• Cloning can help eliminate disease in a population by cloning only the disease-free animals.
• Cloning versus saving the habitat is a false choice. You need to do both. Cloning provides a safety net.
• Cloning members of endangered species can help preserve and propagate species that reproduce poorly in captivity.
• Cloning can introduce new genes back into the gene pool of species that have few remaining members.
• Clones of healthy animals can be introduced into wild populations to give a “booster shot” to a species undergoing a loss of genetic diversity.
In addition, there are other practical reasons for regenerating lost species, and in particular for regenerating Neanderthal man. For one thing, the reintroduction of Neanderthals would give Homo sapiens a sibling species that would allow us to see ourselves in new ways. It might give us an inkling into another form of human intelligence, or of different ways of thinking. There might even be health benefits if Neanderthals proved to be resistant to diseases like AIDS or tuberculosis, for example, or diseases that coevolved with Homo sapiens like smallpox, polio, syphilis, or the next surprise pandemic.
Of course, there are also arguments against extinction reversal. An organism that has been extinct for 30,000 years is more likely to have little or no resistance to diseases that have evolved since then than to have a native resistance to them. Still, as we have seen, the human immune system offers little or no resistance to many of the diseases that our species has coevolved with, and a resurrected Neanderthal might be no worse off than we are in this respect. As a precautionary measure, newly regenerated species could be confined inside sterile environments until their disease resistance was evaluated and perhaps augmented through drugs, vaccines, or other modalities.
Another argument against reviving extinct species is that cloning is hard on the subjects, with any eventual successes being preceded by a long series of failed attempts: stillbirths, as well as misshapen, abnormal, and impaired offspring. Why bring these animals back only to have them suffer in this way?
There are at least two answers to this question. The first is that by the time regenerating these animals becomes economically feasible, cloning technology will have progressed to the point that successes will be far more common than failures. The second is that although nuclear transfer cloning may be hard on the animal, so is natural biological birth. In fact, approximately one in every thirty-three babies born in the United States each year suffers from one or more birth defects, which are the leading cause of infant mortality, accounting for more than 20 percent of all infant deaths annually. Birth is an inherently risky business.
More generally, anything can be done ineptly or expertly, carelessly or carefully, inhumanely or compassionately. This is equally true of attempts to bring back extinct species. There is no reason to think that extinction reversal will be carried out any less humanely than any other medical or experimental procedure. Indeed, the protocols already in place for the humane treatment of experimental subjects, whether human or nonhuman, can and ought to be extended to members of species that we might choose to bring back.
A final argument against extinction reversal is that to bring species back selectively, according to our own tastes and prejudices, will result in an anthropomorphized, “boutique” environment that reflects human values and judgments and which will result in an artificial construct rather than a natural phenomenon. However, we already live in such a world and have done so ever since the beginning of agriculture, if not long before. Everything from skyscrapers to golf courses, poodles to the Panama Canal, the Hoover Dam, Venice, and Las Vegas all attest to the fact that humans remake nature according to their wishes.*
Nor are we alone in this respect. Many other animal species also reconstruct the world according to their own wants and needs: birds build nests, beavers build dams, bees build hives, spiders spin webs and cocoons, and ants construct mounds, entire cities, and even ant cemeteries. A propensity for redesigning nature seems to be an inherent part of life itself.
All of that said, how do we bring back animals that have long since vanished from the scene?
That depends on the species and what there is left of it. For species whose intact cells, tissues, or other genetic materials have been preserved—as in the case of the bucardo, for example, or species well represented in frozen zoos, labs, or other storage facilities—revival will be possible through straightforward interspecies nuclear transfer cloning.
A second category consists of species whose genetic material might or might not be too corrupt for cloning. This is true of the woolly mammoth, for example. Although mammoth specimens buried in permafrost may look remarkably lifelike, their DNA is not in the same condition. The woolly mammoth, however, really falls into a class by itself.
Unlike the Neanderthals, whose remains consist exclusively of teeth, skulls, and other bones, Siberian mammoth carcasses have turned up with hair and even soft tissue on them. In August 1799 a Russian hunter looking for mammoth tusks came across an oddly shaped block of ice on the shoreline of the Laptev Sea in north-central Siberia. The summer sun had melted some of the ice, exposing two projections that later turned out to be tusks.
Two years later, the hunter returned to the area during the summertime and found that one side of the animal had been exposed to view, while the rest of the body was still frozen. It was not until 1806 that Michael Adams, of the Imperial Academy of Science at St. Petersburg, reached the site. By this point, nearby villagers had hacked off some of the flesh and fed it to their dogs. Bears, wolves, and foxes had eaten the rest, leaving only a skeleton. Now known as the Adams mammoth, the skeleton is on display in the St. Petersburg Zoological Museum.
More recently, the Jarkov mammoth was discovered in 1997 by a family of that name who came across a tusk protruding from the frozen ground of the Taymyr peninsula in northernmost Siberia. A group of latter-day mammoth hunters arrived at the scene and speculated that an intact mammoth carcass could be lodged in the ice—an entire mammoth! In October 1999, a helicopter lifted a twenty-three-ton ice block with tusks protruding bizarrely from it up and out of the frozen tundra, and hauled it to an ice cave. There, as recorded by a Discovery Channel film crew, scientists began defrosting the remains with hair dryers.
The Jarkov mammoth turned out to be mostly bones, but even so, a bit of soft tissue remained. It looked like a strip of beef jerky.
Coincidentally, a second defrosting mammoth (the Hook mammoth) happened to be located nearby, and some of the expedition’s researchers traveled to the site. One of them, Alexi Tikhonov, cut off a piece of what appeared to be mammoth muscle. Jokingly, he offered it to those present all of whom refused this morsel. And so, braced by a few shots of vodka, he took a bite himself. “It was awful,” he said. “It tasted like meat left too long in the freezer.” (Mammoth meat is so common in Siberia that fox trappers use it as bait.)
Any mammoth tissue that is fresh enough to eat might harbor intact DNA. Two Japanese scientists have plans for resurrecting the animals. One of them, Kazufumi Goto, proposes finding intact mammoth sperm cells that he will use to inseminate a female elephant to produce a mammoth-elephant hybrid.
Hybrids are usually sterile, but there are known exceptions; whether a mammoth hybrid would be sterile is currently unknown. Assuming it wasn’t sterile, then by injecting additional mammoth DNA into the resulting mammoth-elephant cross, you would get a second hybrid that was even more of a mammoth than an elephant. According to Goto, repetition of the process with successive new offspring would yield, within fifty years, an animal that was 88 percent mammoth. (Elephants have a twenty-two-month pregnancy and don’t produce offspring until they are ten.)
While this scenario is technically feasible, regenerating a woolly mammoth in this way is a speculative possibility at best because intact mammoth sperm cells have never been found—and might never be. The second Japanese researcher, Akira Iritani, is chairman of the Department of Genetic
Engineering at Kinki University, near Osaka. He plans to find a mammoth cell with intact chromosomes and then fuse them with an egg cell from an Asian elephant and let it divide to an early embryonic stage. Finally he plans to implant the embryo into the womb of an Asian elephant and hope for the best.*
Richard Stone, who wrote a book about resurrecting mammoths, calls this “the Mount Everest of biology experiments.” Everything hinges on locating a fresh supply of exceptionally well preserved frozen mammoth tissue, which scientists would then defrost under carefully controlled laboratory conditions. This combination of circumstances has not occurred to date, despite the fact that mammoth hunters have conducted several field searches. Russian mammoth expert Sergey Zimov takes a dim view of these searches. “Frozen mammoths find you, not the opposite,” he says. “Directed searches have almost no chance of success.”
A third class of extinct species is represented by DNA samples that are so fragmented and corrupt that their genomes must be laboriously reconstructed from innumerable isolated pieces. This is true of Neanderthal man, whose draft genome Svante Pääbo reconstructed in that manner. Unfortunately, the draft genome doesn’t exist physically as actual chromosomes or genes, but only as strings of DNA sequences stored in computers.
Theoretically it is possible to convert those sequences into a physical, real-life genome by synthesizing short sequences (oligos) in DNA synthesis machines and then stitching them together into chromosomes. In 2010 Craig Venter created his so-called synthetic Mycoplasma bacterium by chemically synthesizing its entire genome, oligo by oligo. However, there is a huge difference between synthesizing a bacterial genome and synthesizing the genome of an animal as large and complex as Neanderthal man. While Venter’s Mycoplasma genome was 1.08 million base pairs in length, the Neanderthal’s genome consists of 3 billion base pairs, as long as that of a modern human. Synthesizing such an object oligo by oligo would take forever—or at least a very long time.
Fortunately, there’s another way to accomplish the same objective: start with a physical genome that closely resembles the Neanderthal’s and then change it, piecemeal, into the genome of a Neanderthal. Reverse-engineer it into existence.
What genome closely resembles the Neanderthal’s? The modern human genome. In fact, the genomic difference between a modern human and a Neanderthal is about threefold more than between one modern human and another—about 10 million base pairs. Indeed some Melanesian genomes consist of up to 8 percent more closely related to Neanderthal and Denisova genomes than to the African genomes and hence would make a slightly (500,000 base pairs) better starting point.* (The chimpanzee is the next closest contender with about 30 million differences.)
Millions of alterations is a lot, and making them is all but out of the question for traditional genetic engineering methods, which introduce modifications one at a time, serially. We generally try to bring down costs before we undertake a large project (as happened with human genome sequencing). Recent work in my Harvard lab shows that you can reduce the costs of the process considerably by introducing the necessary changes on a batch basis, modifying multiple genetic sites at a time, and in parallel. This is the MAGE method, introduced in Chapter 3. One way to use it here would be to break up the human genome into 10,000 pieces of 300,000 base pairs each, and then replicate them in E. coli as bacterial artificial chromosomes (BACs) or in yeast as yeast artificial chromosomes (YACs). Then each piece can be reprogrammed in parallel by MAGE (about 1,000 changes each). By using chip syntheses, 10 million oligos can be printed at a cost of about $5,000 and at least double that to get them amplified and error-corrected in appropriate subpools. The twenty-three human chromosomes could be reconstructed in parallel (about 500 steps each) and then combined by chromosome transfer using cell or microcell fusion methods and multiple positive and negative selection markers. An example of a positive selection employs a drug resistance gene like neomycin phospho-transferase. When this resistance gene is attached to the BAC and exposed to a cell, then only the cells that take up the BAC will survive in the presence of the drug. Later, if you want to remove the piece of DNA that was needed temporarily, you can use a negative selection. An example used widely in mammalian genetics is a viral thymidine kinase gene not normally found in human cells that makes them sensitive to an antiviral drug.
Supposing, then, that we have recreated the physical genome of Neanderthal man in a stem cell, the next step would be to place it inside a human (or chimpanzee) embryo, and then implant that cell into the uterus of an extraordinarily adventurous human female—or alternatively into the uterus of a chimpanzee. Admittedly, this will only ever happen if human cloning becomes safe and is widely used and if the possible advantages of having one or many Neanderthal children are expected to outweigh the risks.
This same technique could be applied to the wooly mammoth once its genome was fully sequenced. In 2008 a scientific team headed by Stephen Schuster and Webb Miller of Pennsylvania State University reported in Nature that they had reconstructed a substantially complete draft sequence from clumps of mammoth hair. But that was sufficient for them to calculate that the mammoth genome differed at 400,000 sites from the genome of the African elephant. This shows us what the road to regenerating the wooly mammoth is.
You would begin with an intact African or Asian elephant genome (both animals are phylogenetically close to the mammoth), and then by using MAGE technology you’d introduce the modifications that would turn it into a mammoth genome. Finally you would implant that genome into an elephant’s embryonic cell in the now familiar way, and implant it into the womb.
And then, twenty-two months later . . .
A common objection to the idea of resurrecting extinct species is that since many of them disappeared due to the loss of their native habitat, it is pointless to bring them back into a world in which those habitats have long since vanished. But it is possible to bring back the habitat along with the animal itself. In the case of the wooly mammoth, there has already been an attempt at this.
In 1989 Sergey Zimov, director of the Northeast Science Station in Cherskii, Russia, together with a number of partners, established a nature preserve covering a sixty-square-mile area (about three times the size of Manhattan) that they called Pleistocene Park. Although it was in Siberia, within one hundred miles of the Arctic Circle, Zimov did not claim that the park, as it stood, reproduced the mammoth habitat of the Pleistocene epoch. The group’s goal, however, was to turn it into one. “In some places we must not only preserve nature, we have to reconstruct it,” said Zimov.
Zimov’s hypothesis is that it was human hunting, and not climate change, that destroyed the mammoth. In his paper in Science, “Pleistocene Park: Return of the Mammoth’s Ecosystem” (2005), Zimov argued that it was the animals themselves, more than temperature alone, that maintained the ecosystem in which mammoths thrived.
“It might not have been the climate changes that killed off these great animals and their ecosystem,” he wrote. “More consequential, perhaps, were shifts in ecological dynamics wrought by people who relied on increasingly efficient hunting practices, which decimated the very population of grazing animals that maintained the tundra steppe.”
Tundra steppe, the mammoth’s primary habitat, was mainly grassland, the kind of open prairie that is common in the Midwest. But about 10,000 years ago, at the beginning of the Holocene, the mammoth tundra steppes of northern Siberia disappeared completely, replaced by an ecosystem rich with mosses and forests instead of grasses. According to Zimov, the loss of the tundra steppes was due to the loss of the mammoth, whose grazing habits had formerly kept the grasslands alive and fertile.
To return the area into a mammoth ecosystem, Zimov suggested introducing large herbivores selectively. To that end, in the spring of 1998 Zimov brought to the park thirty-two Yakutian horses, the breed that was closest to those that lived in the region during the Pleistocene. Over the following three years the horses converted a confined area of the park from mosses and shrub
s to grassland. Later, Zimov imported some two dozen wood bison from Canada. Gradually, a large, fenced area of Pleistocene Park came to resemble the mammoth ecosystem that was in place when the last mammoths roamed the earth.
If and when woolly mammoths are ever cloned into existence, bringing them to Pleistocene Park would be a case of returning them to their natural habitat. It would be the closest thing to time travel: a return to the flora and fauna of the Pleistocene epoch, a sort of latter-day Siberian Eden. It would also turn the area into an adventure tourist destination, for the park would in effect be a mammoth zoo.
It might be a while before that happens. The first animal to be resurrected from extinction, the clone of Celia, the bucardo, lived for about seven minutes before dying of a lung condition common to cloned mammals.* Seven minutes might not seem like much, but then the first flight of the Wright brothers in December 1903 lasted for all of twelve seconds. Sixty-six years later, in 1969, we were on the moon.
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* In 2009, the Telegraph (UK) ran an article titled “Extinct Ibex Is Resurrected by Cloning.” The many subsequent news stories that reported these experiments erroneously gave 2009 as the year in which they took place. In fact there was a six-year delay between the successful experiment and the first scientific report in the journal Theriogenology, in 2009.
* In 2000, the Nobel Prize-winning atmospheric chemist Paul Crutzen coined the term “Anthropocene” to refer to the geologic era in which human activity has had a significant impact on the face of nature.
* In August 2011 a mammoth thigh bone containing bone marrow was discovered in permafrost soil in Siberia. Kinki University scientists plan to use this material for cloning.
* Denisovans are another recently discovered species of “archaic humans.” (They were named after the Denisova Cave in Russia, where bone fragments were found in 2008.) There is evidence that both Neanderthals and Denisovans interbred with modern humans.
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