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Author(s) of the publication: Vladimir SKULACHEV

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Ever since his birth as a species, man could not put up with the obvious fact: that sooner or later he has to die. Kicking against the pricks, so to speak. Not only in metaphysical terms, but also in a scientific sense, as we can see it in the example of research work carried out at the A. N. Belozersky Institute of Physico-Chemical Biology (Moscow State University). Our correspondent Igor GORYUNOV has approached its director, Academician Vladimir SKULACHEV, to spell it out.

Articles in this rubric reflect the opinion of the author. - Ed.

Pages. 35

Now, what is life and what is death? Is life eternal possible at all? That's the philosophy as old as the world...

- This very question-what is life and what is death?-has been the subject of long and abstract discussions. They concern the gist of the matter, not definitions only. Anyone can tell a live horse from a dead one. And yet a mechanistic approach held sway in science for many years: living organisms were compared to sophisticated machinery, just like that-a machine is bound to break and go out of commission sooner or later. And this means death.

This point of view, however, has its opponents. It's hard to imagine that a horse is subject to wear as a cart is. The horse is a living creature capable of sustaining its own existence and even of self-cure. But the cart is an inanimate thing-if broken, it will keep so until man fixes it up. On the other hand, it's a hopeless undertaking to flog a dead horse.

That is to say, any living organism is endowed with a powerful and complex system of debugging and of sustaining life. Thus, strictly speaking, there is no cogent proof of the inevitability of death where a living creature is concerned. But, if say, a brick falls on your head, you may die, sure. Yet as \bland, the famous personage depicted by the Russian writer Mikhail Bulgakov, has put it, bricks will never fall on your head for no particular reason.

But suppose a brick spares your head. What then ? Will you live on forever?

Of course not, because there is such a thing as death from old age. However, the medics say no one has ever died just because of old age. People depart for the other world because of particular maladies which keep piling up with the passage of so many years. As a result, we are saddled with a lot of ailments. But why? Answering this question is not as simple as it might seem at first sight.

In our opinion-and this is the substance of our hypothesis-dying of old age is the realization of the genetic program of self-annihilation inherent in every living organism; that is, one who is born must die someday.

It was the great German biologist August Weismann (1834 - 1914) who first spoke of the mechanism of predetermined death, or rather, of its necessity for enhancing the adaptive abilities of complex living organisms. He did it more than 120 years ago in his lecture on the nature of heredity. The German scientist claimed in particular that any living system carried in itself a seed of death the slayer.

His postulates made quite a stir, and other scientists begged to differ. Their arguments boiled down to the selfsame mechanistic tenets: any living organism will break anyway, and so no special mechanism is needed for its self-destruction.

More than that, after the British biologist Peter Medawar (Nobel Prize, 1960) had come up with a critique of the Weismann hypothesis in the 1950s, it came to be pushed to the sidelines in the scientific community-written off as something improper to speak of.

Medawar's line of reasoning was as follows: in wild nature individuals never live to venerable old age. Consequently, evolution could not develop a mechanism that touches no one. The British scientist erred in some points of his conclusion, and biologists made a mistake in taking his postulates on trust. The discovery of such a phenomenon as apoptosis-the programmed death of cells in a living

Pages. 36

organism and an essential biological mechanism responsible for sustaining a constant number of cells within and for eliminating defective cells-compelled one to recall the Weismann hypothesis.

It turns out, at least at the level of cells making up our organism, that there is a special mechanism of suicide. Not all cells are condemned to die, of course, but they do it quite often. If a particular cell finds it is doing something wrong that the organism does not need, this cell will eliminate itself in an act of suicide-a signal to this act is switched on automatically.

There may be collective acts of suicide when a community of cells destroys itself. Quite recently we in our laboratory detected a signal to self-annihilation of a community of cancer cells, immortal in principle.

Furthermore, we have shown in one of our latest works that the suicidal mechanism could involve a subcellular level as well. Cell organs, the organelles, must also have a mechanism of suicide. As we have found, such a complex organelle as the mitochondrion, responsible for energy supply to cells, likewise has this mechanism activated at a definite moment in certain situations.

But at this point biologists come up against an intriguing problem: does the suicidal mechanism operate at cellular and subcellular levels only? And what about the predetermined death of integral organisms? We have every reason to believe that this very mechanism is implicated here just as well, as shown in particular by our joint work with a team of German colleagues from Dresden. During our research we have established an effect of suicide in individual yeast cells. Well, the yeast cell is a one- celled organism with all characteristics proper to it, and it commits suicide by touching off certain biochemical processes.

You mean there is a special mechanism controlling the death of a living organism ?

- Yes, I'm quite positive about that, and I call it the "samurai" principle in biology. In my view, any complex biological system possesses a mechanism of self- annihilation if it becomes harmful or useless for higher hierarchy systems. The gene pool of any living organism, man including, has special genes that, if need be, cause its programmed death.

Experiments on worms furnish indirect proof of that. By knocking out two genes in them, biologists could increase their life span by 5.5 times. Similar results have been obtained for the Drosophila fruit fly. Its life expectancy likewise increases after such kind of manipulation.

Of particular interest to us are experiments on mammalians. Say, mice have a gene coding for the protein p66. If this gene is evicted, experimental mice increase their life span by nearly a third and have the cell suicide mechanism upset. But in the end they die anyway, which means there should be other mechanisms of predetermined suicide that are encoded in the genome.

So death is inevitable, isn't it? But why does life need a terrible mechanism like this?

- It is needed for ensuring a succession of generations which, in turn, makes it possible to increase the rate of evolutionary processes. Old individuals are succeeded by the younger set whose genome might not concur quite with the parental one. This enhances the diversity of a population's gene pool and thus creates conditions for the activation of the natural selection mechanisms and in the long run, for the appearance of new species.

According to mathematical modeling data, the world we live in could not come into being by chance. All kinds of examples are cited for the illustration of this fact. The probability of accidental provenance of contemporary forms of life is quite insignificant-like the chances of a monkey that does not know how to use the computer typing Pushkin's novel in verse Eugene Onegin.

Today we can certainly say that nature created the mechanism of ageing and death at a definite stage of evolution, the stage of one-celled eukaryotes. It was then that the circular carrier of genetic information was transformed into a linear one; and this predetermined the reproduction by a living organism of a limited number of its copies and doomed it to ultimate death. Before that protozoa had never died of old age. For instance, bacteria, dividing themselves infinitely, never age, for they do not have appropriate mechanisms.

But why did nature invent the mechanism of slow ageing? Why not have man dying at age 70 while being young and healthy before that? Then we would have a succession of generations, and there would be no troubles related to old age.

- Now let me say this. It would be unethical to talk on man, so I'd rather take the deer. Suppose we have a robust and virile male who always wins in fights for the female. Growing weaker with age, he would be still strong enough to continue overcoming his younger rivals. So he could go on passing his more valuable genome to the progeny-he, but not younger and less "prominent" members of the herd.

In a nutshell, the procedure of slow ageing enables the offspring to inherit some signal characters of one of the ancestors. Not physical characters only, but its intelligence too.

Still and all, why did nature program death?

- Death, among other things, is a mode of protection against frights and monsters that could otherwise come into being should the genome be out of joint. It took billions of years to create the world surrounding us. But, as we can see it in experiments, this world can be destroyed pretty fast and easily. Not only by using the A-bomb, mind you. It would be enough to change the activity of just one single gene out of dozens of thousands making up the genome of multicellular organisms.

My I give you this example. Recently research scientists were asked to tackle a practical task-breed a sturgeon that could be growing faster than usual. They decided to activate the gene of its growth hormone by inserting the human growth hormone gene - all ver-

Pages. 37

tebrates, you see, have similar genes of this hormone.

Fortunately, the scientists began with aquarium fish. Two US researchers, W. Muir and R. Pollack, introduced the human growth hormone gene into the genome of these fish, and they did start growing faster. Well and good, but the scientists noticed something bad: the fish were growing all too fast to huge size-so much so that many skipped the stage of sexual maturity. As a consequence, every third male fish produced no offspring. But worst of all, since females would contact large males, unproductive in this particular case, rather than smaller but productive ones, things came to a critical pass, and the number of fry plummeted. The fish school degenerated fast.

As shown by computer simulation data, if only 60 transgenic fish are let into a fish shoal of 60,000, the shoal will disappear in forty generations. And if we proceed from digital computations, one such fish may undo all of the school. Not in forty, but in many more generations.

It looks that one of the functions of the programmed death mechanism is to sort- identify and eliminate-individuals whose genome is impaired or may become so.

Can we say that the phenomenon of programmed death is a proven fact at the level of organisms?

- It's a fact for one-celled organisms. What concerns higher organisms, we have no proof positive of that. But as we think, research should be carried on. In theory this approach may help achieve a dramatic increase in life expectancy. We cannot tell yet whether it will come off or not. But what I know for certain is this: the traditional approach is bound to fail anyway. We will go on treating one disease after the other ad infinitum, or rather, until our patient dies.

In contrast to classical gerontology that treats age-related diseases, we suggest breaking the mechanism of ageing. That is to say, not patch up the breakages caused by the ongoing process but rather prevent the ageing itself.

It is common knowledge that breaking is easier than building. It would be easier to break the ageing mechanism than cure the diseases (breakages) it causes.

Breakages triggered by the ageing mechanism?

- Yes. Breakages are triggered by the self-annihilation mechanism inherent in us, a mechanism that should carry us off in the end.

You suggest breaking this mechanism?


But would it not be easier to control this mechanism to man's good?

- By "breaking" I mean switching this mechanism off. Experimental genetics is fond of "breaking" genes. Today it is a relatively simple operation. But interfering in the work of genes and regulating their activity calls for subtle approaches. Techniques that can slow down the ageing process are already being developed. But in the first approximation, if we are lucky enough, the gene (rather, genes) of ageing should be wrecked.

Who triggers the death mechanism?

- I think the life span of every species is optimized according to conditions of its life. A mouse will live two years or so. Present-day man-around 80 years. Yet life expectancy depends a good deal on how a given species is adapted to the environment. Young species, poorly adapted to the outside world and not in harmony with it, should avoid a long life so as to increase their fertility and the rate of the succession of generations, and thus have a chance to find some new character. This is what we call the R-strategy which allows to set off the evolutionary flywheel and speed up the process of adjustment to external conditions. Individuals of environment- adapted species live long, but have a low fertility rate (K-strategy). There is a rigorous law whereby a species getting into favorable conditions changes over to the K- strategy. When things are in a bad way, it is the R-strategy that operates: individuals live a short life but proliferate apace.

But who in particular sets off the time counter in each organism-well, the science cannot tell yet. When this counter is on to show that it is time to die, the mechanism of ageing is switched on.

But will the immunity of Homo sapiens from death of old age not tell negatively on the survival of the human race?

- Most of the evolutionary mechanisms are but an atavism to man. He no longer relies on the natural pace of his biological evolution, he is changing his own self and the ambient world with the aid of technology. To fly - he builds aircraft, to float-he builds boats, and to count fast-he makes computers.

As the Russian scientist Ilya Mechnikov, Nobel Prize winner for 1908, has put it, we have inherited from animals many characters we do not need at all, even harmful characters too. I suppose that the most harmful of this heritage is programmed death, or phenoptosis (suicide of an organism).

How does the scientific community respond to your hypothesis ?

- It depends. I would not say that most of the research scientists agree. But we have those who do, and not only in Russia either. I could feel that during my recent trips to Italy and the United States.

But persuading is a thankless job. We should carry out experiments and prove that we are right. A hypothesis, no matter how elegant, will never pass into a category of scientific knowledge unless it is confirmed in experiments.

Research in our field is all too costly. So we are cooperating with scientists of other countries. And this is right. Prolonging life is a global problem and it should be attacked in concert by the world scientific community.



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