Mice have had multiple genes edited simultaneously to grow shaggy coats that resemble those of extinct woolly mammoths. The work was conducted by Texas-based ‘de-extinction’ company Colossal Biosciences, which wants to revive woolly mammoth traits in Asian elephants, their closest living relative, with the aim of breeding them to bioengineer and protect Arctic tundra environments where mammoths once roamed.
‘We have been editing elephant cells for more than two years, using multiple approaches to simultaneously alter genes that we hypothesise will lead to de-extinction of key mammoth traits,’ says Beth Shapiro, Colossal’s chief science officer. ‘The woolly mouse project confirms that these target edits will help restore the woolly coat phenotype.’
Since Asian elephants have a 22-month gestation period and are an endangered species, it’s impractical to use them to explore the genetics of woolly mammoths, which went extinct around 4000 years ago but whose genomes have been sequenced from their remains. Mice, however, have a 20-day gestation period and there are long-established protocols for manipulating their genes.
The Colossal team therefore designed a rapid workflow using gene-editing techniques, including Crispr-Cas9, to disrupt 10 mouse genes that they identified as being potentially linked to key mammoth traits associated with adaptations to cold climates – including hair growth patterns, fat distribution and cold tolerance. However, only three of the 10 genes were established to have direct links to the mammoth genome.
Most of the selected mouse genes had previously been known to affect mouse coat characteristics, including hair length, colour and texture. However, by comparing datasets of mammoth and elephant genomes, the team identified that mammoths lost the function of one of these genes. The researchers also introduced mutations into two of the genes, one of which was previously reported in mammoths. Meanwhile, one gene was selected for its role in lipid metabolism, which was known to possess a kind of mutation called an early stop codon in mammoths.
Most edited mice yet
Experiments with different combinations of edited genes produced healthy mice that grew to have different appearances, including curly, textured coats that were either golden brown or black. The researchers say their woolly mouse is one of the most edited transgenic mice to date, with eight edits delivered simultaneously that precisely alter the sequences of seven genes. The un-peer-reviewed preprint describing the work has been uploaded to the bioRxiv preprint server but has not been published yet.
‘Our preprint describes the scientific process used to create the woolly mice. We are constantly asked for updates to our de-extinction projects and want to be transparent about the work when we have breakthroughs,’ explains Shapiro. ‘Once we have completed the series of behavioural experiments that we have planned for the next six to 12 months to assess the impact of our edits on cold adaptation, we will add these to the preprint and submit to a journal for peer review,’ Shapiro adds.
‘It’s great to see these methods published rapidly in a preprint, enabling the entire field of biotech conservation to advance research that can aid endangered species as well as de-extinction,’ comments Ben Novak, lead scientist at Revive & Restore, a California-based non-profit organisation that aims to enhance biodiversity through the genetic rescue of endangered and extinct species. ‘The work is incredibly cool and an essential first step to validating de-extinction genomics.’
‘Clearly they are able to make many edits at once and create viable mice, so this is a good technological step forward,’ says Tom Gilbert, a palaeogenomics expert at the University of Copenhagen, Denmark, who also sits on Colossal’s scientific advisory board but wasn’t involved in the research. However, he points out a caveat in translating this to elephants – that the natural hair density of elephants is much less than that of mice and mammoths.
‘If they made only these edits on an elephant, it would possibly get long thin blonde hairs but still not have many of them,’ Gilbert explains. ‘So, to make a full mammoth they’d presumably have to also work out and modify the genetic basis of hair density. But overall, it’s a very nice step forward showing feasibility.’
‘A mammoth is much more than just an elephant in a fur coat,’ says Tori Herridge, a fossil elephant expert at the University of Sheffield. ‘Unless you decide to make every edit necessary to the genome, you are only ever going to create a crude approximation of any extinct creature, based on an incomplete idea of what it should look like. You are never going to “bring back” a mammoth.’ She also notes that many of the gene-edited embryos failed and very few had all the desired target edits. Engineering an Asian elephant’s embryo would prove a far more difficult challenge than a mouse’s, she adds.
Denis Headon, a geneticist at the Roslin Institute, says this is an important advance for de-extinction and animal breeding. However, he adds: ‘Further work on either synthesising or understanding the mammoth genome would also be required to go beyond these superficial characteristics to generate an animal that would, for example, have the right behaviour to live in Arctic conditions.’
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