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.
But elephants have cancer rates even lower than humans—a surprising fact given their vast size. One hypothesis for elephants’ cancer-defying biology is that they carry lots of copies of a tumor-suppressing gene called P53. Humans, on the other hand, only have one copy of this gene.
P53 is good for elephant health, but it could be the reason that up until now scientists have struggled to create iPSCs from elephant cells, Lynch says. One way the gene seems to work is by stopping cells from entering a state where they can duplicate indefinitely, which is one of the key features of iPSCs.
Hysolli says that she’d like to reduce the time it takes to create elephant iPSCs, and refine the process so the Colossal team can produce them at a greater scale. The iPSCs will be particularly useful if Colossal’s scientists can turn them into sperm and egg cells, something that Hysolli’s team is already working on. Since there is a relatively limited supply of elephant eggs and sperm, one problem facing the de-extinction project is getting enough genetic diversity to support a population of functional mammoths—develop them from too few individuals, and you risk the negative effects of inbreeding. Being able to create sperm and egg cells in the lab should help with that, Church says.
These cells could also be useful for conservation work, Hysolli says. Colossal has partnered with researchers working on elephant endotheliotropic herpes virus (EEHV), a leading cause of death for young Asian elephants. The iPSCs could be a good way to figure out how the virus infects different cell types. The cells will also be useful for testing whether Colossal’s edits to produce mammoth-like fur and fat layers are working as scientists hope.
“I have no doubt that given enough time and money they will overcome the technical challenges of making a woolly-mammoth-looking elephant,” says Lynch. But he’s less convinced of the ecological benefits of de-extinction. The startup intends to introduce the elephant-mammoth hybrids into the wild to re-create the role once played by the mammoth in the Arctic ecosystem, grazing the land and trampling snow cover, potentially decelerating the melting of permafrost.
“How many hairy Asian elephants do you need to make that work?” Lynch asks. Whether there really is a niche for edited elephants in the Arctic 4,000 years after mammoths last roamed the area is a question that conservationists are still grappling with. Sure, scientists might be able to create mammoth-like Asian elephants, but whether we should is open to much debate.
Colossal’s scientists will be glad if they get to that point. Although they have elephant iPSCs, much of the work of creating elephant-mammoth hybrids is ahead of them. They must figure out how to create elephant sperm and egg cells, master the right edits to tweak their elephants, and take their creation through the 22-month Asian elephant gestation period. And then they have to do it enough times to build a population that can actually deliver on some of their ecological aims.
“It feels very significant,” Church says of the iPSC breakthrough. “This is a very big deal.” If Colossal is going to deliver on its de-extinction mission, then there will be many other moments like this ahead.
