De-extinction company sets its next (first?) target: The thylacine

October 1, 2022
Science
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Image Source: https://arstechnica.com/

Of all the species that humanity has wiped off the face of the Earth, the thylacine is possibly the most tragic loss. A wolf-sized marsupial sometimes called the Tasmanian tiger, the thylacine met its end in part because the government paid its citizens a bounty for every animal killed. That end came recently enough that we have photographs and film clips of the last thylacines ending their days in zoos. Late enough that in just a few decades, countries would start writing laws to prevent other species from seeing the same fate.

On Tuesday, a company called Colossal, which has already said it wants to bring the mammoth back, is announcing a partnership with an Australian lab that it says will de-extinct the thylacine with the goal of re-introducing it into the wild. A number of features of marsupial biology make this a more realistic goal than the mammoth, although there’s still a lot of work to do before we even start the debate about whether reintroducing the species is a good idea.

To find out more about the company’s plans for the thylacine, we had a conversation with Colossal’s founder, Ben Lamm, and the head of the lab he’s partnering with, Andrew Pask.

Branching out

To an extent, Colossal is a way of organizing and funding the ideas of Lamm’s partner, George Church. Church has been talking about de-extincting the mammoth for a number of years, spurred in part by developments in gene editing. The company is structured as a startup, and Lamm said it’s very open to commercializing technology it develops while pursuing its goals. “On our path to de-extinction, Colossal is developing new software, wetware, and hardware innovative technologies that can have profound impacts on both conservation and human health care,” he told Ars. But fundamentally, it’s about developing products for which there’s obviously no market: species that no longer exist.

The general approach it lays out for the mammoth is straightforward, even if the details are extremely complex. There are plenty of samples of mammoth tissue from which we can obtain at least partial genomes, which can then be compared to its closest relatives, the elephants, to find key differences distinct to the mammoth lineage. Thanks to gene editing technology, key differences can be edited into the genome of an elephant stem cell, essentially “mammothifying” the elephant cells. A bit of IVF later, and we’ll have a shaggy beast ready for the sub-Arctic steppes.

Again, the details matter. At the plan’s inception, we had not created elephant stem cells, nor done gene editing at even a fraction of the scale required. There are credible arguments that the peculiarities of the elephant reproductive system make the “bit of IVF” that’s needed a practical impossibility; if it does happen, it will involve a nearly two-year gestation before the results can be evaluated. Elephants are also intelligent, social creatures, and there’s a reasonable debate to be had about whether using them to this end is appropriate.

Given these challenges it may not be a coincidence that Lamm said Colossal had been looking for a second species to de-extinct. And their search turned up a project that was taking a nearly identical approach: the Thylacine Integrated Genomic Restoration Research Lab (TIGRR), based at the University of Melbourne and headed by Andrew Pask.

In the pouch

As with Colossal’s mammoth plans, TIGRR intends to obtain thylacine genomes, identify key differences between that genome and related lineages (mostly quolls), and then edit those differences into marsupial stem cells, which would then be used for IVF. It, too, faces some significant hurdles, in that nobody has made marsupial stem cells yet, nor has anyone cloned a marsupial—two things that have at least been done in placental mammals (though not pachyderms).

But Pask and Lamm pointed out a number of ways that the thylacine is a far more tractable system than a mammoth. For one, the animal’s survival until recent years means there are a lot of museum samples, and thus Pask says we’re likely to obtain enough genomes to get a sense of the population’s genetic diversity—likely critical if we want to re-establish a stable breeding population.

Marsupial reproduction also makes things significantly easier. A marsupial embryo “places far less nutritional demand on getting to the point of birth,” Pask told Ars. “The placenta doesn’t really invade the uterus.” Marsupials are also born at a stage that’s roughly half-way through embryogenesis for a mammal; the rest of development takes place in the mother’s pouch. In contrast to the in utero years needed by a mammoth, the thylacine may only need a few weeks. The marsupial embryos are also so small at birth that the foster mothers can be considerably smaller than a thylacine; Pask said his group plans to work with a fat-tailed dunnart, which is roughly the size of a small rat.

Even after birth, the thylacines would fit in the dunnart’s pouch for a short period, and Lamm is excited by the prospect of developing an artificial pouch to get the animals from there to the point where they can be hand-reared. If not, some larger marsupials could act as foster parents.

The dunnart isn’t the ideal surrogate, as it’s lineage diverged from that of thylacines several million years ago (compared to well under a million for mammoths and elephants). That means a lot more genome editing needs to be done to dunnart cells to get them to a thylacine-like state. That’s one of the reasons that Pask was excited about the opportunity to team up with Colossal, which is working to develop methods for high-throughput genome editing.

None of this is to say that the thylacine is more or less likely to be revived. Colossal will still face challenges identifying which changes are absolutely essential for producing a thylacine-like animal, and which other changes are needed to ensure the genome will survive all of that category of changes (these compensatory mutations can be essential for allowing species to survive evolutionary changes). Still, most of the risks involved appear to be more manageable in its case.

Keystone de-extinction

Both Pask and Lamm indicated that Colossal and TIGRR agreed on far more than the practicalities. Instead, they emphasized the shared motivation. In their view, both the mammoth and thylacine were keystone species in their respective ecosystems, which have been out of balance as a result of their loss. In this view, restoring the currently extinct species is a necessary step to return the ecosystems to health. Lamm said Colossal identified the thylacine project because it was looking for “species that can restore degraded ecosystems,” and Pask referred to the many changes that followed the reintroduction of wolves to Yellowstone.

The argument’s a bit questionable for the mammoth, as the end of the last glacial period has meant a lot of other changes to its former turf. But Pask emphasized that the thylacine went extinct less than a century ago, and Tasmania hasn’t seen as many invasive species as other areas of Australia, so it would be returning to a minimally disrupted ecosystem. In Pask’s view, restoration of an apex predator like the thylacine would help keep the Tasmanian ecology from degrading.

That assumes that thylacines fostered by some other species will have enough instinctual behaviors that they will perform the same ecosystem functions as their extinct ancestors. “Fortunately, most core animal behaviors are hard-wired—things like hunting and breeding,” Pask told Ars. “We have a wealth of knowledge from hand-reared orphaned animals, from placental and marsupial mammals which have been successfully reared and put back into the environment.”

Restoring the ecosystem would also require introducing the animals to the ecosystem, something that will require both government approval and local acceptance. “Nothing has been done on the scale we are doing with this project,” Pask said, “because of this, discussions are ongoing with governments and all interested parties in these kinds of projects.”

Lots of hurdles

All that, of course, assumes that we eventually have thylacines to set loose, which is far from guaranteed. But overall, it’s a more promising target than a mammoth, given that any iteration on failed attempts can be done in a matter of months, rather than two years. And that represents a major step for Colossal, which has a history of hyping how inevitable the return of the mammoth will be.

Lamm is almost certainly right when he argues that the effort will lead to progress in our ability to do high-throughput, low-error genome editing to manipulate stem cells and to bring cloning to a wider range of animals. It’s just not certain that all that progress will produce a mammoth. Assuming all that technology can be developed, it’s far more likely to produce a thylacine.

Story Source: https://arstechnica.com/science/2022/08/de-extinction-company-sets-its-next-first-target-the-thylacine/

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