Scientists create elephant stem cells in the laboratory

When biotech company Colossal launched in 2021, it set an eyebrow-raising goal: genetically engineer elephants with hair and other traits found on extinct woolly mammoths.

Three years later, mammoth-like creatures no longer roam the tundra. But on Wednesday, company researchers reported a remarkable 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. “It is important that you can use a lot of it in a dish,” she says.

Independent researchers were also 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 study, said iPSCs could help scientists learn more about elephants’ strange biology — including why they so rarely develop cancer.

“The opportunity to study this with iPSCs is very exciting,” said Dr. Lynch. The discovery “opens up a world of possibilities to study cancer resistance,” he added.

The data was published online on Wednesday, but has not yet appeared in a scientific journal.

George Church, a biologist at Harvard Medical School, began efforts to revive the woolly mammoth more than a decade ago. At the time, geneticists were extracting DNA from the bones of the extinct animals and mapping the genetic differences between them and their living elephant cousins. Dr. Church reasoned that if he could alter the DNA of an elephant embryo, it would exhibit a number of traits that allowed woolly mammoths to survive in cold climates.

Together with Dr. Hysolli, a postdoctoral researcher in his laboratory, and their colleagues, Dr. Church some preliminary research into elephant DNA editing. But the group faced a limited supply of elephant cells.

So the researchers set out to find their own stock, drawing inspiration from the Nobel Prize-winning work of Japanese biologist Shinya Yamanaka and his colleagues. Dr. Yamanaka discovered how to turn back the clock in adult mouse cells so that they essentially resembled the cells in an embryo. With the right combination of chemicals, these iPSCs can then even develop into many different tissues Eggs.

Researchers have created iPSCs from other species, including humans. For example, some researchers have created groups of human neurons that make brain waves.

But elephant cells are much more difficult to reprogram. Dr. Lynch said he had tried for years to make elephant iPSCs without success. The problem, he suspected, had to do with a remarkable characteristic of elephants: they rarely get cancer.

Simple arithmetic suggests that many elephants should get cancer. A single embryonic elephant cell divides many times to produce the enormous body of an adult animal. With every division, DNA has the chance to mutate. And that mutation can push the new cell toward uncontrolled growth or cancer.

But elephants have developed some additional defense mechanisms 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 begins to show signs of uncontrolled growth. Elephants have 29 genes for TP53. Together they can aggressively destroy cancer cells.

These anti-cancer modifications may have prevented adult elephant cells from being programmed into iPSCs. The changes that occur within the cell can resemble the first steps toward cancer, causing the cells to self-destruct.

“We knew p53 was going to be a big problem,” said Dr. Church. He and his colleagues tried to overcome the challenge by obtaining new supplies of cells from Asian elephants, which are endangered. Although they were unable to take tissue samples from these animals, they were able to obtain the umbilical cords of baby elephants.

The researchers then created molecules that block the production of all p53 proteins in the cells. By combining this treatment with Dr. Yamanaka – and also with other proteins – they succeeded in making iPSCs from elephants.

“They seem to pass all tests with flying colors,” said Dr. Church. He and his colleagues induced these cells to grow into an embryo-like cluster of cells. And the cells have developed into three different types found in early mammalian embryos.

Colossal is still pursuing its greater purpose: “bringing back the woolly mammoth.” Dr. Hysolli and her colleagues plan to change some genes in the stem cells from elephant sequences to woolly mammoth sequences. They will then see whether those operations lead to changes in the cells themselves. With this strategy it could be possible to grow a group of elephant cells from which, for example, mammoth hair can grow.

Dr. 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 resurrecting their extinct cousins.

“We know almost nothing about the genetics of complex behavior,” said Dr. Lynch. “So we end up with a hairy Asian elephant that doesn’t know how to survive in the Arctic?”