So, mammoth cloning is not going to happen. No intact genomes will have survived the 3,700 years since the last mammoth walked on Wrangel Island. No mammoth chromosomes will be found that are sufficiently repairable to transform the cells in which they are found into pluripotent stem cells. From my perspective, it doesn’t matter how many trips are made to deepest Siberia or how many tunnels are blasted into the permafrost. It’s just not going to happen.
Should we just give up? Walk away dejectedly with our tails between our legs? Go back to the rest tent and cry into our mosquito-laden rice soup? Of course not! As it turns out, there are perfectly reasonable, perfectly feasible ways of bringing back a mammoth. Well, of bringing back kind of a mammoth. But let us not drown ourselves in the semantic argument just yet. First, the science.
There are two ways to bring an extinct species back to life that are feasible in the present day. One of these is so straightforward that most people probably have not thought of it in the context of de-extinction. The other is more magical, and by “magical,” I mean the most-incredible-scientific-advance-in-a-long-while kind of magical. Let’s begin with the more straightforward approach.
It is possible to bring an extinct species back right now using technology that our species began to refine some twenty or thirty thousand years ago. It is around this time that we find the first genetic and archaeological evidence of domestication—changing the course of evolution to suit our needs and desires. The approach is not overly sophisticated and requires only a reasonable grasp of basic evolutionary biology. Mainly, the idea is to take advantage of three facts. First, the physical and behavioral characteristics that define an individual—that individual’s phenotype—are determined by the sequence of the individual’s genome—its genotype—and the interaction of that genotype with the environment. Second, genotypes are passed down from parents to offspring. Third, natural selection can change the relative frequencies of different phenotypes within a population. In the wild, phenotypes that are better adapted to the environment in which the organism lives will become more common than phenotypes that are less well adapted to the same environment.
To bring a mammoth back, we can simply take advantage of nature’s own process of genetic engineering. All we have to do is find the hairiest, most cold-tolerant elephants that exist and breed them with each other. After a few generations, we will have created, without calling upon any DNA-sequencing technology at all, an elephant that can live in Siberia.
Henri Kerkdijk-Otten is a friend of mine who lives in the Netherlands and loves cows. Specifically, he loves large brutish cows that may or may not taste very good and probably don’t enjoy being milked. Henri loves aurochs. Unfortunately for Henri, aurochs have been extinct since the middle of the seventeenth century.
Henri, however, has a plan. He will bring his beloved aurochs back from extinction not by finding well-preserved fossils in European forests and not by nuclear transfer but by the comparatively simpler process of selective breeding. His hope is that he can create an auroch by carefully selecting and breeding animals that have physical and behavioral traits reminiscent of the ancient aurochs. After this process of choosing which cow gets to mate with which bull continues for many generations, the aurochs (or at least a close rendition of the aurochs) will be back. They will be able to roam free in the Dutch grasslands, where they will presumably thrive on the ubiquitous tulips.
Aurochs are the wild ancestors of domestic cattle. Around 10,000 years ago, human populations in the Near East and South Asia began farming and taming wild aurochs. Eventually, this gave rise to the two main variations of domestic cattle—humpless taurine cattle and humped zebu. Today, taurine cattle are widely distributed across the globe and belong to familiar-sounding breeds like Holstein, Angus, and Hereford. Zebu tend to be farmed in the tropics, thanks to adaptations that allow them to survive better than taurine cattle in very warm climates. Because domestic cattle are descended from aurochs, much of the genetic diversity that was present in wild aurochs is probably still present in living cattle. It may, however, be distributed among the various breeds. To reengineer an auroch, one simply has to concentrate into a single new lineage all of the auroch-like traits that are present in living zebu and taurine cattle. The end product will not contain the genome sequence of a purebred auroch. It will, however, look like an auroch.
The first genetic-engineering experiments performed by humans involved genetic manipulation of wolves, probably gray wolves that lived in Europe as long as 30,000 years ago. It is at this time that we find the first probable evidence of domestic dogs: bones found in archaeological sites that look similar to but distinct from the bones of gray wolves. These early stages of dog domestication were, of course, not hardcore genetic-engineering experiments. Instead, wolves that were more tolerant of humans and humans who were more tolerant of wolves both benefited from a closer association. Just like my own dogs, these first dogs benefited from access to table scraps. The people living in proximity to these early dogs benefited from early warnings of approaching danger, much the same way I benefit from knowing that the mail has arrived. Once the symbiosis was established, humans put genetic engineering to work. Today we have big dogs, small dogs, strong dogs, fluffy dogs, dogs with short legs, dogs with long ears, hunting dogs, herding dogs, dogs that can find people buried in avalanches, dogs that provide life support for people with disabilities, and dogs that can be carried in leopard-spotted purses on trips to the grocery store.
Henri and his colleagues plan to reverse-engineer the domestication process in cattle. Instead of breeding for traits that we tend to associate with domestic animals—tameness and manageability, for example—they want to re-create the wild ancestor of the domestic cow. Beginning with the more “primitive” breeds— including Maremmana, Moronesa, and two Dutch breeds, Limia and Sayaguesa—they have developed a selective breeding program designed to capture the physical and behavioral characteristics of aurochs and, in doing so, create a new cattle breed. The process is known as back-breeding, which is a name that highlights the goal: to breed back traits that used to exist and hopefully still exist somewhere in the gene pool of living individuals.
Today’s effort is not the first attempt to back-breed the auroch. In the 1920s and ’30s, the German brothers Heinz and Lutz Heck, who happened to be directors of the Hellabrunn Zoological Gardens in Munich and the Berlin Zoological Gardens, respectively, were instructed to re-create the auroch. This directive is said to have come from Hermann Göring, who, as an avid hunter, wished to re-create the folkloric prey of Roman hunters. (Although it is unappealing to attribute the first back- breeding experiments to the Nazis, one cannot ignore the timing of this work in interpreting its motivation.) The Heck brothers had the same goal but performed their experiments separately. They each selected different cattle breeds and used these breeds in different crosses. At the time, no scientific re- constructions of the auroch were available, and so neither brother had a particularly good sense of what an auroch actually looked like.
In 1932, Heinz Heck declared his back-breeding experiment a success. A bull was born that he felt looked similar enough to what he believed an auroch should look like that his new bull could be called an auroch. According to Heinz’s records (which he stopped keeping after the birth of this bull), the bull was 75 percent Corsican cattle, 17.5 percent Gray cattle, and the remaining 17.5 percent was a mix between Scottish Highland, Podolic Gray, Angeln, and Black Pied Lowland cattle. Selective breeding continued after the birth of this bull, eventually giving rise to what is today known as Heck cattle. Around two thousand Heck cattle are alive today, living in zoos and roaming pastures, mostly in Europe.
Are Heck cattle aurochs? Heck cattle certainly look primitive, particularly to someone who (like the Heck brothers) might not have access to accurate reconstructions of real wild aurochs. Heck cattle have dark coats and long, curved horns, which are two characteristics that were definitely found in wild aurochs. Heck cattle are also more cold tolerant than many other domestic breeds and can survive under relatively poor forage conditions, much as their wild ancestors must have done during Pleistocene glacial cycles. That, however, is about where the similarity ends. Heck cattle are large for domestic cattle, but not as large as the average auroch bull would have been. A Heck bull stands around 1.4 meters high at the shoulder and weigh up to 600 kilograms. An auroch bull, with a shoulder height around 2 meters, would have been taller than the average European man. Also, while the coat color of Heck bulls is similar to what we believe was characteristic of auroch bulls, Heck cows are lighter and more variable in color than auroch cows were. The overall body shape of Heck cattle is also different from that of aurochs, mainly in that it is smaller and, like all domestic taurine cattle, lacks the prominent neck musculature of the wild ancestors. Finally, while the horns of Heck cattle are long, relative to those of domestic cattle breeds, their shape and curvature are somewhat different from an auroch’s: they curve slightly too close to the head and point a little bit too far outward.
It is safe to conclude that the Heck brothers did not quite hit the mark. This failure, however, does not spell doom for the present back-breeding project. Today, we know much more than the Heck brothers knew in the early twentieth century about what traits defined aurochs. We have better descriptions of the various breed phenotypes and a better understanding of the temperaments of these breeds. We have abundant genetic data that help to determine which breeds are the most primitive. We even have ancient DNA data from actual aurochs. Using all of these data, there is little doubt that we will make different and more scientifically justified choices about what animals to use in the back- breeding project, which will eventually lead to the birth of animals that better resemble wild aurochs.
Of course, these animals will not actually be aurochs. Not exactly, anyway. Selective breeding is a process by which individuals that display the desired phenotype are bred together to try to replicate that phenotype in the next generation. The phenotype, however, is a consequence of the interaction between genotype and environment. Genetically, the gradual concentration of genes that code for auroch-like traits has to happen by chance. When the gametes—the sperm or egg cells that will go on to become the next generation—are formed, each one contains a shuffled version of that organism’s parents’ genomes. This shuffling of genetic material, called recombination, is an important source of genetic variation within populations. Recombination shuffles genes or parts of genes from mom’s chromosome onto dad’s chromosome and vice versa. When the sperm or eggs are formed, they will contain some DNA from mom and some DNA from dad. If a phenotype that we want to select is coded for by a gene that came from mom, but the egg that is fertilized contains dad’s version of that gene, then the offspring, despite our best intentions, will not display that phenotype.
We can guide the process of concentrating specific traits into a single lineage by selective breeding, but we cannot selectively choose which gametes go on to become that next generation. Some offspring will get the right genes and display the desired phenotype, and others will not. This does not mean that the process will never work. It will, however, be slow. Selecting for multiple traits simultaneously will be particularly challenging, as the genes for each trait need to wind up, by chance, in the same fertilized egg. Despite this, selective breeding is and has been a powerful tool in our species’ history, as attested by the variety of forms of domestic plants and animals that we encounter every day. There is no reason why, with sufficient time, resources, and patience, we cannot recover at least some traits of the wild auroch using the selective breeding approach.
As the auroch back-breeding experiment proceeds, I anticipate that the animals will gradually become more and more auroch-like in their physique and behavior. Some auroch traits may, however, never be recoverable from living cattle breeds. The DNA sequence that coded for a particular trait may have been lost, for example, or the trait may have been the product of a genetic interaction with an environment that no longer exists. Some people (myself included) would argue that this does not matter—that by filling the niche of the auroch, even partially, the experiment is a success. De-extinction purists will, however, never be satisfied with a back-breeding product, because the result will always be something new, not something old. Auroch 2.0 will not be an auroch. Not precisely, anyway.
IS SIMPLER NECESSARILY BETTER?
One advantage to back-breeding as a means of de-extinction is that it relies so little on molecular biology technologies. Genomes don’t have to be sequenced, genes don’t have to be identified, and genetic variants don’t have to be linked to specific traits. The gradual transition from one form to another happens without embryonic stem cells and long hours spent in a lab. And the results of the experiments are validated qualitatively: does it or does it not look more like an auroch?
The simplicity of back-breeding, however, may also be its downfall. While traits such as dark coat color, long forward-facing horns, or strongly expressed neck and shoulder musculature may emerge in the population after some generations of selective breeding, the genes that code for these traits once the traits reemerge may be different genes from those that coded for the same traits in the extinct species.
Does it actually matter? If we want long forward-facing horns, and the bull has long forward-facing horns, does it really matter what specific genes are making it happen? It might matter. Genes don’t always, or even often, have just one function. A gene that makes curved horns might have other consequences on the resulting cattle phenotype that we don’t want. It might make their skull slightly differently shaped, for example, or somehow influence the shape or texture of their hooves. In addition, genes don’t act in isolation but instead act in concert with other genes that are also expressed in the cell.
An example of an interaction between genes that is used in introductory biology classes is the way that coat color in horses is determined. Horses have a single gene that determines whether their coat will be red or black. The dominant allele produces a black coat and the recessive allele produces a red coat. If this gene acted alone, individuals that carried either two copies of the dominant allele or one dominant and one recessive allele would have black coats and individuals that carried two copies of the recessive would have red coats. However, there are many different types of red or reddish horses. This comes about because of yet another gene—the cream dilution gene—that modifies the expression of the red alleles. A horse that has two copies of the recessive red allele can be chestnut colored, palomino, or even white or cream colored, depending on how many copies of the cream dilution allele it carries.
While not all interactions among genes are known, and very few are well understood, this does not mean that selective breeding for specific traits is impossible. Through multiple generations of back-breeding, using different crosses involving different individuals or different breeds, the right combination of genes, or at least combinations of genes that provide the right phenotypes, may eventually be discovered. How long it will take depends on several factors, including how many traits are being selected, how easy the animals are to breed, and how long it takes to go from one generation to the next.
TOO SLOW FOR SUCCESS?
The generation time of cattle is short compared to many species. Female cattle can breed for the first time when they are between one and two years old, and gestation takes around nine months. A selectively bred individual can be born, develop into an adult, get pregnant, and give birth to the next generation all within two to three years. While not a breakneck pace, one can imagine how a selective breeding program could progress reasonably quickly in cattle.
Progress would be much, much slower for some of the other candidate species for de-extinction. For example, male elephants begin making sperm between ten and fifteen years old, and female elephants in the wild will become pregnant for the first time around age twelve. Gestation time in elephants is between twenty and twenty-two months. That means there would be a fourteen-year wait between when the first selectively bred offspring is born and when that offspring can produce the next generation. At that pace, only five generations could be produced in a human lifetime. There must be a better way.
Of course there is. An easy way to minimize the time it takes to selectively breed a trait into a lineage is to make sure that every individual in the next generation contains the target trait. This is not possible with back-breeding, where the offspring of two parents may or may not inherit the target trait or traits. However, new technologies—specifically, the genome engineering technologies that are behind the second presently feasible (and the more magical) pathway to de-extinction—make it possible to edit the genome directly. By manipulating the DNA sequence in a cell and then using that cell to create living individuals, we can be certain that the target trait is present in the next generation. We can make the entire process of resurrecting extinct traits in living species move along much more quickly and efficiently.
For example, we know that mammoth hemoglobin—the protein in red blood cells that takes up oxygen in the lungs and then distributes it via the circulatory system to the rest of the body— differs from elephant hemoglobin by exactly four mutations.
These four differences modify the performance of the hemoglobin by making the mammoth version more efficient than the elephant version at delivering oxygen when the temperature in the body is very low (think mammoth feet standing in the snow).
We will not find a living elephant that has the mammoth version of these hemoglobin genes. The common ancestor of mammoths and living elephants lived in the tropics, and adaptations to life in the cold would have evolved in mammoths only after the mammoth lineage diverged from the Asian elephant lineage. Since all mammoths are extinct, there are precisely no individuals alive who have these particular genes. In order to create an elephant that makes mammoth hemoglobin, we will have to make the mammoth version of those genes from scratch and then somehow insert that version of the gene into an elephant cell. We can do that.
Excerpted from "How to Clone a Mammoth: The Science of De-Extinction" by Beth Shapiro (2015), courtesy of Princeton University Press.