By Carl Zimmer
When biotechnology firm Colossal started in 2021, it set an eyebrow-raising goal: to genetically engineer elephants with hair and other traits found on extinct woolly mammoths.
Three years later, mammothlike creatures do not roam the tundra. But Wednesday, researchers with the company reported a noteworthy advance: They created elephant stem cells that could potentially be developed into any tissue in the body.
Eriona Hysolli, head of biological sciences at Colossal, said the cells could help protect living elephants. For example, researchers could create an abundant supply of elephant eggs for breeding programs. “Being able to derive a lot of them in a dish is important,” she said.
Independent researchers, too, were impressed by the cells, known as induced pluripotent stem cells, or iPSCs. Vincent Lynch, a biologist at the University at Buffalo who was not involved in the research, said iPSCs could help scientists learn about the strange biology of elephants — including why they so rarely develop cancer.
“The ability to study this with iPSCs is very exciting,” Lynch said. The discovery “opens a world of possibilities to study cancer resistance,” he added.
The data was published online Wednesday but has not yet appeared in a scientific journal.
George Church, a biologist at Harvard University Medical School, started trying to resurrect the woolly mammoth more than a decade ago. At the time, geneticists were extracting DNA from the bones of the extinct animals and pinpointing genetic differences between them and their living elephant cousins. Church reasoned that if he could alter an elephant embryo’s DNA, it would sport some of the traits that allowed woolly mammoths to survive in cold climates.
Moonlighting with Hysolli, who was a postdoctoral researcher in his lab, and their colleagues, Church did some preliminary research on editing elephant DNA. But the group struggled with a limited supply of elephant cells.
So, the researchers set out to make their own supply, drawing inspiration from the Nobel Prize-winning work of Japanese biologist Shinya Yamanaka and his colleagues. Yamanaka figured out how to turn back the clock in adult mouse cells so that they were effectively like the cells in an embryo. With the right combination of chemicals, these iPSCs could then develop into many different tissues, even eggs.
Researchers have made iPSCs of other species, including humans. Some researchers, for example, have made clumps of human neurons that make brain waves.
But elephant cells have proved much harder to reprogram. Lynch said he had tried to create elephant iPSCs for years with no success. The trouble, he suspected, had to do with a remarkable feature of elephants: They rarely get cancer.
Simple arithmetic suggests that a lot of elephants should get cancer. A single embryonic elephant cell divides many times over to produce the enormous body of an adult animal. With each division, DNA has a chance to mutate. And that mutation may push the new cell toward uncontrolled growth, or cancer.
But elephants have evolved a number of extra defenses against cancer.
Among them is a protein called TP53. All mammals carry a gene for the protein, which causes a cell to self-destruct if it starts showing signs of uncontrolled growth. Elephants have 29 genes for TP53. Together, they may aggressively quash cancerous cells.
These anti-cancer adaptations may have been what stopped adult elephant cells from being reprogrammed into iPSCs. The changes happening in the cell may resemble the first steps toward cancer, causing the cells to self-destruct.
“We knew p53 was going to be a big deal,” Church said. He and his colleagues tried to overcome the challenge by obtaining fresh supplies of cells from Asian elephants, which are endangered. Although they couldn’t extract tissue samples from those animals, they were able to get the umbilical cords of baby elephants.
The researchers then created molecules to block the production of all p53 proteins in the cells. Combining this treatment with Yamanaka’s cocktail — as well as with other proteins — they succeeded in making elephant iPSCs.
“They seem to pass all the tests with flying colors,” Church said. He and his colleagues have coaxed these cells to grow into an embryolike cluster of cells. And the cells have developed into three distinct types found in early mammal embryos.
Colossal is still aiming to hit its grander goal of “bringing back the woolly mammoth.” Hysolli and her colleagues plan to change some genes in the stem cells from elephant sequences to woolly mammoth sequences. They will then see if those edits lead to changes in the cells themselves. With this strategy, she said, it may be possible to grow a clump of elephant cells that sprout mammoth hair, for example.
Lynch is skeptical about the company’s ultimate goal. He argued that modifying a few genes in a living elephant was a far cry from reviving their extinct cousins.
“We know almost nothing about the genetics of complex behavior,” Lynch said. “So, do we end up with a hairy Asian elephant that doesn’t know how to survive in the Arctic?”