De-extinction startup Colossal Biosciences wants to bring back the woolly mammoth. Well, not the woolly mammoth exactly, but an Asian elephant gene-edited to give it the fuzzy hair and layer of blubber that allowed its close relative to thrive in sub-zero environments.
To get to these so-called “functional mammoths,” Colossal’s scientists need to solve a whole bunch of challenges: making the right genetic tweaks, growing edited cells into fully formed baby functional mammoths, and finding a space where these animals can thrive. It’s a long, uncertain road, but the startup has just announced a small breakthrough that should ease some of the way forward.
Scientists at Colossal have managed to reprogram Asian elephant cells into an embryonic-like state that can give rise to every other cell type. This opens up a path to creating elephant sperm and eggs in the lab and being able to test gene edits without having to frequently take tissue samples from living elephants. The research, which hasn’t yet been released in a peer-reviewed scientific journal, will be published on the preprint server Biorxiv.
There are only around 30,000 to 50,000 Asian elephants in the wild, so access to these animals—and particularly their sperm and eggs—is extremely limited. Yet Colossal needs these cells if they’re going to figure out how to bring their functional mammoths to life. “With so few fertile female elephants, we really don’t want to interfere with their reproduction at all. We want to do it independently,” says George Church, a Harvard geneticist and Colossal cofounder.
The cells that Colossal created are called induced pluripotent stem cells (iPSCs), and they behave a lot like the stems cells found in an embryo. Embryonic stem cells have the ability to give rise to all kinds of different cell types that make up organisms—a quality that scientists call pluripotency. Most cells, however, lose this ability as the organism develops. Human skin, for instance, can’t spontaneously turn into muscle or cells that line the inside of the intestine.
In 2006, the Japanese scientist Shinya Yamanaka showed it was possible to take mature cells and turn them back into a pluripotent state. Yamanaka’s research was in mice cells, but later scientists followed up by deriving iPSCs for lots of different species, including humans, horses, pigs, cattle, monkeys, and the northern white rhino—a functionally extinct subspecies with only two individuals, both females, remaining in the wild.
Reprogramming Asian elephant cells into iPSCs proved trickier than with other species, says Eriona Hysolli, head of biological sciences at Colossal. As with other species, the scientists reprogrammed the elephant cells by exposing them to a series of different chemicals and then adding proteins called transcription factors that turn on particular genes to change how the cells functions. The whole process took two months, which is much longer than the 5 to 10 days it takes to create mouse iPSCs or the three weeks for human iPSCs.
This difficulty might have to do with the unique biology of elephants, says Vincent Lynch, a developmental biologist at the University at Buffalo in New York who wasn’t involved in the Colossal study. Elephants are the classic example of Peto’s paradox—the idea that very large animals have unusually low rates of cancer given their size. Since cancer can be caused by genetic mutations that accumulate as cells divide, you’d expect that animals with 100 times more cells than humans would have a much higher risk of cancer.
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