Dealing with cancer

ELIZABETH H. BLACKBURN is the Morris Herzstein Endowed Professor of Biology and Physiology at the University of California, San Francisco. Her ground-breaking work involves the ends of eukaryotic chromosomes, called telomeres, which serve as protective caps for the genetic information in cells. She is also credited with the discovery of the cell enzyme telomerase, which replenishes telomeres. Her research has led her to demonstrate the significant role that telomeres and telomerase have in human health, in particular age-related diseases such as cardiovascular disease and cancer.

Elizabeth Blackburn was in India in February on a lecture tour as the featured speaker of the 2009 Cell-Press-TNQ India Distinguished Lecture Series, which included her talks on Chromosome Ends and Disease and Human Health in Bangalore, Hyderabad and New Delhi. Continuing with the excerpts from the interview she gave Frontline:

The relationship of the immune system to telomere lengths and the consequent susceptibility to disease should be more dramatic in the case of people infected with the human immunodeficiency virus (HIV) or who have the acquired immune deficiency syndrome (AIDS) where the immune system deteriorates very rapidly. Should it not be so?

Yes. We are looking at that. There are these successfully treated AIDS patients who have been on high activity antiretroviral therapy [HAART] for some years. Their lives have been saved, and they have been kept going for years on these drugs. The virus is kept [at a] very low [level] although it is never completely contained. And do you know whats happening? Its sort of an epidemic. These [successfully treated HAART] individuals are now developing diseases that look like the diseases of the aged. For their age group, these people are getting more cardiovascular diseases, more dementia, more osteoarthritis, more renal disease and a whole spectrum of diseases that are [making them] look as if they are really old.

I wonder if this is sort of a version of what happens to these disease susceptibilities in non-aged people. Will we see something in particular [with regard] to telomerase? We are starting some work now, collaborating with people who have been clinically involved with these patients for many years. They know thousands of these patients and suddenly they notice that this is not anecdotal anymore. It really has become a pattern that is looking like premature aging in the sense of their susceptibility to disease. So the thing to test is: Are their blood telomeres running down faster than you expect?

We have been looking at another group of HIV positive patients with collaborators who are clinicians. Their patients have HIV but have not progressed to AIDS, but they are watching them very carefully. And we have been looking at their immune systems telomeres and telomerase. Of course, their [levels of] CD4 T-cells [a kind of immune system cells] are very low, which is characteristic [of HIV infection] although they are not falling so dangerously low that they are going to be really susceptible to AIDS. So they are watching them like a hawk to make sure that their levels dont fall really low. And actually their distribution of telomerase, in particular in white blood cells, doesnt look too offit looks reasonable. But remember that they havent got AIDS yet and their immune system hasnt been destroyed although it has certainly taken a hit.

So it is really interesting to try and understand whats going on because the longer they can stay without going on medication they are HIV positive, there is nothing genetically special about them, they are just people who are able to stay without getting AIDS we then might be able to understand what helps these people stave off AIDS from developing, what keeps the immune system going as long as possible.

Can you conceive of some biochemical pathway that could act on the telomerase to deplete its activity when the cause is genetic or stress-related or some other external factors?

Certainly, yes. The obvious one that we are testing is stress hormones, which normally are up and down in certain rhythms during the day. When someone is under chronic stress, those rhythms and those quantities are really different and everything in your body is sort of bathed in different amounts of stress hormones. If we take the blood cells and look at them in the lab, and ask what stress hormones do to telomerase, we certainly see that they modulate it.

Now we can use molecular tools to ask, how does it do that? Those cell-biology-type questions are, I think, quite answerable. And I already know the answer. Its going to be inherently complex, like every other set of signals that cells get, because that is what everybody has found with every other signalling system. Will that inform us a whole lot? It might well because well try and see how much that is accounting for the actual effects inside a person.

When it is genetic, it is more severe. If somebody has a genetic disease, things are difficult for them. They succumb to infections, and they do show aging too; their hair goes grey early, their skin is abnormal, fingernails and teeth are not normal, tissue renewal is not going on well, they have digestive disorders. So they are probably also stressed. And that might just compound the problem. Then the question is: How much do stress hormones modulate it? I dont know. No one can replace the genes. But can there be a modulation in some way that can perhaps bring it [the immune system] up to better levels?

You mentioned in a lecture that telomerase is not there just to accumulate DNA to the chromosome ends, it has other functions in the cell as well. Now do you know of situations where it does perform the other functions well but fails to replenish the telomeres?

This is also new. Nobody has really separated those out. Certain things have been done in yeast, but it turns out that some of these other functions that one can see in mammalian systems, one doesnt see any evidence of them in yeast. Maybe its just because yeast is a single-celled organism and doesnt have the layers of extra complexity and functions that one finds in multicellular organisms. And so I can certainly imagine the situations that you are talking about, but we dont really understand well whats going on with telomeraseand [these] other things that are happeningwe call them functions because, when we perturb, we see changes in the cell that cant be explained by telomere length maintenance effects. But how they are working, we dont know.

Now there is this other side of telomerase activity, namely, its role in cancerous cells, which proliferate because of uncontrolled telomerase activity, the opposite of what we have been talking about.

Cancer cells have a lot of other things that are really wrong with them, and we should never forget that these are cells that have become deaf to all the signals that the body sends out, such as you can multiply a certain amount, you can be in a certain place in the body, where to stay, where to move, and so on. Most cells get a barrage of chemical messages from neighbouring cells, from neighbouring tissues, hormones, etc. Cancer cells suffer a variety of changes and they dont listen to the signal that says [for example] that they are supposed to be in a certain part of the body but they migrate and metastasise and keep multiplying.

So if you have a cell that is deaf to a signal that says stop multiplying and keeps multiplying, it will have chromosomes that will get shorter and shorter and the only way that a cancer cell is going to be able to survive is to have telomerase, which now has the ability to replenish those ever-shortening telomeres. And the funny thing about cancer cells is not that they have active telomerase but [that they] actually have a lot more than you think they ought to have. Why so much? Especially when their telomeres are not particularly long; they are actually, if anything, short. These other functions that telomerase has seem to push cancer cells towards having properties that make them more malignant. These other functions we dont understand at all but we see them when we perturb just telomerase in a very targeted way.

Whats remarkable is that if we look at just the whole spectrum of human cancers and we look at how much telomerase activity there is in a tumour sample, 80 to 90 per cent of the time there is a lot of telomerase activity relative to whats going on in the normal cells where its much more closely regulated and reasonable in amount. So whats really interesting is telomerase is a real favourite among cancer cells. There are very few things where 80 to 90 per cent of the cells have a given feature but this is quite unusual.

We know that certain genetic pathways that get unregulated in cancer cells which start with genes and then pathways of signalling that make these cancer cells just multiply and go to the wrong places and [there are] several different ones. But there is this commonality which I find very curious. Eighty to 90 per cent is really high. Now its not a 100 per cent. Some cancer cells get by with low telomerase [activity]. You know the exceptions and those would be instructive to study but if you just look at the generality of human cancer cells its almost like a defining feature. So we have to take notice of what cancers are telling you; weve got to learn something from this. And certainly the telomeres are maintained but what is revealing are these other things.

Do you see a kind of diagnostic technique based on telomere lengths emerging to detect disease-proneness or onset?

I could see that idea. But its a piece of information in the whole clinical picture [that] would be useful to know. More than that, it would be really useful to know the rate of change. But even 80-year-olds, I dont think, have especially long telomeres as far as theres nothing wrong with them. So we dont know how fast the rate is. How that would play out exactly, I am not sure. In a way the information would be very useful if you looked over the trends. You can use that fact as long as you dont jump to conclusions.

Though we know that diseases are caused by a whole lot of factors, do you see a kind of paradigm developing that would ultimately, perhaps in the distant future, lead to a unidirectional telomerase-based approach for attacking disease?

You know part of me wants to say yes. That would be terrific, but you risk hubris when you say something like that because you are then immediately proved wrong. But, as I said, because so much evidence has come in a consistent fashion, this seems like a pretty good attack on the problem. We see [that] these environmental factors like chronic stress are obviously acting on telomerase and telomere lengths through the immune system. We also see [that] when people are dealing with their stress well, it is correlating with having higher [levels of] telomerase and better telomere lengths. We put two and two together and say what if people could be helped to deal with their stresses.

Now you cant change life. You cant change the fact that somebody had a chronically ill childhood or the father has dementia. But, maybe, you can give people these tools, or things they can do that will help them cope. Would that modulate their telomerase up? I love it because it is very, very cheap.

This does not take a drug that has to be developed, which is very slow and complicated. You dont know when a drug is going to surprise you and give unexpected side-effects like some of the anti-inflammatory drugs. But if its you being enabled to cope with this sort of situation, its not your genes or something that you cannot change in the immediate future; I really like the idea. And I am not saying that this should somehow replace the older ways of medication. But if we can stave some of this off by these sorts of things...I am a great believer in trying to use the biology itself. This is biologyreally complex; millions of years have evolved to this. This is doing something that we are not smart enough to reproduce. So why not deploy it, use the system that is already there as much as possible.

This is hardly new. Eastern medicine has been saying this for a thousand yearsmore sort of integrated medicine. Some philosophies have been using this idea for a long, long time. But it is just that when you see something like this, which you can quantify, finding a nice easy-to-understand number like telomerase levels or average telomere lengths that you can see and measure and see for yourself if its useful or not.

In the modern context, could one perhaps even conceive of consuming some kind of drug, probably the enzyme itself, to enhance telomerase activity?

Oh, yes. You can absolutely imagine it. We just havent got around to that. When you have medicines, when you are not yet sick, you want to make sure that the risk is extremely low. Thats been the problem. But every drug, [even if] well designed, will have some risk and until we understand how well it workswhich is always feasible.... There isnt something in the shop right now to say that here is a reliable telomerase activator and we will have one a day. That will be very nice. I am not saying one shouldnt look for it. Right now, we have only got physiology; at least [we should] try to use that as much as possible if it could be harnessed to work in [our] favour.

In your talk, you spoke of how the technique of ribonucleic acid (RNA) interference could bring telomerase RNA levels down. Could cancer be treated by targeting telomerase activity in this way?

When you bring telomerase RNA levels down by using a mechanism that targets the RNA for destruction, the cells which were running on very high telomerase levels are now running on a lean diet of telomerase. They are still proliferating but they change their nature. They stop being so aggressively cancerous in their properties and they start to look a bit more normal.

The most dangerous cancer cells are actually the ones that are more like stem cells, which have this ability to produce themselves over and over again. More and more cancer biologists say stem-cell-like cells in cancers are the most dangerous.

Whats interesting is [by targeting the telomerase RNA] we can work them to being less stem-cell-like. We have also seen less metastasis; less metastatic lung tumours in the case of melanomas [for example]. Thats another way of approaching the problem, to make the cancer cells less dangerous. You might still want to kill them off at the same time. But probably since cancers can change like bacterial populations can grow resistant variants in response to certain antibiotics and then take over the entire bacterial population if you hit them with one thing, they become resistant to evade that and then they are the ones to proliferate.

So you just want to hit the cancer cells in as many ways as possible without causing a whole lot of collateral damage to the normal tissues. Its nice to have other arrows in your armoury. Also, completely knocking out telomerase will make a lot of sense. True, but why not use what the cancer cells have told us, which is that the high [levels of] telomerase is also making the cells, for reasons that we dont understand, apparently more malignant.

But, since there is no clear tag that distinguishes the telomerase of one cell from that of another, is there a danger that you would get at the others as well?

Exactly. This is the whole problem with cancer. Cancer is us. It is not like some foreign bacteria or some malarial parasite. Its us. And thats been the problem and just as with any other anti-cancer approach, they are after all our own cells and they are not completely different from the normal cells . And one of the ways of thinking it out is that cancer cells have sort of become like addicts to certain of their ways of doing things. They seem addicted to their high telomerase [levels], which is a sort of fanciful way of saying it. But it is not a bad way of saying it. They become so adapted to running on very high levels of telomerase that all their cell processes are adapted to that situation.

Now, normal cells in the body are just adapted to running on a nice, lean, regulated diet of telomerase. So, when you suddenly have these addicts and you hit them and knock down their telomerase [levels], they are actually more susceptible than [what] normal cells might be. n analogy might be like a heroin user. It is a little bit of a simplistic analogy, but there is an indication that there is this idea of addiction of the cancer cells. So that gives you hope that if you are hitting something that is really high characteristically in cancer cells like telomerase, even though we have telomerase in normal cells, they might not be quite so shocked when you knock it down because they are already running on low amounts of it. So, thats the logic. Then everything depends on the realities of how well is the drug getting taken up.

The other way, since we want the drug to get to only the cancer cells, is to package up the drug into tiny capsules called liposomes which are almost like tiny grease bubbles coat them with antibodies which recognise surface markers that are particularly [like] dents on the surface of cancer cells.

Again, they are not completely absent in normal cells but they are dents on cancer cells. That differential between the cancer cell and the other cell is a way of making the liposome deliver preferentially to cancer cells. The other advantage is that it protects whatever drug or anti-telomerase agent is inside to be broken down only where the medicine is to be delivered. These ideas are being tried for various things, and we are trying for telomerase agents as well just to see if that might help the situation but it is something one has to be aware of in any kind of anti-cancer approach.

Conversely, do you think telomerase could also be provoked to be more active and thus prevent or slow down the aging process, as some believe?

Here is my take on this. How do we estimate what is going on with aging? One way is to say, how long do people live? I think thats pretty genetically clear. If everything is going right, for humans its not going to be more than 120 years, the maximum known. Its not clear to me how exactly telomere maintenance might relate to that because people have been looking at centenarians and looking for genes whose alleles are more or less represented.

So far nothing relating to telomerase or telomeres has shown up in these people. In fact, their telomeres look pretty good. You would see diseases of aging going up but people who live a long life seem not to get cardiovascular disease very much. Why they die is actually very unclear. Gerontologists would say that suddenly there would be a little crisis and they would just die. But that wont be accompanied necessarily by years of heart disease or anything like that.

Extreme-longevity people look very old but they seem to remain healthy throughout and free of disease for a long, long time. What gets most people are diseases of aging and thats where this link with the shorter telomeres and diseases of aging seem so consistent. I dont want to say completely that telomeres have nothing to do with the death of extreme-longevity people. It might in ways we dont understand. There might be connections but its not unravelled.

So what might be feasible in a sort of dream world would be that if telomerase could be stimulated by any of these methods in a way that it is optimal, and doesnt turn it on to [do] something crazy, then would that be helpful in mitigating getting these diseases like cardiovascular disease and cancer? Because you are programmed pretty much for 100 plus years, you could be healthy up to that time in your life. And then something will happen as it seems to happen with very old people. Suddenly, some small perturbation happens and very quickly you go downhill sometimes its pneumonia, sometimes its a fall or sometimes its just something, and you just dont recover from it.

From what I understand so far, the telomere maintenance part will be much more related to whether you will have a healthy old age. Actually, theres a very nice new terminology that is catching up. People talked about lifespan [earlier]. Now its healthspan. What you would like to have is that healthspan should be as close as possible to your lifespan. As far as we know, there is nothing much we can do about lifespan. I have no particular feeling that humanity would necessarily want to live till 1,200 [years]. It might be fun but for the immediate future, we have got to live with what weve got.