hybrid vigor | the birth of death

The Birth of Death

by Andrew Procter

Why do we die? If biology sees life as a system of chemical reactions, then death is the destruction of this system, the breakage of metabolic pathways. As multicellular creatures, we humans face death at high levels of organization such as heart failure or brain trauma. Still, like any other creature, we die when our cells die.

Often we think of death as accidental; in biology, this form of death is called necrosis. For example, toxins released by disease-causing bacteria may disrupt metabolism in cells, causing their destruction. But a far more interesting death is scripted in advance.

Research into apoptosis, or programmed cell death, has received much recent attention. Apoptosis is widespread in nature. Common examples include the death of leaves in the autumn, the death of a tadpole's tail, and the death of cells in the developing human hand, causing separation of the fingers. Apoptosis is much cleaner than necrosis, which usually afflicts a cell starved of nutrients and oxygen.

During necrosis, the nucleus continues to direct cellular machinery, which strains from lack of energy. Molecular pumps maintaining the cell membrane gradient (an ion concentration difference between the exterior and interior of the cell) shut down, and the membrane bursts, spilling the cell's contents into the surroundings.

No such violence occurs in apoptosis. First the DNA in the nucleus fragments, making the process irreversible. The cell pulls away from neighboring cells, and its cell membrane pinches off and isolates organelles. "It looks like popcorn," says Emory biologist Gregg Orloff. Neighboring cells digest these apoptotic bodies, recycling their molecules for their own purposes.

Scientists have linked apoptosis to death by old age. Like apoptosis, aging appears to be programmed. Barring disease, most human somatic (body) cells have been found to divide about fifty times before they die; Leonard Hayflick investigated this "Hayflick limit" in the 1970s and 1980s.

More recent research has linked cellular aging to the degradation of DNA over time. In the evolution of eukaryotes from prokaryotes, circular prokaryotic DNA became linear, and to keep the ends of the DNA from sticking together, molecular caps called telomeres developed. (Eukaryotes, a class of organisms which includes humans, contain more complex cells than the ancient prokaryotes, which include bacteria.) Telomeres, however, do not replicate along with DNA before cell division, and so degrade with each division. It has been found that in somatic cells, telomeres actually shorten with each division up to the Hayflick limit; this has become a theoretical measure of aging. At a certain point, the telomeres become so ineffective that the DNA sticks together in a useless jumble, and the cell can no longer reproduce. At this cue, the mechanism of apoptosis swings into action, and the cell self-destructs. The trigger is always there, waiting. "What's going on in your cells at all times is a see-saw battle between life and death," says Orloff.

In germ cells (gametes and stem cells) the story is different. Gametes are sex cells--sperm and egg--and stem cells are the undifferentiated precursors of many types of cells. Both cell lines bear large quantities of the enzyme telomerase, which repairs telomeres. For every telomere degradation due to cell division, telomerase winds the aging clock backward.

Why are germ cells immortal but somatic cells doomed to die? Sex and the Origins of Death, a book by cell biologist William Clark, offers an answer. Clark notes that, unlike eukaryotes, prokaryotes enjoy a fountain of youth. Prokaryotes, which originated 4 billion years ago, reproduce asexually by cell division yet never age. But about 2 billion years ago, sometime during the development of eukaryotes from prokaryotes, cells began experimenting with sexual reproduction. In biology, the purpose of sex is to make a new combination of DNA, hopefully creating an organism better suited to its environment. According to Clark, after sex, biology considers the participants' somatic DNA outdated, and this led to mechanisms of its destruction. Thus, early sexually-reproducing eukaryotes began segregating their DNA into one part for cell regulation and another for reproduction. Aging arose as a way to destroy old regulatory DNA and make room for its replacement in the next generation.

This experimental stage is reflected in the paramecium, a single-celled eukaryote living in freshwater ponds. Paramecia can reproduce two ways: by simple cell division, creating offspring genetically identical to themselves, and by conjugation, DNA exchange between two paramecia followed by division. A single paramecium placed in a glass dish with unlimited nutrients and space will divide freely; but with each generation, the rate of division slows, and after about two hundred divisions, all offspring start to die. Only those offspring that manage to conjugate are saved. Conjugation resets the aging clock of the participating cells, moving them two hundred more divisions away from death.

Unlike earlier eukaryotes with a single nucleus, paramecia have two: a micronucleus and a macronucleus. The micronucleus houses a complete diploid chromosome set (containing two copies of each chromosome--one from each of the parents) and is active only in reproduction. The macronucleus is much larger and contains DNA ordering the daily workings of the cell. Often its chromosomes and fragments of chromosomes are replicated hundreds of times.

When a paramecium divides without conjugation, the micronucleus doubles its contents, then divides into two identical micronuclei. The macronucleus does not replicate before division--it simply halves what it has. This may be an origin of aging in paramecia; with each generation, the macronucleus shrinks, and the effect of any mutated genes grows in proportion. At a certain point, the macronucleus becomes too small and scrambled to function, and the cell triggers apoptosis.

During conjugation, however, the micronuclei undergo a form of meiosis, creating two haploid micronuclei (see C in diagram). (Meiosis is a type of cell division, and its haploid products contain only one copy of each chromosome.) The conjugating cells swap one of these, so each partner ends up with one original and one new micronucleus (F). These micronuclei fuse and direct the production of a new macronucleus, while the old macronucleus disintegrates (H and I). The new macronucleus is rejuvenated both in size and in the possible compensation for bad genes by new genes from conjugation.

Clark writes, "...it is in the programmed death of the macronuclei of early eukaryotes like paramecia that our own corporeal deaths are foreshadowed." In multicellular organisms, the micronuclei and macronuclei have counterparts in our germ and somatic cells, respectively. The old drama plays out: germ cells remain immortal, while somatic cells age and die. The difference is that while conjugation resets the aging clock in the original paramecium, sex in multicellular organisms offers youth only to the next generation.

In Clark's view, biology considers our germ cells our true selves. "The only purpose of somatic cells, from nature's point of view, is to optimize the survival and function of the true guardians of the DNA, the germ cells," he writes. Gametes beget gametes, and the fundamental biological beneficiary is DNA. With each generation, that DNA should encode creatures more and more adapted to their environment. It becomes quite a hallowed molecule: DNA, the essence that transcends generations, whose integrity and transmission nature has exquisitely ensured.

There is a resonance here with a Navajo explanation of death. It is said that Coyote says, "If we all live and continue to increase as we have done in the past, the earth will be to small to hold us, and there will be no room for the cornfields. It is better that each of us should live but a limited time on this earth, then leave and make room for the children."

A counterpoint

Though he nods to its literary value, Emory evolutionary ecologist Chris Beck calls the Navajo view a bad evolutionary argument. "There may be some advantage to leaving room for the children," he chuckles, "but from an evolutionary perspective, if Dr. Orloff had kids, I wouldn't care about them because they don't share any of my genes." The Navajo view resembles the group selection argument in evolution, where individuals who act for the good of the group are more likely to survive and pass on their genes. But evolutionary biology suggests that selection acts at the level of the individual. If the group agreed to die off to leave room for its offspring, this would be open to cheating; those that did not die would pass on their longevity genes. "From an evolutionary point of view, an individual would want to live and reproduce forever," Beck says.

Evolutionary biology offers two competing explanations for aging: the mutation accumulation hypothesis and the antagonistic pleiotropy hypothesis. In the first, the accumulation of harmful genetic mutations over a lifespan promotes the breakdown of biological systems. In the second, genes increasing reproduction early on produce harmful, late-acting effects. Both explanations rely on the idea that the strength of natural selection decreases with age, since late-acting traits interfere less with reproductive success than early ones. Investigations of these hypotheses have compared early fitness with late fitness in fruit flies, since a trade-off would support antagonistic pleiotropy. According to Beck, current evidence is evenly split between the two hypotheses.

Extrinsic factors such as predation also factor into lifespan. Creatures with few predators tend to live longer than those with many. Rodents, whose small size renders them vulnerable to predators, have shorter life spans, while birds, protected by flight, have longer ones. Likewise, a study on Georgia possums found that those living on islands had longer lifespans than those on the mainland, where they faced greater predation. "If you're not going to die from predation, there's going to be a reproductive advantage to survive longer," Beck says.

References

1. Beck, Chris W. Interview. 20 November 2002.

2. Clark, William R. Sex and the Origins of Death. New York: Oxford University Press, 1996.

3. Iserson, Kenneth V. Death To Dust: What Happens To Dead Bodies? 2nd ed. Tucson: Galen Press, 2001.

4. Logsdon, John M. Interview. 5 November 2002.

5. Orloff, Gregg M. Interview. 11 November 2002.


	The Birth of Death by Andrew Procter Why do we die? If biology sees life as a system of chemical reactions, then death is the destruction of this system, the breakage of metabolic pathways. As multicellular creatures, we humans face death at high levels of organization such as heart failure or brain trauma. Still, like any other creature, we die when our cells die. Often we think of death as accidental; in biology, this form of death is called necrosis. For example, toxins released by disease-causing bacteria may disrupt metabolism in cells, causing their destruction. But a far more interesting death is scripted in advance. Research into apoptosis, or programmed cell death, has received much recent attention. Apoptosis is widespread in nature. Common examples include the death of leaves in the autumn, the death of a tadpole's tail, and the death of cells in the developing human hand, causing separation of the fingers. Apoptosis is much cleaner than necrosis, which usually afflicts a cell starved of nutrients and oxygen. During necrosis, the nucleus continues to direct cellular machinery, which strains from lack of energy. Molecular pumps maintaining the cell membrane gradient (an ion concentration difference between the exterior and interior of the cell) shut down, and the membrane bursts, spilling the cell's contents into the surroundings. No such violence occurs in apoptosis. First the DNA in the nucleus fragments, making the process irreversible. The cell pulls away from neighboring cells, and its cell membrane pinches off and isolates organelles. "It looks like popcorn," says Emory biologist Gregg Orloff. Neighboring cells digest these apoptotic bodies, recycling their molecules for their own purposes. Scientists have linked apoptosis to death by old age. Like apoptosis, aging appears to be programmed. Barring disease, most human somatic (body) cells have been found to divide about fifty times before they die; Leonard Hayflick investigated this "Hayflick limit" in the 1970s and 1980s. More recent research has linked cellular aging to the degradation of DNA over time. In the evolution of eukaryotes from prokaryotes, circular prokaryotic DNA became linear, and to keep the ends of the DNA from sticking together, molecular caps called telomeres developed. (Eukaryotes, a class of organisms which includes humans, contain more complex cells than the ancient prokaryotes, which include bacteria.) Telomeres, however, do not replicate along with DNA before cell division, and so degrade with each division. It has been found that in somatic cells, telomeres actually shorten with each division up to the Hayflick limit; this has become a theoretical measure of aging. At a certain point, the telomeres become so ineffective that the DNA sticks together in a useless jumble, and the cell can no longer reproduce. At this cue, the mechanism of apoptosis swings into action, and the cell self-destructs. The trigger is always there, waiting. "What's going on in your cells at all times is a see-saw battle between life and death," says Orloff. In germ cells (gametes and stem cells) the story is different. Gametes are sex cells--sperm and egg--and stem cells are the undifferentiated precursors of many types of cells. Both cell lines bear large quantities of the enzyme telomerase, which repairs telomeres. For every telomere degradation due to cell division, telomerase winds the aging clock backward. Why are germ cells immortal but somatic cells doomed to die? Sex and the Origins of Death, a book by cell biologist William Clark, offers an answer. Clark notes that, unlike eukaryotes, prokaryotes enjoy a fountain of youth. Prokaryotes, which originated 4 billion years ago, reproduce asexually by cell division yet never age. But about 2 billion years ago, sometime during the development of eukaryotes from prokaryotes, cells began experimenting with sexual reproduction. In biology, the purpose of sex is to make a new combination of DNA, hopefully creating an organism better suited to its environment. According to Clark, after sex, biology considers the participants' somatic DNA outdated, and this led to mechanisms of its destruction. Thus, early sexually-reproducing eukaryotes began segregating their DNA into one part for cell regulation and another for reproduction. Aging arose as a way to destroy old regulatory DNA and make room for its replacement in the next generation. This experimental stage is reflected in the paramecium, a single-celled eukaryote living in freshwater ponds. Paramecia can reproduce two ways: by simple cell division, creating offspring genetically identical to themselves, and by conjugation, DNA exchange between two paramecia followed by division. A single paramecium placed in a glass dish with unlimited nutrients and space will divide freely; but with each generation, the rate of division slows, and after about two hundred divisions, all offspring start to die. Only those offspring that manage to conjugate are saved. Conjugation resets the aging clock of the participating cells, moving them two hundred more divisions away from death. Unlike earlier eukaryotes with a single nucleus, paramecia have two: a micronucleus and a macronucleus. The micronucleus houses a complete diploid chromosome set (containing two copies of each chromosome--one from each of the parents) and is active only in reproduction. The macronucleus is much larger and contains DNA ordering the daily workings of the cell. Often its chromosomes and fragments of chromosomes are replicated hundreds of times. When a paramecium divides without conjugation, the micronucleus doubles its contents, then divides into two identical micronuclei. The macronucleus does not replicate before division--it simply halves what it has. This may be an origin of aging in paramecia; with each generation, the macronucleus shrinks, and the effect of any mutated genes grows in proportion. At a certain point, the macronucleus becomes too small and scrambled to function, and the cell triggers apoptosis. During conjugation, however, the micronuclei undergo a form of meiosis, creating two haploid micronuclei (see C in diagram). (Meiosis is a type of cell division, and its haploid products contain only one copy of each chromosome.) The conjugating cells swap one of these, so each partner ends up with one original and one new micronucleus (F). These micronuclei fuse and direct the production of a new macronucleus, while the old macronucleus disintegrates (H and I). The new macronucleus is rejuvenated both in size and in the possible compensation for bad genes by new genes from conjugation. Clark writes, "...it is in the programmed death of the macronuclei of early eukaryotes like paramecia that our own corporeal deaths are foreshadowed." In multicellular organisms, the micronuclei and macronuclei have counterparts in our germ and somatic cells, respectively. The old drama plays out: germ cells remain immortal, while somatic cells age and die. The difference is that while conjugation resets the aging clock in the original paramecium, sex in multicellular organisms offers youth only to the next generation. In Clark's view, biology considers our germ cells our true selves. "The only purpose of somatic cells, from nature's point of view, is to optimize the survival and function of the true guardians of the DNA, the germ cells," he writes. Gametes beget gametes, and the fundamental biological beneficiary is DNA. With each generation, that DNA should encode creatures more and more adapted to their environment. It becomes quite a hallowed molecule: DNA, the essence that transcends generations, whose integrity and transmission nature has exquisitely ensured. There is a resonance here with a Navajo explanation of death. It is said that Coyote says, "If we all live and continue to increase as we have done in the past, the earth will be to small to hold us, and there will be no room for the cornfields. It is better that each of us should live but a limited time on this earth, then leave and make room for the children." A counterpoint Though he nods to its literary value, Emory evolutionary ecologist Chris Beck calls the Navajo view a bad evolutionary argument. "There may be some advantage to leaving room for the children," he chuckles, "but from an evolutionary perspective, if Dr. Orloff had kids, I wouldn't care about them because they don't share any of my genes." The Navajo view resembles the group selection argument in evolution, where individuals who act for the good of the group are more likely to survive and pass on their genes. But evolutionary biology suggests that selection acts at the level of the individual. If the group agreed to die off to leave room for its offspring, this would be open to cheating; those that did not die would pass on their longevity genes. "From an evolutionary point of view, an individual would want to live and reproduce forever," Beck says. Evolutionary biology offers two competing explanations for aging: the mutation accumulation hypothesis and the antagonistic pleiotropy hypothesis. In the first, the accumulation of harmful genetic mutations over a lifespan promotes the breakdown of biological systems. In the second, genes increasing reproduction early on produce harmful, late-acting effects. Both explanations rely on the idea that the strength of natural selection decreases with age, since late-acting traits interfere less with reproductive success than early ones. Investigations of these hypotheses have compared early fitness with late fitness in fruit flies, since a trade-off would support antagonistic pleiotropy. According to Beck, current evidence is evenly split between the two hypotheses. Extrinsic factors such as predation also factor into lifespan. Creatures with few predators tend to live longer than those with many. Rodents, whose small size renders them vulnerable to predators, have shorter life spans, while birds, protected by flight, have longer ones. Likewise, a study on Georgia possums found that those living on islands had longer lifespans than those on the mainland, where they faced greater predation. "If you're not going to die from predation, there's going to be a reproductive advantage to survive longer," Beck says. References 1. Beck, Chris W. Interview. 20 November 2002. 2. Clark, William R. Sex and the Origins of Death. New York: Oxford University Press, 1996. 3. Iserson, Kenneth V. Death To Dust: What Happens To Dead Bodies? 2nd ed. Tucson: Galen Press, 2001. 4. Logsdon, John M. Interview. 5 November 2002. 5. Orloff, Gregg M. Interview. 11 November 2002.