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Take a lab mouse, add a powerful genetic engineering tool, a sprinkle of woolly mammoth DNA and wait a few days.
The result? An adorable and potentially scientifically profound creation.
Venture-capital-funded genetic engineering company Colossal Biosciences has unveiled the “Woolly mouse”.
Caption: The ‘Woolly Mouse’
Credit: Colossal Biosciences
This golden fuzzball represents the company’s lofty “de-extinction” goal.
Colossal aims to resurrect long lost species, including the thylacine and the dodo.
Just to be clear, woolly mice only exist in Colossal’s labs (so no, you can’t buy one).
Their creation is driven by the desire to understand how modifying particular genes might change the physical characteristics of an organism. But their ambitions go far beyond that.
Colossal co-founder and CEO Ben Lamm says the woolly mouse brings the company “a step closer to our goal of bringing back the woolly mammoth.”
Mammuthus primigenius last roamed the tundras of Siberia and Alaska some 4,000 years ago.
Caption: A woolly mammoth.
Credit: Andrew Nelmerm/Getty Images/Dorling Kindersley
Colossal claims an animal similar to the woolly mammoth could be revived by 2028.
While the woolly mouse offers a glimpse into the future, there’s still a long way to go.
MAKING A MOUSETERPIECE
The woolly mouse is the culmination of decades of research.
Geneticists have pieced together an organism’s genetic code, extracted ancient DNA and advanced computational biology.
Their efforts have been spurred by the gigantic leap forward by a genetic engineering technology which has revolutionised the field: CRISPR.
To build the woolly mouse, Colossal studied the genomes – or genetic blueprints – of more than 50 woolly mammoths.
Over several decades, researchers extracted ancient DNA from woolly mammoth specimens recovered from permafrost.
Those genomes aren’t always perfect but by pooling them together, the blueprint of a long lost species has been recreated.
A MAMMOTH EFFORT
In tandem, scientists have sequenced the genomes of different elephant species – Asian, African, Savannah and forest elephants.
Colossal’s chief science officer Beth Shapiro says they identify the differences between mammoth DNA and elephant DNA.
“We first look for all the places in the genome where all the mammoths are the same as each other, but different from the elephants,” says Beth.
Those differences are what makes a mammoth, a mammoth.
Although woolly mammoths share more than 99% of their genome with Asian elephants, more than 1,600 genes are affected by the differences.
With the blueprint and CRISPR, the team can make many of those changes.
CODING THE FUTURE
CRISPR can make highly-specific edits to DNA, cutting and pasting genes with high precision.
This is how Colossal created woolly mice. They found nine genes linked to hair texture, length and growth, and one linked to fat metabolism.
Many of the genes had been previously shown to result in different physical characteristics in mice.
Caption: Genes targeted by Colossal to bring back the woolly mammoth.
Credit: Colossal Biosciences
For example, the Fam83g gene creates “woolly” hair, while the Tgfa gene creates wavy hair.
Three genes were classed as “mammoth-specific”, including the one linked to fat metabolism, Fabp2.
“Some of these genes are motivated by looking at elephants, and some of them are pure trait engineering,” says Beth. “That showcases our approach to de-extinction.”
The team was able to make multiple gene edits in individual mice using two techniques.
By directly editing a fertilised egg, they were able to edit five genes simultaneously.
Using another method – in which they introduced traits via stem cells – they were able to edit seven genes.
Ben says this is a significant breakthrough.
“Besides the adorability factor – we did not factor in how cute they would be – now we have produced healthy living animals that have the exact phenotypes that we predicted, based on using ancient DNA and computational analysis in genome engineering,” says Ben.
BACK FROM THE DEAD
Colossal’s reasoning for creating wooly mice is two-fold.
Firstly, it helps to validate their gene editing strategies. If Colossal is to achieve its goal of recreating the woolly mammoth, high-efficiency genetic engineering is a prerequisite.
The mouse model is one way of validating Colossal’s methods, allowing them to quickly evaluate how genetic modifications alter observable traits (at least in mice, for now.)
Secondly, it could be used to evaluate the genetic variations related to mammoths and how they may relate to cold-adaptation.
For example, future experiments will evaluate the impact of the fat metabolism gene on different diets and under different temperature conditions.
“We haven’t done these experiments yet, because they’re long-term experiments,” says Beth. “They’re under review by our ethical board right now.”
SMALL BUT MIGHTY
There’s a showmanship to Colossal’s advances that’s hard to ignore. Ben sees the woolly mouse as inspirational.
While he acknowledges Colossal’s work can be overhyped, Ben says he has received hundreds of hand-drawn pictures from children excited about genetics and STEM.
“I think a teacher is going to be able to talk about this in their classroom,” says Ben.
Michael Archer is a palaeontologist at the University of New South Wales.
He spearheaded efforts to resurrect the thylacine via cloning in the early 2000s, and is impressed by the work.
Caption: A thylacine.
Credit: Benjamin A Sheppard via Tasmanian Museum and Art Gallery
“This is a very important demonstration that the goal of the Mammoth Project – to transform the genome of an Asiatic Elephant to produce a cold-adapted, mammoth-like proboscidean, just as nature did millions of years ago – is almost certainly achievable using existing gene-editing technology,” says Michael.
Colossal has prepared a scientific paper on the Woolly mouse detailing the work, which they expect to release soon.
YOU BET JURASSICAN’T
The term ‘de-extinction’ conjures up an enduring popular culture icon – Jurassic Park.
Before you get excited about the prospect of a dinosaur revival, science won’t ever have good enough DNA to make that happen.
De-extinction in the Colossal sense isn’t about resurrecting one-to-one examples of extinct species.
Instead, Colossal believes its de-extinction program has two benefits.
Bringing back the physical characteristics of extinct species can help restore the ecosystems they used to inhabit, and developing new technologies can help conservation efforts.
It’s an important distinction. Colossal can’t bring back the woolly mammoth. Once a species is extinct, it stays extinct.
What Colossal hopes to do is create a living, breathing mammoth-like creature. An animal which walks and stomps and trumpets like a mammoth, even if it’s a shaggy Asian elephant.
Some scientists believe mammoths played a role in compacting the permafrost. This, in turn, prevents the release of carbon dioxide into the atmosphere. Without mammoths, permafrost will continue to melt.
Other scientists are less sure that mammoths would have such an effect on the ecosystem.
MIXED REACTIONS
Vincent Lynch is an evolutionary and developmental biologist at the University of Buffalo, USA.
“I have no doubt that they’re going to be able to get to the point where they get an Asian elephant that looks similar to a Woolly mammoth,” says Vincent.
“Given enough time, they’re going to be able to do it.”
Vincent led research comparing woolly mammoth and elephantid genomes in 2015. While he believes making one woolly mammoth-like elephant is possible, the idea of making enough to alter ecosystems does not seem plausible.
“Their stated goal is just total bullsh*t,” says Vincent. “Like it’s unreasonable.”
AN ETHICAL DILEMMA?
It’s important to note that except for its striking physical appearance, the woolly mouse isn’t all that different from a regular lab mouse.
While it has “woolly” features, the genetic changes haven’t been proven as relevant for cold-adaptation.
Caption: Visual differences between a standard mouse and Colossal’s ‘Woolly Mouse’.
Credit: Colossal Biosciences
When made in an elephant, these genetic tweaks may not have the same effect. For now, mice will have to do.
“It would be great if that animal model could be an elephant, but it can’t be because ethically, that doesn’t make any sense,” says Beth.
“Also logistically it doesn’t make any sense because elephants have a 22-month gestation and they reach sexual maturity as teenagers.”
When moving from woolly mice to woolly elephants, the ethical dilemmas will be stark.
There have long been curly questions about what it would mean to create a mammoth-like elephant.
How many would you need to make? How can you manage them? When does an Asian elephant become a mammoth and does that distinction matter? What if they don’t fit the ecological role they’re designed to fill?
These questions remain unanswered.
KNOCKING ON DEATH’S DOOR
Colossal, and other de-extinction proponents, claim new technology is how humanity fights its way out of the current, sixth mass extinction.
“It would be amazing if we could just stand back and let everything catch up using evolution by natural selection, but it’s too late,” says Beth.
“I’m not saying that we should stop traditional approaches to conservation. But I am saying that we also need to be investing into research around the risks and the rewards of doing other things.”
Whilst there are many unanswered questions, 59 animal species are listed as critically endangered in WA alone. A further 191 are listed as endangered or vulnerable.
Traditional approaches to conservation are sorely required because once these species die, they’re lost forever. Colossal can’t change that.
But if its work can help to protect or restore species, should we try it?
