Colossal Biosciences create woolly mouse with gene alteration
At first glance, you would be forgiven for thinking these shaggy-haired mice are nothing special. Their fur is a little lighter in colour, longer and more wavy than usual, but a mouse is a mouse — or is it? According to the world’s leading de-extinction experts, the birth of these rodents marks a “watershed moment” in the quest to bring back animals that last roamed the Earth thousands of years ago.
The mice have been genetically engineered by Colossal Biosciences to express traits of the woolly mammoth, which make them better adapted to survive in cold climates. Changes to their DNA have resulted in coats that resemble their namesakes’ in colour, length, texture and thickness. And genes controlling lipid metabolism – the process of absorbing and synthesising fats to store energy – have been altered so they store more fat just beneath the skin.
The mice have longer and thicker hair reminiscent of the woolly mammoth (Image: Colossal Biosciences)
The company’s ambitious chief executive Ben Lamm, who co-founded Colossal in 2021, says this murine milestone “brings us a step closer to our goal of bringing back the woolly mammoth”. “By engineering multiple cold-tolerant traits from mammoth evolutionary pathways into a living model species, we’ve proven our ability to recreate complex genetic combinations that took nature millions of years to create,” he says.
Once considered fanciful, de-extinction is a branch of research that aims to resurrect past species by editing the DNA of modern animals. The process begins with identifying observable characteristics or traits, known as phenotypes, that you want to recreate.
A genome contains all the DNA in an organism, with the information needed for it to function. Colossal used computer science analysis to select targets in the genomes of 59 woolly, Columbian, and steppe mammoths ranging from 3,500 to 1.2 million years old. Researchers also looked at data from Asian and African elephants to see which genes drive key differences between the closely-related animals.
Once targets had been chosen, it was not as simple as “taking a mammoth gene and just cramming it into a mouse”, Lamm explains. “There’s 200 million-plus years of genetic divergence so we do not believe that would be compatible with life, and that’s probably not the best thing from an animal welfare perspective.”
The Colossal woolly mice are ‘massively adorable’, Lamm says (Image: Colossal Biosciences)
Instead, the team looked at previous research in mice to predict which gene edits could produce the same characteristics. For example, tampering with one protein that alters hair growth cycles, causes hair to grow up to three times longer than wild type, while the loss of function in other genes creates a woolly hair texture, wavy coats, and curled whiskers.
More than 100 so-called Colossal woolly mice have now been born. You may be thinking that a slightly altered mouse is a far cry from a woolly mammoth – and you would be right. But their talent for breeding made them an excellent candidate for testing this approach.
The ultimate goal is to one day birth a woolly mammoth from an Asian elephant, but “elephants take 22 months to gestate and mice take 23 days,” Lamm says. “It’s a lot easier to [use mice to] test these hypotheses from our computer analysis to see if the edits we’re making to the genes actually drive the cold-tolerant phenotypes.
“I couldn’t be more excited because now we have this mouse model that not only helps us test things for our mammoth project very, very quickly, but we also know that the end-to-end de-extinction pipeline we’ve been building and working on for years, and spent quite a bit of money on, is actually working.”
The last woolly mammoth died on a remote island in the Arctic Ocean around 3,500 years ago, and the idea of bringing them back is nothing new. There is a joke among science journalists that de-extinction researchers are always “five years away” from achieving this feat.
Scientists selected mammoth traits and recreated them in mice (Image: Colossal Biosciences)
No animal has yet been brought back from extinction. In 2003, scientists announced they had birthed a Pyrenean ibex, which died out in 2000, by producing a clone from preserved tissues. But its death minutes later from a lung defect sparked a debate about the ethics of such experiments.
Colossal has set a goal of 2028 for the woolly mammoth. Despite previous false dawns, Lamm believes the explosion of AI and advances in computing mean we now have the necessary technology.
However, the woolly mammoth may not be the first animal to be brought back; the team is also working on the dodo and the Tasmanian tiger. Lamm answers the obvious question before I get to it: “Don’t ask me which one [will be first] because I’m not going to tell you.”
All this talk of resurrecting extinct species might bring to mind a certain film franchise. Sadly, Colossal’s chief science officer, Dr Beth Shapiro, is quick to pour cold water on dreams of a real life Jurassic Park. Dinosaurs died out more than 65 million years ago and the oldest DNA recovered is only one to two million years old and very degraded.
It is also important to note that animals made through this process would not be identical to the real thing, but recreations with the chosen traits. Dr Shapiro explains: “It’s never going to be possible to recreate something that is genetically, behaviourally and ecologically identical – that has never been our target.
“The environment of the late Pleistocene also isn’t here anymore, so when we’re creating these animals, we need to engineer them so they can thrive in the ecosystems of now and 50 years from now.
“It’s a functional de-extinction of these animals so we can help to make the ecosystems of tomorrow more robust and more resilient by improving biodiversity and replacing these missing ecological interactions.”
Mammoths roamed the Earth during the late Pleistocene era (Image: Getty)
Dr Saad Arif, an expert in evolutionary genetics and senior lecturer at Oxford Brookes University, says the ultimate goal of bringing back the woolly mammoth still seems “quite far off”. Reading Colossal’s mouse announcement, he notes that editing mice to have longer hair is “interesting, but not that novel in itself. At the end of the day, you just have this funny-looking mouse, it’s not really a mammoth.”
It is also not clear how you would decide at what point you have created a mammoth, as opposed to an Asian elephant with a few mammoth-like traits. Dr Arif adds: “It’s a tricky question: when does an elephant become a mammoth?”
But, for now, the real breakthrough may lie in Colossal’s reported success in editing multiple mouse genes simultaneously with high efficiency. Full results remain to be seen, but if the results are as impressive as claimed Dr Arif says: “That opens up the possibility of treating and understanding diseases and traits that are under the control of multiple genes.”
Gene editing techniques have seen major advances in the last decade. They are now being used to treat health conditions caused by single mutations, like the blood disorder sickle cell anaemia.
The NHS received the green light in January to roll out a one-time therapy that involves removing a patient’s stem cells and editing them to repair the mutation that drives the disease, so the patient produces healthy haemoglobin when the cells are returned.
However, many diseases are driven by multiple genes. “The more we understand the better we can get at multiplex editing without unintended consequences,” Lamm says. “These are tools that could spin out technologies that can be applied to humans.
Colossal woolly mice look very different to wild type mice (Image: Colossal Biosciences)
“Our goal is to get to the point where we’re doing hundreds to thousands of edits at a time. We’ve got some pretty cool things coming down the pipe that I think could be not only helpful for our de-extinction efforts, but for conservation.”
Gene editing could also play a role in preventing endangered species from dying out. In Australia, cane toads that produce a deadly neurotoxin were introduced from South and Central America in the 1930s.Their rapid spread has left the northern quoll, a native marsupial which likes to eat them, critically endangered.
Working with academics, Colossal hopes to artificially introduce adaptations that could save the quoll. Tests in stem cells from the fat-tailed dunnart found that changing their DNA could confer “a 5,000 times [greater] resistance to the neurotoxin”, Lamm says.
As the science advances, he hopes Colossal’s techniques will provide “one thread of a giant tapestry that needs to be made” to combat a global biodiversity crisis.
“We are going to lose 50% of biodiversity between now and 2050 if we don’t do anything. Modern conservation works, it just doesn’t work at the speed at which we are changing and eradicating species.
“This is a biodiversity crisis, we’re in the sixth mass extinction and we need more people doing more conservation, building new tools and technologies. This is just one.”
Colossal hopes its techniques will help battle a global biodiversity crisis (Image: Colossal Biosciences)
Dr Shapiro adds: “It’s not just about the end product — getting to a mammoth, a dodo or a Thylacine, but also the process of getting there. Every one of these animals is in a different branch of the Tree of Life and they all have different technical hurdles that need to be overcome.
“As we work with these breakthroughs, as we develop protocols and tools, all of these can be applied immediately to help prevent extinctions from happening today.
“Conservation is an area where we’re going to see tremendous benefits from de-extinction projects, because these tools are really needed to grow the resources at our fingertips to stop species from becoming extinct.”
As for Colossal’s mice, they will be closely monitored over the coming months and put through their tiny paces in cold tolerance tests. Then, they will live out their natural lives in the company’s vivarium.
The choice of animal was a practical one but it helps that the woolly mice are “massively adorable, something we did not plan for or engineer”, Lamm adds. “That’s just a byproduct, which means our mammoths are probably going to be massively adorable as well.”
