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Cells continuously want to kill themselves


Why cell death is important
Martin Raff Scientist
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I guess you could start by asking, why would evolution have selected this rather peculiar way to build an animal, and I think the simplest way of thinking about it is that this is a mechanism that ensures a cell only lives where and when it’s needed. So if a cell ends up in the wrong location, it’ll automatically kill itself. If it’s needed at one time in development but not needed at some other time, it’ll automatically kill itself. Cells are constantly changing the signals they need to survive during development and so if the cell doesn’t keep up and develop on exactly the right schedule, it’ll automatically kill itself.

And many, many cells die during normal development. In fact, even in adult tissues cells die in large numbers. So during this conversation we’re having, hundreds of millions of your cells die in this way… they kill themselves. Perfectly normal, healthy cells are killing themselves all the time. One of the little miracles here is that for every cell that dies, a cell divides to replace it and we have no clue how you balance this death and cell division so that it is balanced. I mean, if it weren’t balanced of course you’d be growing and shrinking and of course that doesn’t happen, so we don’t understand how that balance is maintained but it is.

So you can now ask a number of questions about what the implications are of having this dependence on survival signals and it’s used for a variety of things. One is to get cell numbers right, adjusted properly in development, but it also has implications for cancer, because in cancer when you see… when you look in a cancer, there are many cells that are dead and there are other cells that are dividing, and the cancer grows depending on how much greater the division is than the cell death, and cancer is a disease where cells are not obeying these kinds of social controls.

So these social controls are these controls where cells control the behaviour of other cells by these signals to ensure that cells behave appropriately for the whole organism. You can’t have cells dividing when they want, they should only divide when another cell is needed, and that’s done by cells only dividing when they’re signalled to divide, cells only surviving when they’re signalled to survive, and so on. So in cancer the problem is it’s a social disease, if you like, in that these cells don’t obey these controls. They divide when they shouldn’t divide. They survive in places they shouldn’t survive because of these mutations that screw up their genes so that they’re now able to divide out of control and survive, even though they’ve moved to a place they shouldn’t be. So it has implications for cancer in terms of helping you understand cancer and hopefully one can use our understanding of the death programme, this suicide programme that’s built into every cell, to maybe kill cancer cells more efficiently.

Now, it turns out that all… virtually all of the cytotoxic drugs used now to treat cancer work by inducing cell death, by activating this suicide programme. So when we started getting interested in death, this kind of cell death, nothing was known about this suicide programme, not a clue how it worked, and now some eight, nine years later one understands it in enormous molecular detail and the reason for that is that there were genetic studies done in this simple nematode worm. This little worm that only contains about 1,000 cells gave us the answer for how cell death works in us.

So this… it’s I think a very important discovery of the last ten or 20 years, is how similar we are in the way we develop to things like worms and flies and all other animals. I mean, it’s shocking. Not even Darwin would have predicted how highly conserved all these mechanisms are. It’s quite remarkable. So in the worm there’s only 1,000 cells in the adult animal and during the development of the worm 131 cells die by this programmed cell death, this suicide thing. They were able to do genetic studies where you treat the worm with a mutagen, a chemical, it causes damage to genes and select for worms where none of these deaths occur, and they found two genes. When you inactivate these genes, none of those deaths occur and the worm goes around with an extra 131 cells. Quite remarkable.

Then when they cloned and sequenced these genes it turned out that they encoded proteins that were the same, were very similar to human genes that were already known, proteins that were known in humans, and one of these genes turned out to be an enzyme involved in cell death, and another one turned out to be a protein that regulated cell death. So you knew immediately that here this suicide programme has been conserved in evolution from these simple little nematode worms to humans. I mean, quite remarkable.

And now everybody became interested in cell death. Before that, almost no one was interested in cell death, a basic fundamental problem, and yet hardly anyone was interested in… which takes us to another point that we were not going to discuss but I think we probably should which is, how do people choose what to work on? How can you explain that there’s 50 or 100 laboratories working on one type of cell doing one type of thing when there’s huge areas of total mystery where no one is working that are equally important? How… how do you explain that?

I mean, if you were a young scientist you would think the imperative would be enormous to move into an area where there… which wasn’t crowded, where your mentor wasn’t working because your mentor, for example, usually has a big lab. When you start, you have a little lab. Why would you want to compete with your mentor? It would make more sense to move into an area where there’s very few people working, and yet that rarely happens.

So somewhere along the line the system isn’t working properly because if you ask a young person, why don’t you move into one of these areas where no one is working, and they will say, I can’t do that because I’ll never get funded to do it, I won’t get a job, I won’t get my papers published, and that’s sort of a universal conception that young scientists have. If it’s true, it’s a disaster. No one thinks the system should be encouraging young scientists to do conservative science, yet it clearly is so we need to change the way this works. I mean, there are such big problems that almost no one works on – that’s crazy. When you think that there’s hundreds, thousands of people working on some narrow little area, I mean, it’s madness. So the sociology of science, how people choose one area versus another is another interest of mine. I think it’s really an important area. We don’t do it well. We need to think more about what it is that pushes people to choose to do the same things.

Martin Raff is a Canadian-born neurologist and research biologist who has made important contributions to immunology and cell development. He has a special interest in apoptosis, the phenomenon of cell death. Recently retired from his professorship at University College, London, these stories were recorded in 2000.

Listeners: Christopher Sykes

Christopher Sykes is a London-based television producer and director who has made a number of documentary films for BBC TV, Channel 4 and PBS.

Tags: Charles Darwin

Duration: 7 minutes, 21 seconds

Date story recorded: 2000

Date story went live: 13 July 2010