'Woolly mouse' created on the quest to bring back the mammoth

US de-extinction company Colossal Biosciences has announced the creation of the Colossal Woolly Mouse — a mouse that has been genetically engineered to express multiple key mammoth-like traits that provide adaptations to life in cold climates.

By modifying seven genes simultaneously, Colossal’s team created mice with a coat colour, texture and thickness reminiscent of the woolly mammoth’s core phenotypes. According to the company, this demonstrates the feasibility of expressing traits using information learned from the computational analysis of 59 woolly, Columbian and steppe mammoth genomes ranging from 3500 to over 1,200,000 years old, confirming these pathways as the crucial targets for mammoth de-extinction.

“The Colossal Woolly Mouse marks a watershed moment in our de-extinction mission,” said Ben Lamm, co-founder and CEO of Colossal Biosciences. “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 Colossal team explored a dataset of 121 mammoth and elephant genomes, including Colossal-created high-quality reference genomes for Asian and African elephants, to identify significant genes that impact hair and other cold-adaptation traits. The team focused on a suite of genes in which mammoths had evolved fixed differences compared to their closely related Asian elephant cousins. The scientists refined the list to include 10 genes related to hair length, thickness, texture and colour, as well as lipid metabolism, compatible with expression in a mouse.

The team then edited the mouse genome using a streamlined strategy that combined three editing technologies — RNP-mediated knockout, multiplex precision genome editing and precision homology directed repair (HDR) — and made eight edits simultaneously, some with editing efficiencies as high as 100%, to modify seven genes.

The gene editing resulted in mice with the predicted traits from the team’s computational analysis and design for specific phenotypic changes. Colossal Woolly Mice all have an edit that causes loss of function in the gene FGF5, which alters hair growth cycles, leading to hair that can grow as much as three times longer than wild type. Similarly, loss of function of FAM83G, FZD6 or TGM3 leads to Colossal Woolly Mice demonstrating hair phenotypes with a woolly hair texture, wavy coats and curled whiskers through changes to hair follicle development and structure. To recreate the lighter coat colours observed in woolly mammoth mummies, Colossal Woolly Mice have a modified version of the gene MC1R, which regulates melanin production, that produces mice with golden hair rather than the black/agouti wild type coat colour. The mice also express a truncated version of FABP2, which is associated with lipid metabolism and fatty acid absorption.

Not only is the Colossal Woolly Mouse the first living animal engineered to express multiple cold-adapted traits using mammoth gene orthologs, according to Colossal Biosciences — it is also a living model for studying cold-climate adaptations in mammals. Additional future analyses of the mouse will improve our understanding of how multiple genes work together to manifest physical traits.

“The Colossal Woolly Mouse showcases our ability to use the latest genome-editing tools and approaches to drive predictable phenotypes,” said Dr Beth Shapiro, Chief Science Officer at Colossal. “It is an important step toward validating our approach to resurrecting traits that have been lost to extinction and that our goal is to restore.”

Australian scientists have reacted to the news with a mix of admiration and scepticism, stating that Colossal’s approach could have important future use cases but that these won’t include de-extinction.

“The engineering of cold-tolerant traits from woolly mammoths into a living model species is a fascinating scientific breakthrough, showing how far gene editing has advanced in recent years,” said Associate Professor Damien Fordham, Deputy Director of the Environment Institute at The University of Adelaide. “However, it does not mean that we will be able to resurrect the woolly mammoth, which went extinct due to complex interactions with humans and climate some 5000–10,000 years ago.

“In addition to the immense scientific challenge that still lies ahead for the Colossal team, the threats that caused the demise of the woolly mammoth have only worsened in recent years. Therefore, it is somewhat fanciful to believe that one day we will again have self-sustaining populations of mammoths roaming Siberia.

“Nevertheless, the technology could potentially rescue living species from extinction through engineering of their phenotypes. For example, it could be used to re-establish warm-tolerant traits lost in dwindling populations of species who are at risk of extinction from human-driven climate change.”

Professor Merlin Crossley, a molecular biologist and Deputy Vice-Chancellor (Education) at UNSW Sydney, added, “In my professional view, we won’t be seeing a woolly mammoth, a dodo or a thylacine for decades, because it’s not a matter of changing seven genes — you would have to change thousands, and you have to do the reproductive biology too. Overall, it would be like stacking up ladders to get to the moon.

“But there is power in this technology and if used wisely we’ll see progress in conventional medicine and agriculture.”

Image caption: The Colossal Woolly Mouse, created by Colossal Biosciences, expresses multiple mammoth-identified traits relevant to cold adaptation and provides a platform for validation of genome engineering targets. (Photo: Business Wire)