. Don’t go any further. We’ve got a problem here.” And some cells just simply sit there and never multiply again. Some cells in our body altruistically commit suicide for you, and they say, “This is a dangerous situation. This DNA can go badly awry,” and they kindly commit suicide when that happens. So there are ways in which not having the DNA replenished, through having active telomerase, sets off signals in cells which stop then multiplying.
We know that as we age, certain cells do lose some of their ability to multiply, so it’s very tempting to think that perhaps if one could replenish back telomerase, perhaps one could keep that multiplying capability of cells. So would that be good or would that be bad? This is where we get completely into the unknown complexity of the whole human body.
We can’t just have cells multiplying out of sight. There’s a very bad category of cells that keep multiplying, of course, and those are cancer cells. And one thing cancer cells do is they just love telomerase. That’s very unscientific. What I mean is that telomerase gets selected for in cancer cells. It helps them keep proliferating against all the odds. And so in that way, an activity of cells, which when it’s not regulated, helps cancer cells to keep on multiplying. So clearly there’s one extreme, and the other extreme is no telomerase, and somewhere is some biological window in which there may be some useful potential applications. I don’t think there’s a single panacea. Far from it. Would that biology was so simple, but we can’t fool ourselves. There might be useful applications for sure. So I think this is something that shouldn’t be allowed to just be dropped, but on the other hand we shouldn’t have unrealistic hopes either.
You won’t be buying a bottle of it in the drug store next week to combat aging?
Elizabeth Blackburn: Well, who knows? I have my daily dose of telomerase, but it’s in the mind. I mean it’s the intellectual fun of it. But people joke about that. It’s sort of an attractive idea without any particular immediate outlook right now, but on paper it’s okay. How many wonderful ideas have been thought of to cure cancer or aging on paper? We’re inching forward. There are other things that we are starting to understand about aging, and the interplay of all the cells in our body as aging goes on. So it’s not as if it’s hopeless, and it may very well have some part. I think it’s interesting. I talked once to somebody who said the idea of the DNA wearing down, this sort of metaphor of the candle burning down, this idea seems to have a very deep appeal to people, and maybe this is partly why this idea caught on. There’s something about the metaphor that we like. So it’s going to be interesting to see what can be done, and what directions this will all go.
Dr. Greider, could you talk about some of the potential medical applications of telomerase? Researchers have already engineered laboratory mice with extra telomerase. You bet a co-worker a six pack of beer that these mice would get cancer.
Carol Greider: That’s my typical bet. The idea of telomerase, either turning it on or turning it off, has been talked about in sort of two separate realms. So people talk about the aging aspect and the cancer aspect. And, I think that it’s not two separate realms. It’s really one and the same. The aging realm that people talk about is that cells have a limited capacity to divide. They only divide for certain number of times and then they stop. And then the cancer realm is that telomerase is needed for cancer cells to keep on growing. It’s really the same thing. If you take normal cells and allow them to divide more times than they normally would, then what you have is a cancer cell. Or potentially, that you at least have the potential for a cell that could divide more times than it should. So I don’t see these as a dichotomy. I see them as really the same thing, because I believe that the aspects in which telomerase is going to be important for “aging” will be really age-related disease.
When you hear about it a lot of times in the media, you’ll hear that telomeres have to do with aging, and people automatically think, “organismal lifespan.” By changing the length of the telomeres, they’re going to change how long the human species can live. There are books written about this, and fiction books that put telomerase in the middle of this whole thing. There’s no evidence that the telomere length really has anything to do with the organismal lifespan, but rather, potentially, with age-related diseases, that this inability of cells to divide indefinitely may play out in certain disease models. So I certainly think that there are some implications in those diseases that are associated with aging — that don’t determine lifespan but are age-related diseases— but there may be some role for telomerase to increase the lifespan of cells, and therefore be able to ameliorate some diseases that require more cell divisions.
And then the flip side is the cancer side. It’s pretty clear that cancer cells — many cancer cells — have activated telomerase. And it’s been shown in a number of different systems that if you take cells that have short telomeres, as tumors normally do, and you inhibit the telomerase by a variety of mechanisms, that telomeres get short and then the cells die. So that’s a very good basic set of experiments that suggest that, in fact, when telomeres are short, cells die and so you might be able to target telomerase, in certain cancers, for telomerase inhibition being a cancer chemotherapeutic. I think that the error that people make — and it’s again a generalization — we talk about cancer all the time as if it’s a disease when, in fact, cancer is not one disease. It’s a whole bunch of different related diseases, all of which have to do with the increased ability of cells to divide. And so I don’t think that — as has been written in some press accounts — that telomerase is the final magic bullet that will finally cure cancer, but rather that there will be certain cancers in which inhibition of telomerase may play a very key role, but what one needs to do now is to go and find out what are those particular diseases where inhibition of telomerase might play a role. That’s really the next step. A lot of the basic cell biology has been worked out to suggest there is some promise here, and now some of the more clinical studies need to be carried out.
What are you working on now, Dr. Greider?
Carol Greider: We’re still interested in a lot of the basic questions, and we’ve created some tools. For instance, a mouse that completely lacks the telomerase enzyme, where we can find out what happens in a normal organism in the absence of telomerase. And it turns out that we initially created that tool as a means to get to the cancer question. What happens if a mouse doesn’t have telomerase? Can it get cancer? But we find that with that tool we can ask some really fundamental questions about what happens when a chromosome loses its telomere. Does it fuse to other chromosomes? Yes, as we expected it would. And what chromosomes does it fuse to? And what is it that determines which chromosome fuses to which? Very basic questions about how telomeres normally function. And so we have these tools, and we’re having a really good time sort of trying to think of some of the fundamental questions that we want to ask that’s going to be true probably for many cells, if not all cells, in terms of how they maintain chromosome integrity during normal cell division.
Are you focusing on the cancer application at this point or is the whole thing open to you in this realm of research?
Carol Greider: Yeah, the whole thing is open but we’re not really getting into the clinical side of things. We’re not working with inhibiting telomerase in human tumors. There are a lot of major pharmaceutical companies and some biotech companies that are out there doing that. We’re happy to talk to them, but that’s not really where I think my strengths are. What I’d really like to be able to do is come into the lab and have an idea, “I wonder how that works,” and go and do it. And there are so many areas right now, in how our chromosomes are maintained during cell division. How do the telomeres play a role in that? I can probably ask questions for a number of years and still be excited by the very fundamental questions. So that’s where I see our work going.
Dr. Blackburn, you’re not only a research scientist, but a teacher as well. Is teaching helpful to you as a scientist?
Elizabeth Blackburn: It’s a terrific help. One thing teaching makes you very, very clearly aware of is, if you don’t really understand something, and think about it, you will never be able to teach it. So particularly starting at Berkeley, where I really had to learn how to teach undergraduates pretty early on, and that took a lot of work. That was a fairly daunting thing to have to teach undergraduates at Berkeley, without any kind of real training for it, and I remember feeling pretty under pressure while I was doing that. But it was worth going through that kind of crucible, because it was something that taught me a whole lot, and I learned the hard way. I have to say, I made a lot of mistakes in how I went about it. The poor students had to put up with a lot, but I realize that it is so important that if you teach, then it means that you’ve understood it, and then you’ve cleared your brain, and you’ve forced your brain to think about it, and that’s really good. I think the two just go so much hand in hand, the science and the teaching. And then the students come back with wonderful ideas. There’s always this back and forth between you, the teacher, and the people who you’re supposedly teaching. Very much a two-way street.
Not many young people are as attracted to science as you were. What makes it so exciting for you?
Carol Greider: The ability to ask a question, to be curious about something, and get in and get the tools to answer it, and that nobody else knows that. It’s something completely unknown. It’s not like going to the library and looking something up. It’s more probably the equivalent of some sort of a synthesis. To be the first one to really understand something, and it’s fun. And a lot of times — it started out with telomerase in the early days. Basically any experiment I would decide to go in and do in the lab would be totally new. There wouldn’t be anyone else doing it and I could just go and play. Well, as it is now, Liz and I have both sort of created our own competition in a fairly large way. I mean, the graph of the number of publications with the title “telomerase” in it starts off very low and then goes up more than exponentially. So there are four or five hundred — already in 2000 — publications with this title. Whereas, when we started out there was maybe one or two per year. So as a result, there are a lot of other labs that are now doing this — and a lot of other really good labs that have switched their labs over— and weren’t studying telomerase and now are. So I always tell myself, imitation is the sincerest form of flattery.
There are some really good people that are now doing this. As a result, there are some experiments we do, but it turns out somebody else has already done them before us. So what we think we could do, to still have fun doing it, is do things that maybe aren’t obvious things that are so directly clinically related that we can work with other people to do that, but try and find areas that are still really interesting, where we can come in and just design an experiment and do it on our own.
Dr. Greider, we know you’ve been involved with ethical issues in research. What are some of the ethical concerns that pertain to your work?
Carol Greider: I don’t think there are any particular ethical issues per se in the kind of basic research that we do in the lab, so it’s not something that I deal with in my own research day to day. I am on the National Bioethics Advisory Commission, and one of the issues that have come up recently is the issue of stem cells. There’s a lot of experiments that one can do, it turns out, with these very early cell types, and the idea that we take these cell types and differentiate them into particular kinds of cells, for instance neurons to treat Parkinson’s, or pancreas cells to treat diabetes. And telomerase plays in there in a certain realm, because these stem cells have telomerase, or people have proposed putting telomerase back, although in most of them it’s already there. So it doesn’t really touch that much on my day-to-day research. But the issues play into the abortion debate, because there are questions about if we wanted more to use human embryos, which is where some of these stem cells come from. Not all of them. There are other ways to get these stem cells. And so it has been very interesting to be involved in the various debates. One of the arguments that at least we have come up with on the Bioethics Advisory Commission is that there is a store of frozen embryos around that people had for infertility reasons that aren’t going to be used, and that would be a reasonable source ethically. One could use them with the aim of the treatment of disease. I certainly am a proponent of having basic scientists be able to do experiments with those kinds of stem cells.
Another issue that comes up in connection with stem cells is the possibility of cloning. When we were children, that was pure science fiction, but now we’ve seen Dolly the Sheep and friends.
Carol Greider: Right. Cloning and stem cells also go together because cloning, strictly speaking, is taking the nucleus out from one cell, and putting another nucleus in. So for a lot of these stem cell applications, what people are talking about is if you have a particular disease like diabetes, and we want to take these cells and differentiate them into cells to treat you, the best thing would be if they were immunologically very similar, so you don’t have graft rejection kinds of problems. In order to do that, right now the most straightforward way would be to use a kind of cloning technique where you put the nucleus inside the cell. Now that’s not what people typically think of when they think of cloning. They think of generating new organisms, and that’s a somewhat different issue.
As a scientist, where do you think cloning is going to take us?
Carol Greider: I don’t know where cloning is going to take us. One of my immediate concerns is that there is a lot of potential for the cell-based kinds of cloning, and so I don’t want us to throw the baby out with the bath water. I think that one can certainly say that you wouldn’t want to clone a human being, in terms of implanting a cloned embryo into a human female and having them give birth to a child. That’s a very different kind of thing than using cells in culture. The problem is that the terminology gets a little bit muddied, and so I think that we need to speak a little bit more specifically. Certainly, generating individuals the way Dolly was generated — as an individual sheep in her case — but individual people, I would think that we would want to definitely avoid that.
But using embryonic stem cells to find cures for human diseases is another matter.
Carol Greider: Curing diabetes and Parkinson’s and these other things. I think that it’s not one or the other. I think that one can put certain ethical regulations on what we called on the NBAC, colloquially “baby making,” the baby-making side of cloning. One can simply say that one won’t do that, and still be able to get these other uses out of the cells.
We often discuss the idea of the American Dream. Dr. Blackburn, since you were not born in America, I wonder if you have a particular view on that concept.
Elizabeth Blackburn: I feel very much a recipient of it. I grew up in Australia and then did my Ph.D. in Cambridge in England, and I had a wonderful time being in a scientific environment. There was lots of interchange of ideas, and it was a very exciting time to be doing the kind of science that I was doing. But I also strongly felt that the possibilities would be much more limited in Britain to do science. At the time when I was at this research laboratory in Cambridge, a lot of American postdoctoral fellows would be coming and spending a few years doing research, because it was a very good place to do research of this kind then. I had picked up on this sense, that this was a good place to be doing science, because of the sorts of people I could see, and worked with, one of whom actually became my husband. So I met my husband, who is a Californian, in England and he was one of these people, too.
I just kind of knew that I wanted to come to the U.S. to do science, because I did feel that, also as a woman, and also the British sort of system was such that you had to be kind of much more into it, and in Australia I felt much more constrained. And so this was definitely — the possibilities, both as a person, even apart from my personal life, fortunately it did coincide — but it was very much a situation where I could see the U.S. would be the place to be doing science. So it was just a wonderful opportunity. I had the great good fortune of being able to do research at Yale first, as a postdoctoral fellow, and then to go to the University of California at Berkeley for 12 years. What a gift to be given a laboratory and to be told, “Look, you can do research!” What a wonderful thing to be having that opportunity.
I very much feel I was a recipient of that, living as I do in the West, and living in the Bay Area where the air is just filled with people excited about the future. Right now it’s the dot-com, the Internet, and so forth, but all of this sort of permeates. There’s a lot of interest in biotech. Some of it is very commercial, but I think much of the frontiers are intellectual, and exciting science frontiers too. You don’t need to do commercial things to have exciting challenges, so my personal preference has been in the scientific ones. Part of it is also, I think, particularly that kind of sense that one gets in a place like California. There are lots of interesting possibilities, and you can do things that don’t have to be done the way they were before.
What kind of scientist is your husband?
Elizabeth Blackburn: He’s a scientist who looks at chromosomes, and he uses very high tech sort of technologies to look at chromosomes. It’s very Californian. He looks at chromosomes in ways that people didn’t look at them before, so he goes to scientific conferences with people from the jet propulsion labs and astronomy, and he wants to use the kinds of technologies — and now he does — that they use to look at a very distant star. You could barely pick it up, so you have to have very sensitive detection. He decided we should use this same technology to look inside cells to pick up very faint signals of light. That’s now much more common, to look at cells by this kind of microscopy and this kind of technology. So he works on chromosomes. I just work on the ends, and he works on how they’re all arranged — What are their dynamics? How do they work? — and trying to apply new technologies to look at them in their live dynamic state.
Dr. Blackburn, what are you looking at now, in terms of the science? Where are you going?
Elizabeth Blackburn: We are very much interested more in the telomere and telomerase as sort of a dynamic system, in which there’s a two-way conversation between the telomere and the cells. Telomeres do certain molecular things, and then cells respond, and then the cell talks back to the telomeres. So there’s this dynamic conversation that’s going on. Before, we tried to get things reduced down to their simplest — just to even get a handle on it — and now, instead of thinking of collections of DNAs and proteins, and collection of RNA and proteins — because telomerase is an RNA protein enzyme — we’re now trying to think of it as a very dynamic process. It is more complicated, but then there are also many more tools in biology. There’s chip technologies of various kinds. There are things that you can do now which you could never have done a short while ago.
So there are ways we can answer these much more difficult next-level questions. There’s a fascination with how this works, but now I think there’s a sort of dynamic aspect to it, which I like, and which I think is where biology is more taking us. We’re now seeing more and more the complexities, and starting to venture into trying to deal with them.
The other side of what we do is we are very interested in how this does relate to cancer cells. So while we do experiments in simpler organisms, where we can get fast answers and they are complicated enough as they are, we also are trying to apply certain of these questions directly into human cancer cells and say, “What can we learn there, because there may be directions that could be, eventually, down the line perhaps, therapeutically useful. It would be wonderful to see. So maybe all this medical background is starting to sort of sneak out again, and everybody probably dreams that their research might do some concrete good, but you also know it’s a long road, because drugs and therapeutics don’t just fall into your lap. They’re tough. Humans are complex, and things that work in cells, things that work in molecules really well, it’s very complicated how it plays out in the whole human body. So you know, we can have great hopes, but we also know that things may never work out in quite the same way that we planned. But I have a hunch that they’ll work out in some way. I’m just not exactly sure how it would play out The scientist in me says, “Well, I hope it turns out to be in some completely different direction,” because that would be very intellectually interesting, to see what else is going on, but it would be good to see it turned into something beneficial.
We can be sure it will. Thank you so much, Dr. Blackburn, Dr. Greider. It’s been a great pleasure talking to both of you.