Mammoth: scientists create stem cells in the laboratory – 03/10/2024 – Science

When it started in 2021, Colossal set a goal: genetically engineer elephants with fur and other characteristics found in extinct woolly mammoths.

Three years later, mammoth-like creatures no longer roam the tundra. But, last Wednesday (6), researchers from the biotechnology company reported a notable advance. They created elephant stem cells that could potentially be developed into any tissue in the body.

Colossal’s head of biological sciences, Eriona Hysolli, said the cells could help protect living elephants. It would be possible, for example, to create an abundant supply of the species’ eggs for breeding programs.

Independent researchers were also impressed by the cells, known as induced pluripotent stem cells (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 peculiar biology of elephants — including why they rarely develop cancer.

“The ability to study this with IPSCs is very exciting,” Lynch said. The discovery “opens up a world of possibilities for studying cancer resistance.”

The data was published online on Wednesday (6), but has not yet appeared in a scientific journal.

George Church of Harvard University School of Medicine began trying to resurrect the woolly mammoth more than a decade ago. At the time, geneticists were extracting DNA from the bones of extinct animals and identifying genetic differences between them and their living elephant cousins.

The biologist thought that if he could alter the DNA of an elephant embryo, it would have some of the characteristics that allowed woolly mammoths to survive in cold climates.

Working in parallel with Hysolli, who was a postdoctoral researcher in his lab, and his colleagues, Church did some preliminary research into editing elephant DNA — but the group found a limited supply of these cells.

The researchers then set out to get their own supply, inspired by the Nobel Prize-winning work Shinya Yamanaka and his colleagues. The Japanese biologist discovered how to turn back the clock in adult mouse cells so that they are effectively like the cells of an embryo. With the right combination of chemicals, these IPSCs could develop into different tissues and even into eggs.

They created IPSCs from other species, including humans, and clusters of human neurons that produce brain waves.

But elephant cells proved much more difficult to reprogram. Lynch said he has tried to generate elephant IPSCs for years without success. The problem, he suspected, had to do with a notable feature of these animals: They rarely develop cancer.

Simple arithmetic suggests that many elephants should have the disease. A single embryonic elephant cell divides several times to produce the enormous body of an adult animal. With each division, DNA has the chance to mutate. And this mutation can lead the new cell to uncontrolled growth, or cancer.

Elephants, however, have evolved several extra defenses against cancer.

Among them is a protein called TP53. All mammals carry a gene for the protein, which causes a cell to destroy itself if it starts to show signs of uncontrolled growth. Elephants have 29 genes for TP53. Together, they can aggressively suppress cancer cells.

These anticancer adaptations may have been what prevented adult elephant cells from being reprogrammed into IPSCs. The changes that occur in the cell can resemble the first steps towards cancer, causing cells to destroy themselves.

“We already knew the P53 was going to be a big problem,” Church said. He and his colleagues tried to overcome the challenge by obtaining new supplies of cells from endangered Asian elephants. Although they could not extract tissue samples from these animals, they were able to obtain umbilical cords from baby elephants.

The researchers then produced molecules to block the production of all P53 proteins in cells. Combining this treatment with the Yamanaka cocktail —as well as other proteins—, they arrived at elephant IPSCs.

“They seem to pass all the tests,” Church said. He and his colleagues were able to get these cells to develop into an embryo-like cluster of cells. And the cells developed into three distinct types found in early mammalian embryos.

Colossal is still aiming for its larger goal of “bringing back the woolly mammoth.” Hysolli and his colleagues plan to change some genes in stem cells from elephant sequences to woolly mammoth sequences. This way, they will be able to see if these edits lead to changes in the cells themselves.

With this strategy, she said, it might be possible to grow a cluster 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 is far from reviving its extinct cousins.

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