Regenesis (15 page)

As a physical specimen, the naked mole rat is the stuff of nightmares. With its saggy pink skin, piglike nose, spindly legs, tiny, almost vestigial eyes, and mere holes for ears, it looks like the ultimate misbegotten animal.

This highly unusual specimen isn't even a rat, strictly speaking, nor is it a mole. It belongs to a genus (
Heterocephalus
) that has no other known members. It lives up to its name in being “naked,” for it is almost hairless. The mole rat spends virtually its entire life underground in total darkness, in a complex maze of subterranean channels and tunnels whose cumulative length can add up to two miles or more. This is remarkable because these are small animals, generally about the length of a human finger, and
weigh little more than a mouse. Native to the hot grassland regions of Kenya, Ethiopia, and Somalia, the mole rat does not drink water (or anything else!). It can run backward and forward equally fast. Because its skin lacks a key neurotransmitter that in mammals is responsible for transmitting pain signals, the naked mole rat can feel no skin pain.

As if it's not already distinctive enough, the mole rat has a social structure that is almost unique among mammals. The species is “eusocial,” meaning that its colonies are organized like those of ants or bees, with the members existing in strict hierarchical castes. At the top is a queen who breeds with only a few select males. Next down are the soldiers, who defend the colony against predatory snakes or foreign invader rats. At the bottom of the social scale are the workers, who forage for food, mainly roots and tubers.

But however odd their appearance and behavior—one observer has called them “fauna incognita”—naked mole rats possesses two additional characteristics that make them of special interest to biologists. The first is that they are the world's longest-lived rodent. Whereas the house mouse, for example, has an average life span of two or three years, the naked mole rat can live for twenty-five years or more (the current record is 28.3 years). The second is that they are extremely resistant to cancer. Indeed, cancer has never been detected among these animals.

These two facts illustrate the importance of the new science of comparative genomics. Genomics in general relies on our ability to read, or sequence, the DNA of a given organism. One goal of sequencing the human genome is to identify genes that play a role in disease (see
Chapter 9
). But reading genomes has another and equally important objective, which is to find useful biological widgets in other organisms—special-purpose apps, as it were. Comparative genomics, the study of how similar genes function across different species, will allow us to locate genetic structures that confer distinct advantages on certain classes of organisms. The long life span of the naked mole rat is one example. Its longevity is a trait that must be rooted somewhere in its genetic makeup. If we can find the gene—or more likely the combination of genes—that gives such great
longevity to the animal, this will be a genomic component that we can exploit to our benefit, and perhaps even import to the human genome.

In humans, old age is a factor in ailments such as heart disease, type 2 diabetes, cancer, and neurodegenerative diseases including Parkinson's and Alzheimer's. But nobody knows why some organisms have fleeting life spans while others live for a century or more. There is at least a forty-fold variation in maximum longevity among mammals. The white-faced capuchin monkey has a life span of over fifty years. Humans can live for over one hundred years. And then there's the case of the bowhead whale: with an estimated life span of over two hundred years, the bowhead whale is the only mammal known to outlive human beings, and is possibly the longest-lived mammal on earth.

Still, it's a mystery why different species that share a similar body plan, biochemistry, and physiology nevertheless age at such different rates. Comparative genomics may help us solve the riddle. Sequencing the genomes of these long-lived mammalian species may reveal a set of homologous (similar or shared) genes responsible for their extended life spans. Discovering these genetic structures would provide us with insights into the mechanisms of aging and of age-related human diseases, and this in turn will lead to better diagnoses and treatments.

In 2007 a group of researchers, including myself and my colleague Joao Pedro Magalhaes at the University of Liverpool, supported by seventy-nine scientists from other institutions, formally proposed sequencing the genomes of the naked mole rat, the capuchin monkey, and the bowhead whale to the National Human Genome Research Institute (
NHGRI
). This initial proposal was rejected, essentially on the grounds that it is a long way from knowing the respective sequences to understanding exactly how the genetic structures in question function to lengthen life span. This may be true, but knowing the sequences would nevertheless be a genuine first step toward making progress in solving the problem.

A year later, the same group, supported by the same seventy-nine scientists, submitted a second proposal, this time to sequence the genome of the naked mole rat alone. Not only does the mole rat have exceptional longevity, but it also seems to be immune to cancer. But this proposal too was
rejected, on the grounds that identifying the precise complex of genetic structures that underpin the longevity of the animal would be difficult.

Subsequently we started the sequencing ourselves, on a shoestring budget, and cadging spare sequencing capacity from friends. The first data for the naked mole rat genome and RNA started flowing in the spring of 2011. By summer Magalhaes and his team at Liverpool had made the first draft sequence and put it online. As of this writing we are still in the midst of interpreting the sequence (the hard part), as well as planning follow-up experiments.

The list of genes that scientists have discovered grows by the day: there are genes for cystic fibrosis, skin cancer, lung cancer, and on and on. Other genes control height, weight, and a host of other traits. Comparative genomics has been a huge help in finding those structures, and genome engineering will make it possible to incorporate them, gradually or swiftly, into the human genome.

Undoubtedly, some people will object to modifying the human genome in this way on a variety of grounds: moral, philosophical, political, religious, aesthetic—and let's not forget just plain emotional grounds (or even no grounds whatsoever). Objections to new technologies (see the technology prohibition plot in the Epilogue) typically peak as the technology is poised to spread among early adopters but doesn't yet work well. Then, once the technical bugs are ironed out, the moral high ground can invert. For example, in vitro fertilization was considered unnatural and risky at first, but eventually withholding access to the procedure from infertile couples became unacceptable. Vaccines have had numerous periods of bad press since Pasteur's rabies tests, and even Edward Jenner's first trials of smallpox vaccination were ridiculed by some British cartoonists. But whenever an outbreak occurs, especially after a public campaign that reduces local vaccinations, the popularity of vaccines mysteriously increases. Sometimes people invoke the precautionary principle of “do no harm,” but in some cases doing nothing is harmful in and of itself.

So, with respect to human longevity, how many of us really want the status quo prolonged? Or how about the longevity of our pets? Dog owners and cat lovers typically outlive several successive pets, experiencing wrenching
partings with their animals every time one of them dies a natural death or is euthanized. Wouldn't it be better if your pet could be made to live as long as you (or at least double its normal life span), all the while remaining in good health?

And then there's this question: Is anyone actually in favor of aging? Some worry that a widespread increase in human life span could cause overpopulation. But “overpopulation” is a relative concept, and by some people's reckoning the world is already overpopulated and indeed it was overpopulated decades ago (see
Chapter 9
). As our human population is dramatically shifting to cities, the average family size is falling to below the replacement level of 2.1 children per couple. Further, it is a well-established trend that as people become wealthier, they have fewer children. Finally, as we have seen, there is also the option of getting some of the population off the planet.

The ideas surrounding eugenics and Lysenkoism are nearly synonymous with bad science—worse than merely mediocre science because of their huge and adverse political and economic consequences. Here we will reexamine these ideas from a radical new perspective to see if, against all expectation, some value can come from these most unlikely quarters.

Trofim Lysenko was a Soviet biologist who accepted the Lamarckian theory of the inheritance of acquired characteristics, which opposed the Mendelian theory's view that inherited characteristics are inborn and not affected by the environment. In 1940 Lysenko became the director of the Soviet Institute of Genetics, and, with Stalin's backing, applied his version of Lamarck's 1822 theory to agriculture. Lysenko's one big idea was vernalization—pretreating seeds with cold and moisture so that they would sprout and grow earlier in the spring than untreated seeds. He further held that vernalized seeds would give rise to plants whose seeds were also vernalized because they had acquired that characteristic through inheritance. (Which they did not in fact do.)

Although this practice did not bode well for Soviet agricultural production, Lysenko's ideas, collectively termed Lysenkoism, nonetheless became
the official agricultural dogma of the USSR. Those who opposed it were persecuted, imprisoned, and sometimes even killed.

In the 1960s, Andrei Sakharov and other Soviet physicists finally precipitated the fall of Lysenkoism, blaming it for the “shameful backwardness of Soviet biology and of genetics in particular . . . and for the defamation, firing, arrest, even death, of many genuine scientists.”

At the opposite (yet equally discredited) end of the genetic theory spectrum was the Galtonian eugenic movement, which from 1883 onward grew in popularity in many countries (including the United States, the United Kingdom, and Germany). In its extreme form, eugenics propounded the forced sterilization of various “undesirables,” and this was perpetuated despite the 1948 Universal Declaration of Human Rights, which proclaimed that “men and women of full age, without any limitation due to race, nationality or religion, have the right to marry and to found a family.” In fact, forced sterilization persisted into the 1970s in Sweden and Canada.

The conventional wisdom regarding these two pseudoscientific movements is that Lysenkoism overestimated the impact of environmental influences while eugenics overestimated the role of genetics. But an interesting and radical alternative interpretation is that both theories
underestimated
and in fact hobbled both of these powerful forces: they tried to apply genetics on a grand economic and human scale without being able to directly recode the genome.

One form of scientific blindness occurs, as above, when a theory displays exceptional political, faith-based, or intuitive appeal. But another source of blindness arises when we rebound from catastrophic failures of pseudoscience (or science). For example, Lysenko's spectacular failure in his attempts to apply a Lamarckian view of evolution can blind us to the ways in which we do in fact inherit acquired characteristics, for example, through epigenetics. The grandchildren of those who survived the 1944 Dutch hunger winter had smaller than average birth weights.

Our children already inherit our computers and cars as surely as they inherit our brains and brawn. Indeed, we have inherited acquisitions ever since we developed tools and domesticated animals. But now this form of inheritance has become increasingly dominant (over genetic inheritance)
and rapidly exponential. Even genetic inheritance could become genuinely Lamarckian if we became as confident and adept in applying our synthetic biotechnologies as we have been in the application of our inorganic technologies. We have always applied genetics in a weak sense, and in general unwittingly, at the individual family level, by marrying whomever we want, and for the genetically based characteristics we see embodied in those we choose.

Many have speculated that human evolution has stopped. But we are well into an unprecedented new phase of evolution in which we must generalize beyond our DNA-centric worldview. Evolution can accelerate from geologic speed to Internet speed—still employing the processes of random mutation and selection, but also by the use of nonrandom, intelligently designed genomes, and by use of lab selections, which makes the process even faster. We are losing species—not just by extinction but by merger. The species barriers separating humans, bacteria, and plants were breached occasionally over vast evolutionary time frames through horizontal gene transfer. But today those high barriers have vanished. Genes for bacterial insecticides and for herbicide resistance are permanently integrated into current crop genomes. Even the barrier between humans and machines is porous—think of pacemakers, artificial hearts, hearing aids, and cochlear implants. Between humans and other animals we have xenotransplantation, the use of pig heart valves in human hearts, and so on.

One objective of eugenics was to improve the intelligence of the general population. But this is happening already, without the use of Galtonian-style eugenics measures. Consider the “Flynn effect,” the observation that standardized test scores for general intelligence aptitude have been increasing since 1932, when the first of these tests was introduced. Various explanations have been offered for this, including better nutrition, greater public exposure to testing, an overall increase of stimulation and information by means of television and the Web, the increased use of “shorthand abstractions” (scientific terms that have been exported to general usage, such as “placebo effect” and “random sample”), lowered infectious load, and the crossbreeding of formerly inbred populations (heterosis), among other things.