Sex and Death

1. Sexual Genesis in the Microworld, or When Eating was Sex

from "What is Life?" by Lynn Margulis and Dorion Sagan

Animal sex always involves meiosis. In meiosis, as in mitosis, chromosomes attach to spindle microtubules and are partitioned out to offspring cells. However, meiosis omits a crucial step: the doubling of the chromosomes. Meiotic cell division thus produces two offspring cells each with only half the number of chromosomes that were present in the original parent cell ... Meiotic sex evolved in mitotic protoctists long before any animal appeared in the record of life. Nevertheless, some modern protoctists show neither mitosis nor meiosis. ... Meiosis is a variation on the theme of mitosis. Meiosis likely evolved in doubled cells that already divided by mitosis. The first fertilization event probably satisfied an urge not to merge but to eat. ... Hypermastigotes, which contain only a single set of chromosomes, sometimes engulf one another. Some of these doubled beings reproduce. Although sloppily, a doubled microbial monster would undergo cell division and give rise to another doubled microbial monster.

The cells in our own animal bodies are in a diploid, or double chromosome, state except for the protist-like ova and sperm, which are in a haploid, single-chromosome state. Each animal body is a sort of diploid husk, morbidly discarded by those haploid sex cells that manage to produce each generation a fresh new body and thus continue beyond the death of the "individual." The diploid body pays the ultimate price - death - for transmission of haploid sex cells. Perhaps originally cannibals in distress, chromosomally doubled protists are our ancestors. Humans and all animals inherited death from these early eukaryotes. Each generation starts where the last left off and, depending on who survives, each follows a slightly different course. Over time, this leads to new species.

Aggregated into colonies, layers of eukaryotic cells eventually evolved into tissues. It is an amazing fact that all zygotes -fertilized egg cells that survive to become embryos -grow into plants or animals composed not just of many cells but of several (or many) kinds of cells that assemble into distinct tissues.

Even in single-celled parasite apicomplexa, gender differentiation into motile micro-gametes
and larger non-motile macro-gametes has occurred. Certain fungi display external symmetry of the form of gametes, but in all animals, the larger oocyte forms the global physical matrix for embryogenic differentiation of the multi-celled organism. Note the diploid parthenogenesis.

Sex and Death

Only accidental, externally caused death, existed at the origin of life. So it was for a long time thereafter. But with protoctists came "programmed death": death in which cells age and die as part of the life of the individual. In familiar animals - insects, mammals, and birds -the difference between the part that dies and the part that poten- tially lives on is the difference between the body and the sex cells. In mammals the sex cells (or "germ plasm," as biologists sometimes say) are the only cells whose direct progeny survive into the next gen- eration. In contrast to the ova and sperm, the soma - the animal body- has a discrete life span. With a high degree of precision, animal cells must reproduce - or cease reproducing. For example, during the intrauterine development of the mammal brain more than ninety percent of the cells that develop die before the fetus becomes an infant. These brain cells stop growing and disintegrate, are sacrificed in the process of growing a healthy infant. The essential difference between the living germ cells and the dying body cells of animals is likely very old.

Upper-left the centriole linked to the 9(2)+2 structure of the flagellum.
The axial complex core of the sperm flagellum [ ] the distal centriole Dc, nucleus N.

We speculate that the ancestors of animals were composed of relatively few cells that differentiated into at least two distinct kinds. One kind specialized in using their 9(2)+2 Microtubule organelles to form undulipodia for propulsion, for sensing prey, for fostering water flow over or through the animal, or for sweeping food particles into and along digestive systems. But it is an oddity of physiology that once animal cells dedicate their centrioles to forming undulipodial shafts they can no longer use them to create the motility apparatus for mitotic cell division. This means that animal cells stood to gain by sticking together in specialized colonies. Even today an animal cell, whether of a tissue or a sperm after growing the undulipodium, no longer divides. A centriole forms a kinetosome and relinquishes cell immortality; a kinetosome cannot revert to a centriole. The irreversibility of kinetosome formation appears to be an inviolable rule within the animal kingdom. Animal cells can either form kinetosomes (grow undulipodia from centrioles) or reproduce by mitosis -but not both. An animal cell with a kinetosome is a dead animal cell - its days are numbered, as it will not divide again. Perhaps the DNA reported by David Luck and John Hall to be in the kinetosome-centriole is used for mitosis or to form an undulipodium but not for both. Like choking from inhaling water, any attempts of cells to simultaneously reproduce and maintain undulipodia would have been thwarted. And yet animals seem to have found an answer to this genetic dilemma: by sticking together in colonies-colonies where some cells reproduce while others form undulipodia -they could in effect have their cake and eat it too. The restriction of a cell unable to divide after growth of its 9(2)+2 organelle was overcome by colony formation. The great majority of cells retained their option to divide, while a few sacrificed immortality to be undulipodiated. But even the cells that do divide in the animal do not do so indefinitely. After 6oo million years the adult animal is still a mated protist's way of making other mating protists. Our whole life from womb to tomb is in fact an interim stage in the life cycle of tiny fused cells. Animals emerge into another dimension, visible life and consciousness, only to return via sex to their ancient single-celled, microbial state.

Planaria and other simpler organisms retain a capacity to regenerate from their parts, so are in principal immortal. In some simpler organisms the germ-line has not completely differentiated from the soma and there remains a class of totipotent mesenchymal cells in the ectoderm.

Death is the price we all pay for this ancient history of multicellular compounding, for this inability of hungry protists to undo their Proterozoic entanglements. What "dies" is the body, the adult flesh after it has released into the water or body fluid the protist-like tailed sperm and chubbier egg. Animal life did not appear de novo, but from protoctist predecessors. Protoctists with elaborate cycles of fertilization, multicellularity, and meiosis became animals. Like programmed death, gender is not intrinsic to life. Gender evolved. Cells of different mating types, like protoctist lovers today, were initially identical to each other in appearance. The seasonal merging and restoration of chromosomal numbers in fertilization set the stage for the origin of gender. ... The many small sperm of males compared to the few larger eggs of females was the beginning of an evolutionary asymmetry which today expands into the realms of political, sociolinguistic, and psychological debate. Evolutionary biologists suggest that early sexual inequality-males maximize reproduction by inseminating the largest possible number of females, whereas after a certain limit mating becomes super- fluous to females constrained by devotion to their lesser quantity of eggs -is behind distinct male and female attitudes toward sex.


2. Resurrection of the Dead

from In the Blood by Steve Jones : an extract

So also is the resurrection of the dead.
It is sown in corruption; it is raised in incorruption
I Corinthians 15:42

"Life is an unlikely business. That it has lasted for three billion years is surprising enough. What is astonishing is that living creatures can survive and make copies of themselves in the face of physical laws that should lead to immediate destruction. An animal is a chemical reaction so unstable that it is instantly reversed at death. How, then (to paraphrase The Book of Common Prayer) can our own vile bodies, bound as they are to return to dust, attain a resurrection to eternal life as one generation succeeds the last? How - almost miraculously - are young babies born to old parents?

Some creeds have a naive faith that those who die live on. Their bodies are merely removed, and may return. The dead speak to the living; Saul, the first king of Israel, consulted the Witch of Endor to find out their views and was much criticized for so doing by those who preferred God, rather than ancestors, to rule their affairs. This literal version of a victory over death ignores the simple fact of corruption. All religions have, at their heart, renewal: the resurrection, in one form or another, of a body defiled by death. Plato realized that it can best be achieved by detaching the flesh from its essence, the soul. This can persist although the body decays. The same idea came to Mendel. His work disengaged the genetic message a survivor until all life comes to an end - from the ephemeral existence of its carriers. The German embryologist August Weismann went further. He invoked a physical entity, the germ plasm, that transmits life but is insulated froin the fate of the soma , the body. The paradox was that a decrepit soma produces, each generation, fresh germ plasm. How does it do it? What is the rejuvenating principle that has granted life a thousand million resurrections since it began? Weismann did not know.

In the Symposium the prophet Diotima addresses Socrates:" The object of love, Socrates, is not, as you think, beauty ... Its object ... is to procreate ... because procreation is the nearest thing to perpetuity and immortality that a mortal being can attain. It is in this way that everything mortal is preserved, not by remaining for ever the same, which is the prerogative of divinity, but by a process in which the losses caused by age are repaired by new acquisitions of a similar kind. It is in order to secure immortality that each individual is haunted by eager desire and love."

In other words, sex is the key to eternal life; it allows the body to be born again and reverses the damage done by age. Weismann disagreed. In his view, 'twice times nothing cannot make one.' Why should two old and decayed individuals be better at making a young one than a single elderly but asexual female? Mixing two degraded sets of germ plasm together would not rejuvenate them. Sex alone was not enough. Indeed, it was - if anything - a cause of decline. There is plenty of evidence that he was right. Reproduction is expensive for both males and feinales. In many creatures, males die in the act of mating (occasionally sacrificing themselves as a nuptial meal to their mate). One species of slug bites off its own penis after sex, leaving it as a plug to ensure that the female can find no other partner. Even fruit flies live for longer when celibate, and the same is true for men and women. Sex, although it has long been known to connect life's beginnings to its end, is usually seen as a source of debasement rather than salvation. It led to the expulsion of Adam and Eve from the Garden of Eden, Eve the more culpable as she tempted Adam towards immorality (a persistent theme in the ideology of gender, in which sexual blame is usually placed on females.)

The tie between sex and religion is, as a result, deeply ambiguous. Each is an inner experience; each contains both threat and promise, and each achieves some kind of victory over death. Sometimes the link between them is embarrassingly clear. St Teresa of Avila had a vision of Christ. 'In his hands I saw a long golden spear ... he seemed to pierce my heart several times so that it penetrated to my entrails. When he drew it out ... he left me afire with a continual love of God. It is not bodily pain, but spiritual, though the body has a share in it - indeed a great share. So sweet the the colloquies of love that pass between the soul and God that if anyone thinks I am lying I beseech God, in his goodness, to give hitil the same experience.'

Genetics casts new light on the alliance of sex, age and death. It shows how all derive from errors, mutations, in copying the genetic message. They cause individuals to decay but genes to be preserved. Each generation, sex redeems the germ plasm and is the stuff of the evolutionary change that ensures its long-term survival. More and more it seems that this sexual renewal is paid for by somatic degeneration, in which mutations in body cells lead to the afflictions - cancer, heart disease, mental decline - that beset everyone who reaches old age." (Jones 243-6).

Of course we now know that the mistakes have an evolutionary function and that the faithful copying of the genetic message ensures each generation preserves the genetic endowment as meticulously as it can, with the help of repair enzymes, subject to rearrangement through sexual recombination to produce an almost unlimited variation of genetic types. Unlike mutations, which are often lethal or disabling because of a loss of critical function, and can only occur at a tolerable load of around 0.5 per generation, sexual recombination almost always leads to a viable offspring becuse recombination exchanges a precise set of identically positioned genes, retaining a full complement of human genes in each germ cell. In fact, by introducing such variety sex has facilitated the evolution of complex multi-celled organisms. In artificial life simulations, sexual recombination even by itself is a very effective evolutionary algorithm. Inbreeding studies suggest most individuals carry an avergage of two recessive lethal alleles in their genome, indicating the tolerable level of deleterious mutations.

"Chromosomes are a bit like shoelaces. At their ends are caps, made not of metal but of DNA bases. just like laces, these 'telomeres' fray away with use; in this case by mutation. They are made from thousands of repeats of a simple six-part motif. In a typical lineage of dividing cells about a hundred DNA bases per division are lost. The telomeres act as a timer of mortality. Giving up cell division depends on how much of the protective telomere cap is left. Once the number has been chipped away by mutation to four thousand or so, the cell is no longer able to divide. The telomere is a clock that pilots the cell through its designed life-span. Counting the amount that remains is a good way to predict when it is likely to enter old age. What is true of cells is also true of people. An eighty year old has fewer of these units than does a child because so many have been lost. Telomeres are a sort of genetic nemesis, waiting to catapult their carriers - cells or people - into senility. Just as Nemesis (the goddess who distributed bad and good fortune at whim) might have arranged, not everyone is born equal. The number in young children ranges from about six thousand to around twice that. Identical twins have chromosome caps of about the same length suggesting that telomere size is under genetic control. The smallest yet found was in a man of ninety-seven, who had fewer than five thousand repeats left at the end of each chromosome. Goethe's Faust, it may be recalled, died at the age of a hundred (his telomeres, no doubt, suitably reduced) having renounced immortality as he was bored with life. Goethe, biologist though he was, did not realize how much of that choice was already coded into his hero's genes. The rate of frayng of telomeres means that some babies - those born with short chromosome ends - may fall below the crucial length earlier than others. Perhaps they will enter old age sooner than their more fortunate colleagues. How, or even whether, telomere mutations lead to decay is not known. A simple, simplistic, but sinister calculation suggests that a baby at the lower end of the telomere range is programmed to live for threescore years and ten while a child with a more generous endow- ment could linger on for another twenty years before he expires, sans eyes, sans teeth, sans telomeres, sans everything. It may soon be possible, by checking the genes, to guess whether a baby born in the year 2000 has any chance of seeing the first century of the new millennium almost to its end. Sex resets the telomere clock. As the chromosomes pair up during the formation of sperm and egg they are revitalized by a enzyme that makes new chromosome ends. The gene - a veritable fountain of youth - produces an enzyme, telomerase (sometlines called, with the leaden humour of science, TLC or Telomere Lengthening Component). It is not active in tissues other than those producing germ cells; only sperm and egg can be rejuvenated. There is, though, an exception to this rule. The TLC gene is switched on in cancer cells. It gives them renewed life. It inay even be the gene that allows them to continue to divide and, in the end, to outrun cells which have obeyed the instructions to die. Its level of activity is at least a thousand times greater in cancer cells (and in the precursors of sperm and egg) than in others. Those whose cancerous tissues have found everlasting life are likely to die before those whose cells accept their predestined dei-nise. Telomeres show how close is the tie between mutation and age and how Faustian the bargain between sex and death. No doubt they are just a part, perhaps a small part, of the machinery of rejuvenation that works its magic each time a baby is born. They affirm, though, that - when the dead are metaphorically raised, in the shape of their offspring - their genes will be changed. St Paul himself described the conflict between the fate of the genetic message in the body and that in the cells which transmit it to the next generation in terms familiar to a biologist: 'For this corruptible must put on incorruption, and this mortal must put on immortality.' Biology shows how right he was: that, although the life of those who bear them is transient, the world of the genes will live for ever." (Jones 281-2).

The Telomerase Gene is Isolated

AS THE HUMAN BODY AGES, IT LOSES bone. individual cells lose something equally vital. Every time one divides, it sheds tiny snippets Of DNA known as telomeres, which serve as protective caps on the ends of chromosomes. After perhaps a hundred divisions, a cell's telomeres become so truncated that its chromosomessite of the cell's genes-begin to fray, rather like shoelaces that have lost their plastic tips. Eventually, such aged cells die-unless, like "immortal" cancer cells, they produce telomerase, an enzyme that protects and even rebuilds telomeres. Scientists have long dreamed of drugs that would inhibit the immortalizing enzyme because, observes M.I.T. biochemist Robert Weinberg, "then maybe cancer cells would run out of telomeres and just poop out." Wishful thinking? Maybe not. In papers published just a week apart in the journals Science and Cell, two teams of researchers-one led by Nobel-prizewinning biochemist Thomas Cech of the University of Colorado, the other by M.I.T.'s Weinberg-have announced a breakthrough that could help bring about such a drug. Both teams have managed to clone a gene that controls the activity of the telomerase enzyme in human cells. That could set the stage for development not only of inhibiting drugs but also of substances that switch on the enzyme-which might help combat degenerative diseases associated with aging. Such possibilities, to be sure, are speculative, but that didn't stop Wall Street, where the stock of Geron Corp., a small biotech company based in Menlo Park, Calif., that helped Cech's group discover the gene, more than doubled, to 161/8 a share. In fact, Geron researchers have been looking for antitelomerase compounds for several years, using indirect-screening methods. Because tumor cells-the main source of the human enzyme-produce it in vanishingly small quantities, the scientists lacked pure telomerase, which could have sped the search for drugs that might be used against it. With the new gene in hand, the researchers should be able to churn out the protein for which it provides the genetic blueprint. That protein, they believe, is telomerase's most important building block. "For us," exults Calvin Harley, Geron's chief scientist, "it's like having access to an organism's brain." The new protein, it turns out, bears an intriguing resemblance to an enzyme produced by Hiv, the retrovirus that causes AIDS. Indeed, the AIDs drug AZT has already been shown to inhibit telomerase activity. But the viral enzyme and the human enzyme, says Colorado's Cech, are only 20% identical, which explains why it is not an ideal telomerase inhibitor. "What we want," he declares, "is a compound that fits telomerase the way a hand fits a glove." The odds that such a compound will materialize now seem high. But experts caution that it could take years before the first telomerase inhibitors are ready to be tested on humans to determine if they'll have any serious side effects - or if they'll actually inhibit tumor growth. Such questions are perhaps one reason Geron's stock leveled off at week's end, closing at 121/4 a share. -By L Madeleine Nash

Telomere Setback: In New Scientist 4 Oct 97 it is noted that mouse cells lacking telomerase could grow into tumours in immune-defective mice and that telomerase-deficient mice grew normally, suggesting telomerase is a supplementary enzyme to DNA recombinases. However mice have longer telomeres than humans which may delay shortening defects and may also indicate a different telomeric system.