Colossal Biosciences Unveils Woolly Mouse, Wooly Mammoth Precursor

In the early 1990s, Michael Crichton and Steven Spielberg brought the concept of de-extinction to the masses with Jurassic Park. Today, the franchise lives on with this summer’s Jurassic World Rebirth, and de-extinction is slowly but steadily making its way off the page and screen and into the real world.

In 2000, the Pyrenean ibex went extinct when the last living individual was crushed beneath a fallen tree. Three years later, scientists in Spain pulled a frozen tissue sample out of cold storage and cloned her. A lung defect made it impossible for the baby to breathe, the resurrected ibex lived for only a few minutes, and humanity’s first real-world de-extinction effort ended faster than it began.

Twenty years later and the bioengineering company Colossal Biosciences has set its sights on resurrecting the legendary woolly mammoth. But before that, they’ve delivered the most adorable laboratory creation in history or prehistory: the woolly mouse.

Taking a mouse-sized step down the path toward de-extinction

Colossal’s woolly mammoth de-extinction efforts are focused on modifying an Asian elephant, the mammoth’s closest living relative, to express mammoth-like traits. Over the past few years, the company has developed a suite of tools designed to analyze and edit DNA, among other moonshot endeavors like creating artificial wombs.

The company’s multi-step pipeline involves identifying genes related to key traits, genetic modification of cells or embryos, implantation, gestation, and finally birth. Rather than creating a mammoth from the jump, an experiment which involves a 22-month gestation period, the folks at Colossal elected to test their pipeline through the creation of the woolly mouse.

“It’s a validation, we’ve spent a lot of time and effort and money doing the computational analysis across 100+ genomes to identify these core targets that will drive both cold tolerance and some of these phenotypes that we’re looking for,” Ben Lamm, Co-Founder and CEO of Colossal Biosciences, told SYFY WIRE. What’s great about our woolly mice is that it proves that our end-to-end pipeline for de-extinction works.”

How Colossal Biosciences made the woolly mouse

The journey to the woolly mouse began with the woolly mammoth. Scientists at Colossal examined more than 100 genomes of Asian elephants and woolly mammoths. They lined up those genomes side by side and compared them to find the parts which are crucial for making a mammoth.

“The way we identified these genes was we looked for places in our multi-elephant alignments to see where all the mammoths are the same as each other but different from the elephants, suggesting they’re variants that evolved along the lineage to mammoths,” Dr. Beth Shapiro, Chief Science Officer at Colossal, told SYFY WIRE. “Then we narrow that down to genes that are associated with these particular phenotypes that we’re interested in. Anything about hair length, wooliness, color, etc. Then we did one gene associated with fat metabolism.”

Colossal edited fatty acid binding protein 2 (FABP2), a gene associated with fat metabolism. They also triggered a loss of function in fibroblast growth factor 5 (FGF5) and associated genes, leading to mice with woolly hair texture, wavy coats, and curled whiskers. Changes to TGFA and a mutation to the keratin gene KRT27 also contributed to a mammoth-like coat, and a change to the gene MC1R gave the mice a mammoth’s trademark rusty color.

To avoid any concerns about mouse health, researchers used gene variants which have been observed in healthy mice before. Creating the woolly mouse was about making a specific suite of mousy variations to make them as mammoth-like as possible.

“We can’t just put a mammoth gene into a mouse, right, because there are 200 million years of evolutionary divergence between them… fortunately, there’s decades of work done on mice and many times mutations or variants have spontaneously arisen,” Shapiro said. “What we look for is an overlap between these genes we’ve identified in the mammoth and then in the mouse literature, variants that have been observed before that contribute to this phenotype.”

Colossal made several different versions of woolly mouse with different combinations of gene edits. In the end, they achieved eight edits on seven genes, and a handful of healthy animals.

“We’re pretty excited about this because it means that all of the optimization that we’ve been doing up to now has really paid off. We can readily design really efficient guides as well as push them into the cells,” Shapiro said.

“It also shows that the end of the process where we can screen either cells for somatic cell nuclear transfer or screening the embryos for off-target effects works really well,” Lamm said, “because all the mice that were born were healthy with no off-target effects.”

Next steps for Colossal’s woolly mouse and woolly mammoth

Only some of the gene edits needed to make a mammoth could be tested in a mouse model. Researchers looked at genes related to ear size, for instance, but decided against making those edits.

“There is a gene that we think is associated with smaller ear size we see in mammoths. We thought about testing it in mice but the mouse version of that gene is very different and it’s conditionally expressed at some point, it just doesn’t seem like a very safe one to do,” Shapiro said. “That’s an example of a gene that we evaluated and we thought, ‘No, that’s not going to be one that’s possible in a safe way.’”

Other gene edits have been tested and are being tested using elephant stem cells, tissues, and organoids, in the lab. In the meantime, researchers are observing the woolly mice to see how the edits play out throughout their lives and testing to see if they are better adapted to the cold.

“We’ve applied to our ethics board for some of these cold tolerance experiments to test out the fat metabolism and how some of the edits we’ve made confer cold tolerance. Are they happier, are they healthier, in a little bit of a colder environment?” Lamm said. “We’re keeping them separate, we’re not breeding them, and we’re not selling them.”

“We can see them, we can see that the edits worked and produced this phenotype, but it’s important to us to know what the actual physiological consequences of this would be. It’s a longer-term experiment,” Shapiro said. “We’ll be doing that work over the next 6 to 12 months.”

Get another dose of de-extinction with Jurassic World Rebirth, in theaters July 2, 2025.