Beth Shapiro: How to Clone a Mammoth

## De-extinction science When people hear about “ancient DNA” in fossils, Shapiro began, the first question always is “Can we clone a dinosaur?” Dinosaurs died out so many millions of years ago, their fossils are nothing but rock (and by the way, there’s no workaround with mosquitoes in amber because amber totally destroys DNA). With no DNA, there’s no chance of cloning a dinosaur. (Sorry.) The fossils of woolly mammoths, though, are not rock. They died out only thousands of years ago, and their remains are pretty well preserved in frozen tundra, which means there is recoverable DNA. So, Plan A, can we clone a mammoth? It would be like Dolly-the-sheep, where you take nuclear DNA from somewhere in the preserved mammoth body, inject it into the egg of a closely related species (Asian elephant), plant the mammoth embryo in a surrogate mother, and in two years, a newborn woolly mammoth! But as soon as any animal dies, unless it is cyropreserved with great care, all the DNA is attacked by gut bacteria, by water, by temperature change, and soon you have nothing but tiny fragments. Nobody has found any intact cells or intact DNA in frozen mammoth mummies, and probably they never will. So, you can’t clone a mammoth. (Sorry.) Okay, Plan B, can you _sequence_ a mammoth—reconstruct the entire genome through digital analysis and then rebuild it chemically and plant that in an elephant egg? Ancient DNA, even from the best specimens, is so badly fragmented and contaminated it’s hard to tell what bits are mammoth and how they go together. Using the elephant genome for comparison, though, you can do a pretty good job of approximating the original. Just last week the successful sequencing and assembly of the full woolly mammoth genome—4 billion base pairs—was announced. But all sequencing is incomplete, including the human genome, and maybe important elements got left out. A genome rebuilt from scratch won’t be functional, and you can’t create a mammoth with it. (Sorry.) Alright, Plan C, can you _engineer_ a mammoth? Take a living elephant genome and cut and paste important mammoth genes into it so you get all the mammoth traits you want. There is an incredibly powerful new tool for genome editing called CRISPR Cas 9 that can indeed swap synthetic mammoth genes into an elephant genome, and this has been done by George Church and his team at Harvard. They swapped in 14 genes governing mammoth traits for long hair, extra fat, and special cold-adapted blood cells. _If_ you can figure out the right genes to swap, _and_ you get them all working in an elephant genome, _and_ you manage the difficult process of cross-species cloning and cross-species parenthood, _then_ you may get mammoth-like Asian elephants capable of living in the cold. (During the Q & A, Shapiro pointed out that with birds the process is different than with mammals. Instead of cloning, you take the edited genome and inject it into primordial germ cells of the embryo of a closely related bird. If all goes well, when the embryo grows up, it has the gonads of the extinct bird and will lay some eggs carrying the traits of the extinct animal.) Why bring back extinct animals? Certainly not to live in zoos. But in the wild they could restore missing ecological interactions. Shapiro described Sergey Zimov’s “Pleistocene Park” in northern Siberia, where he proved that a dense herd of large herbivores can turn tundra into grassland—”the animals create and maintain their own grazing environment.” The woolly mammoth was a very large herbivore. Its return to the Arctic could provide new habitat for endangered species, help temper climate change, increase the population of elephants in the world, and bring excitement and a reframed sense of what is possible to conservation. Furthermore, Shapiro concluded, the technology of de-extinction can be applied to endangered species. Revive & Restore is working on the black-footed ferret, which has inbreeding problems and extreme vulnerability to a disease called sylvatic plague. Gene variants that are now absent in the population might be recovered from the DNA of specimens in museums, and the living ferrets could get a booster shot from their ancestors.