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Source: The Conversation – UK – By Benjamin Tapon, PhD student, Queen Mary University of London

US biotechnology company Colossal Laboratories and Biosciences has a radical proposal: it wants to resurrect the woolly mammoth from extinction. In a preprint paper published on March 4, scientists at Colossal report making a significant step towards this objective. They genetically modified the DNA of mice to give them mammoth-like traits in their hair shape, colour and length.

By testing out their methods in a familiar laboratory animal, the researchers can make sure they work before applying them to Asian elephants – the closest living relatives of the mammoth.

De-extinction is an idea which, if successfully implemented, would allow us to bring back any species from the dead. It means that no animal could go truly extinct as long as we can obtain its DNA.

However, mammoths were heavily adapted to a cold climate and a biome – an area with specific climate, vegetation and animal life – that no longer exists.

The Siberian habitats once roamed by the creatures – known as the mammoth steppe – are significantly warmer today. Many of the animals and plants they lived among have also disappeared, and the regions are now home to new ones that never lived alongside the mammoth.

Attempts to reintroduce woolly mammoths in our modern tundras could therefore prove difficult, and have untold repercussions on the current ecosystem. Against a background of climate change, these tundras are only going to get warmer and less suitable for an animal like the mammoth.

Nevertheless, Colossal is pushing ahead with efforts to recreate these striking creatures. Asian elephants diverged from mammoths around 6.7 million years ago and share over 95% of their DNA. Colossal plans to bridge this gap by transforming the genomes of Asian elephants to make them more like those of woolly mammoths.

Scientists have obtained high-quality woolly mammoth DNA sequences from carcasses preserved in Siberian permafrost. These genomes (the full complement of DNA in the cell) have allowed scientists to compare the genes that differ between the mammoth and the Asian elephant.

Multiplex editing

In order to generate their beauty prize-worthy mice, Colossal’s scientists used a range of highly advanced genome editing techniques to modify the sequence of DNA in the mouse. Regions of mouse DNA can be changed so they resemble genes in other organisms, such as a woolly mammoth.

These techniques are known collectively as multiplex editing and include the best known method, Crispr-Cas9. Multiplex genome editing gives scientists the ability to target and affect several genes at once (up to seven at a time in this case).

The scientists modified ten genes in total in their mice, in different combinations. Interestingly, only three were changed to resemble genes found in the woolly mammoth. The other seven had been previously identified to cause hair variation in mice, and produce traits somewhat similar to those found in mammoth hair. Although these are not mammoth gene variants, modifying them demonstrates the team’s ability to edit several genes at once through multiplex editing.

Two of the three mammoth-associated genes (Krt27 and Tgfa) have previously been linked to hair texture, based on comparisons with Asian elephants. Another gene, Fabp2, is thought to have facilitated efficient fat metabolism in mammoths – a presumed evolutionary adaptation to cold.

Modifying the Krt27 and Tgfa hair genes in mice led to a change in texture, making some hairs longer and rougher and others wavier and zigzaggy. The fact these gene modifications produced physical traits seen in mammoth hair provides a way of verifying the genes are indeed associated with changes in hair pattern, and therefore contribute to the mammoth’s distinctive woolliness. But editing the mice so they had the Fabp2 gene variant from mammoths led to no observable physical difference.

Of the seven mouse-identified genes modified by the researchers, one (a variant of the Mc1r gene) led to the shiny blond coat colour. At least one mammoth carcass dug up from the Siberian permafrost has a similar coat colour, so the change is certainly evocative of these ice age creatures.

A much bigger task

Although this is an exciting study into an area of research with incredible potential, there are a few limitations to keep in mind. While Asian elephants are the closest thing we currently have to mammoths, it would take a lot more than a few tweaks to hair length and squiggliness to meaningfully make a mammoth out of an elephant.

While George Church, the Harvard genetics professor who founded Colossal, claims that modifying 65 genes in Asian elephants will accomplish this goal, the reality is likely to be more complicated.

Indeed, the fact that editing the Fabp2 gene – associated with fat metabolism in mammoths – led to no observable difference in the mice is one example of the many gaps in our understanding of mammoth genetics. Put another way, this shows that we have some way to go to fully understand the causal relationship between genes and phenotype – the visible characteristics in a living organism.

Increasing the number of simultaneously targeted genes from seven to 65 could also introduce various unintended consequences, including accidentally modifying unintended DNA regions similar to the target sequence (known as the off-target effects of genome editing). It also remains difficult to achieve changes in all genes at once; here too, scaling up from seven to 65 will pose a noteworthy challenge.

On top of this, even if Colossal manages to make all 65 gene changes in their Asian elephants, there are likely to be many more differences between mammoth and elephant genomes that have not yet been identified. These include genes involved in behaviour, and in regions of the genome that dictate when genes are switched on or off. While mice are an extremely well studied experimental organism, elephants are less well characterised.

As a proof of concept, this research is fascinating, although it remains to be seen whether Colossal’s goal of creating an elephant-mammoth hybrid by 2028 is achievable. It would be more likely to generate a mammoth-like Asian elephant than something exactly like the ice age creature.

Finally, it is worth considering the end goal of this branch of research. Mammoths went extinct only 4,000 years ago, but at this point they had already been pushed into a fraction of their initial range – restricted to a tiny surviving population on Wrangel island in the Russian Arctic.

Another of Colossal’s objectives is to bring back the thylacine, a carnivore that once lived in Tasmania. Given it went extinct due to active hunting in the 20th century, the thylacine should at least still have suitable habitat.

However, if the goal is simply to counteract extinction, more sustainable efforts to avoid future extinctions might be better than expensive genetic engineering. De-extinction cannot replace efforts to preserve the one planet we have, and all the living organisms we share it with.

Benjamin Tapon receives funding from the Biotechnology and Biological Sciences Research Council, through the LIDo DTP.

Alex de Mendoza receives funding from European Research Council and the Royal Society.

– ref. Woolly mice are a first step to resurrecting mammoths, but there’s a very long way to go – https://theconversation.com/woolly-mice-are-a-first-step-to-resurrecting-mammoths-but-theres-a-very-long-way-to-go-251640