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| Elizabeth Blackburn, PhD |
Interview with Elizabeth Blackburn, PhD Blackburn is a professor of microbiology and biochemistry at the University of California at San Francisco and an expert on telomeres. She is credited for discovering the substance called telomerase and has published extensively on the subject of these protective caps on the ends of chromosomes.
If you look back on the decades from the 1970s, what have we learned in the field of cancer research?
When we look back from the 1970s when Richard Nixon first declared a war on cancer and we see what's been learned since then, an enormous sweep of knowledge has come our way. Things are much more hopeful now in terms of attacking cancer as a disease, because we know so very much more. The thing that is hard to understand often is that the cures for cancer, which you hope would follow the knowledge, don't just come instantaneously.
A great example is the knowledge that came maybe 30 years ago that a particular way a chromosome broke in a certain kind of cancer, leukemia. [This break] caused a gene to get turned on more than it should have been turned on because the gene got put under the control of a different controlling region of the chromosome. [This] caused the cells to become cancerous. And that led to a drug which has just been tested in the last few years very successfully called Gleevec and it's a very well known drug, but it took about 30 years from that knowledge. That's very important to think about, that the great amount of knowledge that you learn about cells and chromosomes doesn't instantaneously translate into something as complex as the human body in terms of a drug or a cure, but it'll happen.
I think a great deal of knowledge has come, but it's not going to instantly turn into cures. But clearly that's the right direction to go if we really want to attack cancer.
Do you think that it can be considered a certainty that once we have the knowledge, this will eventually lead to a cure?
You never know what's going to be the most useful knowledge and you also never know what kind of knowledge will be useful for learning about cancer. I had started studying telomerase, and we discovered telomeres 15 years ago. We weren't looking to cure cancer and yet it turns out that the enzyme telomerase is one of the most frequently found characteristics of cancer cells. That was not expected.
Knowledge is very, very important, but you often can't direct exactly where it's going to go. We'll have a much more high chance of having a cure if we know more than if we know less, so definitely more knowledge is very, very important. But we won't always be able to predict the linear pathway from a particular kind of knowledge that one gets to what its impact will be in the clinic and in curing patients.
It's often very slow, although these days things do move a lot faster. I gave [the Gleevec] example because it's fairly extreme, but it makes the point. But it's an accelerating situation because we do know more and more now about how to understand the subtleties of making a medicine that looks really good on paper or in the test tube or the subtleties that we have to surmount in order to make that work in the human body. So, that kind of knowledge is increasing. But it can be slow and it can be unpredictable.
The majority of your research is on telomeres. Can you explain what a telomere is?
The telomere is the end of the chromosome. Every good thing has an end and chromosomes are linear so there are two ends. A DNA end is a very vulnerable spot for a DNA molecule. What the cell has to do is protect that end. So that's called the telomere. It's a little protective cap. People liken it to the little plastic tip at the end of your shoelace that protects the end of your shoelace from fraying. What happens if your shoelace frays? It won't tie properly, you might trip over it. So a fraying chromosome end is bad news because it will get all tied up in things it shouldn't get tied up in or it'll get chewed away and you'll lose genetic information.
Cells go to enormous lengths to protect their chromosomal ends, the telomeres. They have layers upon layers of protections, proteins that coalesce onto the DNA ends and just physically protect them, other proteins that protect those ones, proteins that come in and sense if there's something wrong and send signals to cells if there isn't everything perfect about the protective complexes. Cells really protect their chromosome ends because they've learned through evolution, if they don't then the DNA will get trashed.
What telomeres do in terms of how cells can keep multiplying is quite interesting. At the ends of the telomeric DNA, there's a lot of DNA which form little repeated modules, which themselves don't have any meaning in terms of encoding a protein. But the DNA repeat sequences form a big buffer of extra DNA at the end of the chromosome that allows all this protection to happen.
When chromosomes multiply, every time one cell divides into two daughter cells, the DNA of all the chromosomes has to be replicated. But that very sophisticated machinery in the cell that replicates the DNA has a funny glitch. It cannot replicate the very last end of the chromosome-the little machine doesn't have the way to copy the very last nucleotides. Each time those cells divide and the DNA has been replicated each time, it gets shorter and shorter and shorter. So what would happen? Well, we're not extinct yet, so something happened to compensate for that.
And that something was the enzyme telomerase, which we discovered back in the 1980s. Telomerase has a special way in which it adds back extra little modules of DNA to the ends of chromosomes and keeps them from getting shorter and shorter. When is telomerase active and when is it not active in our bodies? It's very interesting. All the time you're growing up from a fertilized egg into a baby, telomerase is active all of the time, [because]your cells are doing lots of multiplication. When you turn into an adult, telomerase is turned down or maybe almost completely off in many, many cells. Some of those cells do keep on dividing somewhat and then you see that their chromosome ends do get a little bit shorter because they don't have that telomerase in them. There is a shortening of certain cells in the body-so certain cells in the body have their telomerase get shorter as they multiply. In fact when you look [the cells] in older people, versus younger people or babies, older people do have somewhat shorter telomeres than younger people because many of their cells have been multiplying without benefit of telomerase.
There are some cells in our body that really love to keep on multiplying. Of course our favorite that keeps our hair from going gray, is our hair follicle cells-they keep multiplying and if they don't your hair goes gray, so they have telomerase. Immune system cells have to multiply in huge numbers every day to fight off bacteria and pathogens and invaders. Every time their signaling tells them to start multiplying to fight off an infection, they turn on telomerase. So we know that's very important throughout adulthood. We get colds all through adulthood and we want to be able to fight off things by multiplying our cells in our immune system.
The human clinic told us something very important about telomerase. There are families who have the very sad misfortune that they die in early to middle adulthood of something called progressive bone marrow failure. Their immune system cells just can't keep multiplying enough. And what happens is they get only one good gene for telomerase from one parent and the other gene, which came from the other parent, is not working. Two genes' worth is enough for us to get through a normal life barring other accidents, but if you only have one gene's worth, you run out of bone marrow cells. That told us that you need to have telomerase on.
It's an interesting situation because some cells in our body, if they're not multiplying too much, the telomeres can run down and get a bit shorter. Some people think that that might be a part of the aging process. That's a very interesting and still unknown question, whether the telomeres running down really causes some aspects of aging. So, telomerase is on in a lot of our normal cells, but in a very regulated kind of way and that is going to be in big contrast with cancer cells.
So what is the tie between telomerase and cancer cells?
[Telomerase] is on in cells that do a lot of multiplying because they're always copying their DNA each time the cell multiplies. Cancer cells are classic cells that just keep on multiplying. They've lost all the brakes, they've lost all the signals that tell them when to stop. They're unreasonable; they're just unchecked, multiplying out of control.
Interestingly, the more advanced the cancer is, the more likely it is to have made a mistake in its regulation of telomerase and now telomerase is just turned right on-it's like the rheostat got turned full on, and it's making a ton of telomerase. A remarkably high percentage of tumors that people have looked at have activated telomerase. Numbers have put it [at] 90% plus of tumors. When you think about what telomerase is doing, it makes sense because it's continually topping up the ends of the chromosomes as these cells are multiplying out of hand. If the chromosome end doesn't get topped up, then the end becomes very sticky and starts sticking to other chromosomes, [which] causes the chromosomes to start ripping apart, and that causes chaos and the cells can die.
Cancer cells have selected against that happening [by turning on] telomerase. Telomerase is definitely helping those advanced cancer cells keep on multiplying. But telomerase has another very interesting role in early stages of cancer progression. [It] turns out to be a kind of a Dr. Jeckyl and Mr. Hyde with respect to cancer. There's a sort of a yin and a yang of telomerase with respect to cancer.
I've just told you about telomerase the bad guy with respect to cancer because it's allowing advanced cancer cells to keep on multiplying-now I'll tell you about the good guy. It's a good enzyme because you need to have the full dose to get you through a normal life span, otherwise you run out of your cells multiplying and producing enough immune system cells [as well as] other cells, too. Your normal body has a regulated small amount of telomerase on in proper ways in certain cells. But in many cells telomerase is turned very far down or maybe even completely off. Those are the cell types that happen to be the sort that in people are the most likely to give rise to cancers. They're a class of cells called epithelial cells and in humans, our kinds of cancers most often come from epithelial cells-not all, leukemias don't-but often many cancer cells are of epithelial origin. What happens is something goes wrong with those epithelial cells at some not high frequency and those cells lose some of [their] "checkpoints." Sometimes tumor suppressor genes can be checkpoint genes.
Checkpoint genes are the genes that say stop multiplying, stop your cell cycle, if something is not quite in order. One of the early accidents in the development of cancer cells is that they lose checkpoint genes. That means they'll keep on multiplying. But now these cells don't normally have telomerase, they've turned it off in their normal correct way because they're not normally going to do too much multiplying. But they've lost their checkpoints and they start doing too much multiplying and then the telomeres-remember, they don't have telomerase-get dangerously short and start to stick to each other, and that starts to cause a lot of chaos in the genome. Chromosomes are getting broken and rearranged. Because these cells are multiplying, the lucky ones survive-lucky for the cells, but not lucky for the person, because those cells now can select for the ones that keep multiplying and those are the ones that will eventually, with more accidents in the genome, turn into cancer cells.
What's been found is that at this early stage in cancer development, if those cells get a little bit of telomerase in them they won't go through this genomic chaos. So telomerase very early in a normal sort of regulated amount is protective against the first steps down the road to cancer. It's a long road down the road to cancer and they haven't started tumbling down all the way, but they're poised on the brink of this. You can think of it like a staircase going to cancer, if you can hold them back, then they won't fall down this chaotic staircase and eventually become cancer cells. Telomerase is one thing that helps protect the genome against the kinds of genetic accidents that can lead so often to cancer.
Like everything, there's a yin and yang for telomerase. Dr. Jeckyl, of course, is the good aspect of telomerase. It holds cancer cells back from the brink of going down that path of disastrously turning into cancer cells. But Mr. Hyde, once the cells have made that decision to go down that path, then it's sort of too late and then telomerase, when it gets turned on, now just helps all those bad cells multiply.
Can you describe the specific work you do in the laboratory regarding your research on telomerase?
Telomerase and telomeres have been full of surprises for us and there's a great deal we don't understand about exactly how it works. When does telomerase decide to work on a telomere and when does it decide not to? In my laboratory we need to find out these kinds of things because if we want to use that information intelligently in the clinic against cancer, we have to understand how it works so we won't get a nasty shock when we go in and do something and get an unexpected kind of finding. We use every arrow in our bow that we can, so that means in the laboratory using the kind of cell type or the kind of system or the kind of experiment that will give you the answer.
We may not look very much like baker's yeast, but baker's yeast and humans have shared very, very deep fundamental similarities between their telomeres and our telomeres. If we want to get an answer very quickly and very cheaply, we can do experiments in baker's yeast, which is one of the most thoroughly studied organisms; it's just a single cell and it can be grown very easily, and all sorts of genetics and biochemistry and molecular manipulations can be done. We study yeast cells as much as we study human cancer cells growing in the laboratory. Human cancer cells growing in the laboratory tell a lot of useful things. But they don't tell you ultimately how the cells will grow in the human body; that's work that has to come from the medical side of things, from the clinic, and we can find out many things from clinical observations.
For example, we discovered telomerase in a small organism that grows in pond scum, of all things, and we used it because it had a lot of very short chromosomes, lots of telomeres, and that's how we discovered telomerase. We discovered if we made the DNA sequence at the ends of the chromosome different by making telomerase different, then we could very quickly kill these pond scum cells.
We're now trying to use exactly that approach with human telomerase and human cancer cells. We can kill human cancer cells within a few days, very quickly by that same method. We found this out by studying little single-celled, cheap, fast-growing organisms and then carrying the principles over. In my laboratory we use all those sorts of techniques to try to get an understanding of what makes the tealomere able to protect the end of the chromosome and what makes telomerase able to do its work at the end of the chromosome. Because if we can understand that, we'll be able to exploit it.
So how this will research eventually help in the treatment of cancer?
One of the things in general about cancer is that it's part of us. So we can't just hit it on the head.
[If] you hit it on the head with a poison, you're going to poison yourself as well. The trick with cancer is to try to tease out what makes the cancer cell different from the good normal cells. One of these differences that shows up so often in cancer-something like 90% of tumors-have turned their telomerase way up high. The difference is not really completely black and white, it's not that our normal cells have zero telomerase and cancer cells have it, but there's shades of gray. And like every medical situation, that's the way it usually is; there's usually shades of gray. You want to find a window and try and exploit that quantitative difference between the cancer cell and the good cell. That quantitative difference is that cancer cells just love their telomerase.
In fact, we have done experiments which really suggest they're addicted to telomerase. If you take away their telomerase fast, they actually die quicker than you would have thought, [which surprised us]. They've become addicted and if you try to make them go cold turkey without telomerase, they will kill themselves sometimes. That's very different from what we had expected. We actually had expected that if you take away telomerase, gradually the cells would have their telomeres get shorter and shorter. It might take a long time. That happens in some cancer cells, but other cancer cells very quickly die if you withdraw their telomerase-they don't like going cold turkey without it. That's one thing that people are very interested in doing, is trying to see if you can quickly turn telomerase off in cancer cells because they're more addicted to it, we think, than normal human cells.
Once one finds something in the lab, then the next thing [is] to try and see what would be non-toxic versions of things and what would be things that would be deliverable as drugs. Another way is to trick the cells into making that very large amount of telomerase that they have and put it to work. That's another approach we've used. What does telomerase do? It makes telomeric DNA. Let's make bad telomeric DNA. When we do that by tricking the telomerase into making the wrong kind of DNA, the ends of Chromosomes were very susceptible to that. We were surprised again. We probably came in by a little stealth bomber approach here, they were not expecting this assault, because they die on us within a few days. That's another way that we can think about exploiting what we understand about telomerase and telomeres.
It's not the only thing, there are many, many ways that cancer cells differ from their normal counterparts, but cancer is still a very unconquered disease so we need everything in the armamentarium that we can get. Maybe combining approaches will be one way of going about these things.
If we were trying to only kill yeast, would you say we have cured cancer? That is, we have figured it out in the test tube, correct?
We've figured out how to kill human cancer cells in the test tube and also in animal pre-clinical models. We have also figured out that we can greatly reduce tumor growth, in fact cause it to regress, by making telomerase into a dangerous substance for tumor cells by tricking it into making bad telomeres. So that's very encouraging. But we all know that the road to the clinic is a long one because the human body is very complex and what will work in even an isolated animal model system. [These systems are] a pretty good mimic but not completely: the only way you find out is by trying to find out what really happens in people.
Things have to be done very carefully and very slowly and very right because you can't do experiments on people, clearly. That's where things will become necessarily much, much slower. Telomeres and telomerase look very good as targets against cancer cells in all those settings. But the real unknown territory now is how will any of this really play out.
It's like every other idea against cancer, you can have very, very good ideas, but you won't really know which cancers may or may not be susceptible or which people might have the right sort of genetic background in which they are more susceptible to the cancer. There's a lot of unknowns, which as we understand more about how humans vary and how their cancers vary, that'll probably allow better decisions to be made about when attacking cells through their telomeres and telomerase is going to work and when it's not going to work.
We realize that your specialty is telomeres, but could you briefly discuss another aspect of cancer, angiogenesis?
As a tumor grows, the cells in the tumor, just like any other part of the body, need to be fed with blood vessels to bring them oxygen and nutrients so they can keep on growing. In this case, what's keeping on growing is the cells you don't want to have keep growing, the tumor cells. Tumor cells seem to attract blood vessels to grow into them in a certain way and produce plenty of nutrition and oxygen for the tumor. If we could stop the blood vessels from growing, this is called angiogenesis, then perhaps you'd starve the tumor, you'd choke off its food and oxygen supply.
There's been a lot of interest in trying to attack certain kinds of tumors by choking off their blood supply by sending chemical signals to the blood vessels that normally would be coming in and providing the tumor with its abnormal blood supply. If you could choke that process off, then there's much hope that perhaps you could choke off the growth of a tumor. That's one of the many lines of attack that people are trying now against cancer.
We don't know quite how the tumor tells the blood vessels to come in, do we?
We understand some of the signals that the tumor cells are sending that are calling the blood vessels in and saying, come on, let's make lots of blood vessels here. They're kind of unusual blood vessels, too, they're not quite normal. So some things are known about those chemical signals that are made by the cells. That's one form of trying to stop the blood vessels from going to tumors, by choking off those signals. If you can block them, then you can hopefully block the blood vessels and then the tumor will starve, it won't get oxygen, it won't get food, and so hopefully the tumor then will not be able to grow.
In the big picture, what are the still unanswered questions in cancer research?
I think some of the huge questions are what sorts of triggers make cancer cells continue to go down the path towards full-blown cancer. Even in people who have no obvious clinical problems, it seems like a lot of normal epithelial cells have started those few little faltering steps down the road to cancer: they've lost some of their checkpoint controls, and yet, it's interesting, they don't keep going. So in a way, [the question is] why aren't we all just one big mess of cancer? Or, why are we so good at stopping cancers? That's a fascinating question, because the deeper people have looked into people who seem to not be sick, but they find early signs of cancer. What stops it? It would be great if we could understand what is stopping that process, because then perhaps we could even try and make that more efficient to really stop even those earliest steps.
Prevention is by far the best approach medically for any disease and if we can prevent the next steps in cancer-it gets worse and worse, the more the cancer cells advance-the better off we'll be. If we could stop cancers, I think the really big challenge is: what is making the early steps, which are so frequent in so many of us? What's making them not advance any further? By the time you've discovered a cancer, typically it's way too late.
What would you say is your big dream? What do you hope to see happen?
I would hope to see that very early prevention and very early interference with the advancement of cancer could be held up. The stage you don't want to be at, of course, is the stage when it's discovered, because that's when it's very difficult. The cancer has become a very successful tumor, usually, by the time it's discovered. Of course modern medicine is terrific at dealing with a lot of it and cancer is no longer the death sentence that it used to be, it's very often now a chronic disease, but it's still not something that people want to have obviously.
My dream would be to find ways in which you could protect cells from advancing down the road to cancer so they wouldn't get to the stage when it was effectively causing disease. If we could prevent it, if we could choke it off at the very beginning, that would be the ideal way of dealing with cancer.
Do I feel hopeful? I think every researcher has to have hope because you're always fighting tremendous odds. Nature is very complex, biology is very complex. All the easy stuff has been done, so the questions are hard. Cancer is hard because it's us, it's not something separate that we can just hit on the head. We have to be subtle about understanding how cancer works because we can't just randomly kill cancer cells and all the cells around them. You have to be very careful about what you are going for in a cancer cell.
Cancer is difficult and I think every researcher must in some way be a very naive optimist because you have to continually have hope. If you look at what's happened around you can see that yes, that hope has been justified, but you know that it'll come at the expense of a lot of setbacks, too. You really have to look and say, yes, the track record has been that we continue to see advances and so it's rational to feel hopeful, but it also has to be played out in the context of a lot of failures along the way as well.