Much like the tips of shoelaces, telomeres are molecular caps that protect chromosomes. What might be feasible in a sort of dream world would be that telomerase could be stimulated in an optimal way and that would be helpful in mitigating, say, cardiovascular disease and cancer.
Elizabeth H. Blackburn won the 2009 Nobel Prize in Physiology or Medicine along with Carol Greider and Jack Szostak for discovering “how chromosomes are protected by telomeres and the enzyme telomerase.” This was for solving a major problem in biology, “how the chromosomes can be copied in a complete way during cell divisions and how they were protected against degradation.” Dr. Blackburn, a Tasmania-born American scientist who is Professor of Biology and Physiology at the University of California, San Francisco, has likened telomeres, which serve as protective caps for the genetic information in the cells, to the end caps of shoelaces known as aglets. Dr. Blackburn, along with Dr. Greider, is credited with the identification of the cell enzyme telomerase, which replenishes the telomere. Research over the years in the area 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.
Dr. Blackburn was in India in February 2009 on a lecture tour as the featured speaker of the 2009 Cell-Press-TnQ India Distinguished Lecture Series, which included talks on “Chromosome Ends and Human Health and Disease” in Bangalore, Hyderabad and New Delhi.
This is an edited excerpt from a wide-ranging interview Dr. Blackburn gave Frontline ’s Science Correspondent, which was published in two issues of the magazine in April-May 2009:
Your work is concerned with the role of chromosomes in human health and disease. What aspect or component of a chromosome is critically involved in this?
The part that we work on is the very ends of chromosomes, which are called telomeres. Much like the tips of shoelaces, telomeres are molecular caps that protect chromosomes [which carry the genetic information inside the nucleus of a cell]. Because without special protection the chromosome ends are susceptible to being chewed away and frayed away by natural processes taking place inside cells.
So we focus on how those ends carry out their biological roles and what they consist of in terms of molecular features and how an enzyme that we discovered some years ago, called telomerase, replenishes the ends as they wear out.
Telomeres wear down with time, and when these become so worn that they cannot sustain cell division any more without causing chromosome instability, cell division stops [senescence]. This is what leads to ageing. One characteristic aspect of ageing is the increased susceptibility to disease, particularly age-related diseases such as cardiovascular diseases and cancer. Then the question is: Over time can the balance of telomeres wearing down versus the telomeres being replenished [by the action of telomerase], first of all, affect human disease? And the answer is yes. Then is there anything that we can learn which changes the balance between the wearing down and the replenishment that might have impact on human diseases?
How does this wearing down of telomeres happen?
There are a couple of known reasons as to how the telomeres wear down. We can ask a bigger question as to ‘why’ but let’s answer the ‘how’ first. It is twofold.
One is DNA replication, which has to happen for the genetic material to be completely copied so that there are two copies of the genetic material before a cell divides and then each copy goes into the two daughter cells. That molecular machinery made of enzymes and associated proteins is very good at copying very accurately almost all the length of the entire chromosomal DNA with very high accuracy. But for some strange reason that a human cannot think why, it cannot copy the very ends of a linear DNA. It’s just an odd deficiency in this enzyme that is otherwise engineered to be so exquisitely very accurate and thorough in copying.
Bacteria have circular chromosomes. Bacteria are much smarter than us; they don’t have this problem. But eukaryotes – everything from humans to plants to yeasts to single-celled organisms except bacteria — have linear chromosomal DNA. The other reason is that there are enzymes in the cell that naturally chew away on DNA ends because of the repair processes that they sometimes can carry out. But the primary reason is the inability of the DNA replication machinery to carry out copying at these very ends. Telomerase is the enzyme that adds the extra DNA to the ends. Basically, it just adds a buffer of DNA that does not code for proteins but acts as an attraction for protective proteins, which form a kind of a sheath around the ends of the chromosomes.
You have been emphasising that what is observed as telomere shortening and the role of telomerase in human health is an association and not really a causal connection.
We know that in rare genetic diseases there is clear causality though these genetic diseases are a more extreme by definition and so they are not in the general population. But when you look at them, they give you an idea of what’s happening in a relatively extreme case. When you compare what happens in more common situations — with modulated amounts of telomerase action — with what happens in extreme cases in genetically engineered mouse models, can you put them all together? We can make a case for causality that when telomerase is down, it does have consequences. But one just wants to be careful not to over-interpret the shades of grey kind of thing. As a scientist, as somebody who is looking at it all, I always want to be careful because biology has a way of turning around and surprising you. So the weight of evidence is pretty much like this: lower [levels of] telomerase could indeed plausibly contribute to things like diseases of aging.”
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 don’t listen to the signal that says 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. The only way 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 don’t understand at all but we see them when we perturb just telomerase in a very targeted way.
What’s 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 what’s going on in the normal cells where it’s much more closely regulated and reasonable in amount. So what’s 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 it’s 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 it’s almost like a defining feature. So we have to take notice of what cancers are telling you; we’ve got to learn something from this. And certainly the telomeres are maintained but what is revealing are these other things.
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.
What’s 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]. That’s 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. It’s 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 don’t understand, apparently more malignant.
Conversely, do you think telomerase could also be provoked to be more active and thus prevent or slow down the ageing process, as some believe?
Here is my take on this. How do we estimate what is going on with ageing? One way is to say, how long do people live? I think that’s pretty genetically clear. If everything is going right, for humans it’s not going to be more than 120 years, the maximum known. It’s 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 ageing 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 won’t 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 ageing and that’s where this link with the shorter telomeres and diseases of ageing seems so consistent. I don’t want to say completely that telomeres have nothing to do with the death of extreme-longevity people. It might in ways we don’t understand. There might be connections but it’s 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 doesn’t 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 it’s pneumonia, sometimes it’s a fall or sometimes it’s just something, and you just don’t 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, there’s a very nice new terminology that is catching up. People talked about lifespan [earlier], now it’s ‘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 we’ve got.
( The full 7000-word Frontline interview, in two parts, can be read at http://www.frontlineonnet.com/fl2608/fl260800.htm and http://www.frontlineonnet.com/fl2609/ stories /20090508260909100.htm.
The Nobel announcement and press release of October 5, 2009 can be read at http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html.)