As part of their ambitious goal to bring back the woolly mammoth by 2028, Colossal Biosciences has created what they’ve named the “Colossal woolly mouse”. By pinpointing gene families linked to mammoth woolliness, their team used advanced multiplexed genome engineering to target seven genes, creating mice with some of the mammoth’s core phenotypes.
Those traits include mammoth-like coat color, texture, and thickness, as well as altered lipid metabolism. Suffice to say, the results are very, very fluffy.
Mammoths VS Asian elephants
One of the biggest challenges on the path to woolly mammoth de-extinction is identifying which genes in the Asian elephant, the closest living relatives of mammoths, would need to be altered to make it cold-tolerant. This involves searching for genome sequences that could be associated with how an animal looks and behaves, and then testing them in cell cultures.
The same genes and gene families that are associated with traits like wooliness in an elephant and a mammoth occur in mice.
Dr Beth Shapiro
To tackle this, Colossal analyzed 59 woolly, Columbian, and steppe mammoth genomes ranging from 3,500 to over 1.2 million years old, and used computational analysis to compare a data set of 121 mammoth and elephant genomes, including the high-quality reference genomes for Asian and African elephants the company previously created. In doing so, they could search for the right genes to control cold-tolerant phenotypes, like fur and lipid metabolism.
How to make a Colossal woolly mouse.
Image courtesy of Colossal Biosciences
However, even armed with this remarkable dataset, a whole animal model remains the best way to test for the ultimate consequences of DNA edits. So, where do you start?
“An Asian elephant has a 22-month gestation, and they’re an endangered species that we don’t want to be doing experiments like this on,” said evolutionary biologist and chief science officer at Colossal Beth Shapiro to IFLScience. “A mouse has a 20-day gestation. It’s also a mammal. They’re quite distantly related to each other, about 200 million years of evolution [apart], but the same genes and gene families that are associated with traits like wooliness in an elephant and a mammoth occur in mice.”
Creating the Colossal woolly mouse
We didn’t just shove mammoth genes into a mouse, that wouldn’t make any sense.
Dr Beth Shapiro
By identifying DNA sequences that were the same in the mammoths, but different from Asian elephants, the team could single out the specific gene variants and families that were associated with the physical phenotype of a woolly mammoth. As an important animal model system, there was already plenty of data available on the developmental biology and genetics of mice, and by editing their versions of these elephant and mammoth genes, Colossal were able to bring about the same phenotypes despite them being so distantly related.
Doing so required three editing technologies: RNP-mediated knockout, multiplex precision genome editing, and precision homology directed repair (HDR). This enabled them to make eight edits simultaneously, some with editing efficiencies as high as 100 percent, to modify seven genes.
Colossal woolly mouse vs wild type mouse.
Image courtesy of Colossal Biosciences
“We didn’t just shove mammoth genes into a mouse, that wouldn’t make any sense,” said Shapiro. “We found that there was an interesting change in mammoths and also an interesting change in the mouse version of these genes that led to a predictable phenotype. This was the sweet spot, and to test our ability to edit multiple things at the same time, we picked 10 of those genes and we edited all of them at the same time.”
There were no unintended consequences except adorability.
Ben Lamm
“In some of our mice, we used different combinations of them, so the most edited mouse has changes to seven different loci. There’s actually eight edits, but one of them is edited in two different places, and we have our ultra woolly mice.”
What the Colossal woolly mouse represents
Colossal woolly mice grow hair up to three times longer than wild type mice. This comes down to alterations in hair growth cycle that were modified using an edit that causes loss of function in the gene Fibroblast growth factor 5, or FGF5. The woolly hair texture comes from the loss of function of FAM83G, FZD6, or TGM3, and changes to hair follicle development and structure resulted in curly whiskers.
What we’re thinking about is a functional de-extinction. It’s never going to be possible to bring something back that’s 100 percent identical in its genetics, physiology, and behavior, to species that’s extinct, but that’s not our goal.
Dr Beth Shapiro
The edits were carefully screened and tested to ensure that the animals’ welfare was maintained, with CEO and co-founder of Colossal Ben Lamm appearing very happy as he told IFLScience, “There were no unintended consequences except adorability. We didn’t think that they would be as cute as they are.”
We know from mammoths retrieved from the permafrost that they too shared the orange fur seen on the Colossal woolly mouse, but Lamm and Shapiro were careful to point out that what they’ve created here isn’t an entirely new animal, but a variant that boasts phenotypes borrowed from an ancient and long-extinct creature.
“This is a really good example of the way we’re approaching de-extinction,” said Shapiro. “So, what we’re thinking about is a functional de-extinction. It’s never going to be possible to bring something back that’s 100 percent identical in its genetics, physiology, and behavior to a species that’s extinct, but that’s not our goal.”
“Our goal is to create species that are able to thrive in the habitats that exist today, and that means bringing back some of these traits that help to restore missing interactions between organisms in an ecosystem. Interactions that aren’t there anymore because the species is extinct. So, we’re trying to model these things, and it’s going to take a combination of ancient DNA, searching for changes that are directly seen in the extinct animals, and engineering.”
Why de-extinct a mammoth?
The Colossal woolly mouse marks a remarkable leap forward in the goal to de-extinct the mammoth, a goal that Lamm says is still on track for its 2028 timeline. Along the way, they’re developing a de-extinction toolkit that has already contributed to advancements in species preservation and human healthcare. They currently have their sights set on the de-extinction of the mammoth, dodo, and thylacine, the latter for which they recently achieved mid-gestation marsupial embryo development in an artificial uterus – a step that could be pivotal in upscaling rewilding efforts without the need for surrogates.
As for why de-extinct the mammoth at all, the ultimate vision really comes down to recognizing how animals shape the environment.
“We hope we can affect an ecosystem in a positive way, that maybe 10,000 years ago was degraded by humans contributing to the demise of almost all major herbivores in the Arctic, causing a transition from grass to trees,” geneticist and co-founder of Colossal Biosciences George Church told IFLScience. “Trees are less photosynthetically productive, they trap more heat because they’re kind of like these black lightning rods, and they also trap snow in the winter, so that they insulate the ground from freezing quickly.”
“These three things, the lower productivity, the lower ability to sequester (carbon), and higher temperatures means that a lot of carbon can be released as methane, which is 80 times worse than carbon dioxide. If we can reintroduce the megafauna, mega herbivores that would keep it in grass, it could transition back towards the more robust and fruitful ecosystem.”
Church hastened to add that these kinds of environmental benefits are a long-term goal that nobody alive today will live to see, but if we’re to one day harness the sequestration power of a woolly mammoth, we need to work out how to bring about its unique talents in an Asian elephant. Now that Colossal have introduced to the world the Colossal woolly mouse, it seems we’re getting that much closer.
“The Colossal Woolly Mouse marks a watershed moment in our de-extinction mission,” said Lamm in a statement emailed to IFLScience. “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. This success brings us a step closer to our goal of bringing back the woolly mammoth.”
The research is presented in a pre-print that has not yet undergone peer review.
