13 Things That Don't Make Sense (16 page)

9

DEATH

Evolution’s problem with self-destruction

I
n the summer of 1965, a young researcher from the University of Georgia caught a turtle in a Michigan marsh. It was a mature
male Blanding’s turtle, at least twenty-five years old. After noting its characteristics, he put it back. Thirty-three years
later, in 1998, J. Whitfield Gibbons caught that turtle again. It was doing just fine.

Blanding’s turtles are a biological enigma. The oldest known specimen was clocked at seventy-seven years old in the 1980s—a
female that was still laying eggs. It’s likely that, if she hasn’t had her spine snapped by a passing truck, she is still
reproducing now. Blanding’s turtles don’t get old and decrepit; they don’t show any increased susceptibility to disease through
their lifetimes. If anything, they get more vigorous with age; on average, the females lay more eggs every year.

Senescence
, the deterioration with time that leads ultimately to death, is meant to be universal in the animal kingdom. According to
the standard theory, everything gets old, falls apart, and dies. It’s a good theory, but, in the light of the evidence, it
doesn’t add up—and it fails to add up in a very tantalizing way. The turtles are vertebrates and thus closely related to us
in evolutionary terms. If our molecular machinery breaks down over time, so should theirs. But it doesn’t. According to Caleb
Finch, a professor of gerontology at the University of Southern California, the turtles are certainly “a sharp challenge”
to the idea that our senescence is inevitable.

The turtles are not alone. Among the vertebrates there are several species of fish, amphibians, and reptiles that don’t senesce.
Finding out why they don’t—and why we do—will have obvious immediate benefits. But it is a much more complicated story than
anyone could have imagined. It’s not really the Blanding’s turtles that don’t make sense. It’s death itself that is the next
anomaly.

WHY
do living things die? Obviously, things kill each other—that’s part of the natural order. But what causes “natural” death?
It is a question that splits biologists. It has become like a game of Ping-Pong; over the years, theories have been batted
back and forth as new evidence comes to light. Then, occasionally, someone steps in and ruins the game by pointing out that
none of the theories fit all of the available evidence; we still have no winner.

One answer is that death is simply necessary—to avoid overcrowding, for instance. If nothing ages and dies, the biosphere
is just going to start bursting at the seams. Even if each subsequent generation is stronger and fitter, survival will become
ever harder as more and more organisms compete for the limited food resources. The best solution, then, is for the individual
to sacrifice itself for the sake of the species. A simple piece of genetic programming that brings forth the next generation,
then instigates self-destruction—or at least stops the repair process, allowing degradation to take its toll—is surely a sensible
option, isn’t it?

The nineteenth-century German biologist August Weismann thought so. He suggested that the body’s resources can be categorized
as either
germ
or
soma
. The germ carries the hereditary information, and its integrity must be maintained at whatever cost. Soma, which carries
out the rest of the body’s functioning, was “disposable”; once reproduction had occurred, the body would be wasting its resources
if it put too much effort into repairing the havoc that time inevitably wreaked on the organism.

It sounds attractive, but it’s a no-go. Evolution is supposed to select genes to benefit individuals and their offspring,
not to benefit the group or species as a whole. If group selection works, evolution doesn’t. In a famous rebuttal to group
selection, the Oxford evolutionist Richard Dawkins dismissed it as “sheer, wanton, head-in-bag perversity.”

In 1952 the British biologist Peter Medawar got around the problem. With great insight, he proposed a mechanism that would
give a genetic selection for senescence. The power of natural selection is reduced as a creature gets older, Medawar pointed
out, so a trait that gives an advantage before the creature has reached maturity (and entered into reproduction) will be selected
for; a trait whose advantage only shows after the creature has ended its reproductive life will not. The converse is also
true. A gene that disables you before you reach maturity will be (negatively) selected for; it will lower the chances of the
organism passing on its genes. A gene that disables the organism much later in life will be, if not exactly selected for,
at least able to survive into the next generation. And here, Medawar said, is the source of senescence. It’s not about the
inevitable ravages of time; it’s the fact that late-blooming problematic mutations—genes for cellular machinery that breaks
down late in life, for example—will be passed on, and will thus accumulate in a creature’s genome. In humans, Huntington’s
and Alzheimer’s disease provide examples of this process.

In 1957 George Williams expanded on Medawar’s theme, introducing the idea of
antagonistic pleiotropy.
Pleiotropy occurs when a single gene influences more than one trait in an organism. Antagonistic pleiotropy occurs when that
influence is advantageous on one trait while problematic on another. Medawar’s effect could be achieved by a single gene that
confers advantage—particularly reproductive advantage—when young but creates harm in the later stages of life. This quickly
became the bedrock of the theory of aging.

Then, in 1977, Tom Kirkwood turned up to play. Kirkwood, a British mathematician, was unaware of Weismann’s disposable soma
idea when he lay in the bath contemplating the issue of aging (perhaps not an image one wants to dwell on). His idea, like
Weismann’s, was that aging was due to failures to repair somatic cells in the body. Kirkwood’s insight was that those failures
came from evolved traits that favored investment in reproduction. This would manifest in the work—or lack of it—done by cellular
machinery such as DNA repair genes and antioxidant enzymes on the somatic cells.

Kirkwood recalls his idea as being “highly controversial.” That’s because the prevailing view of the time, thanks to Medawar
and Williams, was that aging is programmed. Over the years, though, evidence mounted up supporting Kirkwood’s idea that aging
is due to a slow, steady buildup of defects in our cells and organs. Gradually, programmed death fell out of favor. So much
so, in fact, that when Thomas Johnson and David Friedman joined the Ping-Pong game by announcing they had found evidence of
a genetic program for aging in 1988, some of their colleagues accused them of making up the whole ridiculous idea.

The pair were working at the University of California, Irvine, at the time. Their paper, published in the journal
Genetics
, showed that changing a single gene could make nematode worms live up to 65 percent longer than normal. Johnson and Friedman’s
paper went headfirst against the then-received wisdom that aging is the result of accumulated mutations in the genome. Apart
from the snipes from colleagues, though, almost everyone ignored them. Until, that is, Cynthia Kenyon burst onto the scene
and confirmed everything Johnson and Friedman had been saying.

Kenyon has close to celebrity status as a scientist. She is a molecular biologist at the University of California, San Francisco,
and a founder and director of Elixir Pharmaceuticals, a company focused on “extending the quality and length of human life.”
Perhaps her most reported move was to put herself on a restricted diet as a result of her research: she stopped eating carbs
like potatoes and pasta on the very day she discovered that the worms she was studying lived longer when there was no sugar
added to their food.

Kenyon’s initial breakthrough was not about
caloric restriction
, though. She had found another gene that increased a nematode worm’s life span—and this time by 100 percent. The December
2, 1993, issue of
Nature
reported that
Caenorhabditis elegans
worms, which normally lived for two to three weeks, were living for up to six weeks. Worms that lived twice as long as they
should seemed to tip the balance, and people started to discuss the possibility of a genetic switch for aging—and whether
we could turn it off.

Since Kenyon’s breakthrough, researchers have determined some of what makes the difference. The genetic tweak in the worms
causes a cascade of molecular signals to go wrong. Those signals are similar to signals that the hormone insulin triggers
in humans. Humans are hard to experiment on, though; it was when researchers discovered the signals are also similar to a
hormone-driven cascade of signals in fruit flies that everything took off. Fruit flies have such a fast life cycle that they
had already been co-opted as the workhorse of genetics research worldwide. The aging research worked too, and we can now use
a genetic switch to lengthen fruit flies’ lives. The same trick also works with bigger animals. We have a whole string of
gene switches that we can flick to produce long-lived mammals—Methuselah mice, for example.

We still haven’t got to extending human life spans, though, and for good reason. Our understanding of the processes of aging
is still rudimentary, and no one is sure exactly what the trade-offs between longevity and ill health might be. Nevertheless,
when you see what we
can
do for mice, it makes you wonder what we could do for humans. It’s enough to give you, as the University of Michigan biologist
Richard Miller puts it, “organism envy.” No wonder many genetics researchers—Kenyon first among them—are now busy setting
up companies whose aim is to find the elixir of life.

While those start-ups started up, however, a controversy was developing—and it is one that goes to the heart of the puzzle
about aging and, ultimately, death.

In 2002 a large number of senescence researchers put their heads together and issued a “position statement.” The group was
headed up by Leonard Hayflick, one of the grand old men of gerontology, and the statement was signed by fifty-one scientists.
Intended for public consumption, it warned against claims that misrepresented the science of aging and “victimized” those
seduced by promises of eternal youth. “No genetic instructions are required to age animals,” it said. “Survival beyond the
reproductive years and, in some cases raising progeny to independence, is not favored by evolution … The processes of
aging are not genetically programmed.” In 2004, in the
Journal of Gerontology
, Hayflick opened an article with a blunt statement: “No intervention will slow, stop, or reverse the aging process in humans.”

It contradicted everything the worm, fruit fly, and Methuselah mouse researchers were saying. How could Hayflick think, in
the light of the published evidence, that you couldn’t switch off aging? The answer lies in Hayflick’s most celebrated discovery:
replicative senescence.

IN
October 1951 the research biologist George Gey went on national television in the United States and announced that a new era
of medical research had just begun. He and his wife, Margaret, worked at Johns Hopkins University, where George was head of
tissue culture research. The pair had spent the previous two decades searching for a human cell that would live forever in
laboratory conditions; it would be the perfect tool with which to find a cure for cancer. When a thirty-one-year-old woman
called Henrietta Lacks contracted cervical cancer and had a biopsy taken, the Geys found what they were looking for. George
Gey faced the cameras and held up a vial containing cells cultured from Henrietta Lacks’s cancer—the most robust and fastest-growing
cells scientists had ever seen. “It is possible that, from a fundamental study such as this,” he said, “we will be able to
learn a way by which cancer can be completely wiped out.”

Henrietta Lacks died from the cancer on the day that Gey went on TV. But, suddenly, cancer seemed like a prizefighter on the
ropes, and huge resources were channeled into finishing off the fight. Lacks’s legacy, the
HeLa
line of cells cultured from her cancer, have become another workhorse of biology. Her cells were instrumental in the development
of the polio vaccine, they have been placed at atomic bomb test sites, and have even flown on the space shuttle. They continue
to be used in biology labs worldwide, and their greatest achievement may be yet to come. In the fifty or so years that have
passed since Henrietta Lacks’s death, researchers have discovered many connections between cellular immortality, senescence,
and the formation of tumors. What is perhaps the most important discovery came from the laboratory of Leonard Hayflick.

In the early 1960s Hayflick had been working toward understanding the mechanisms of cancer when he stumbled across the fact
that normal cells could not be recultivated more than fifty or so times; in culture the populations would double for ten months,
then suddenly die. Surprised but intrigued, Hayflick and his collaborator Paul Moorhead successfully repeated the process,
then sent some samples to skeptical colleagues and told them when the populations would die. “Our predictions were met with
disbelief, but when the telephone rang with the good news that the cultures had died when expected, we decided to publish,”
Hayflick later recalled.

The phenomenon Hayflick observed is known as
replicative senescence
. The truly intriguing thing about the process is that it has survived more than a billion years of evolution; it works in
yeast in exactly the same way as it does in some human cells. Remove some of your fibroblast cells, for example, which are
involved in creating the scaffolds on which new tissues grow, and you can culture them in a Petri dish. Then, suddenly, they
just stop dividing and die.

Why should this be? It seems to be associated with damage to the DNA packed into the chromosomes of the cell nucleus. The
counting mechanism, the ticking clock for senescence in our cells, is the
telomere
, a string of repetitive DNA sequences that cap the end of every chromosome. Telomeres stop the chromosomes from sticking
together, but when the cell divides, the telomeres are not fully reproduced and become shorter on each division. Eventually,
cells with enough depleted telomeres die. No one knows for sure how this mechanism progresses, but it has become central to
the fight against cancer.