Scientists in several countries are engaged in dedicated projects to bring extinct animals back from the dead — from the thylacine to the woolly mammoth, the passenger pigeon to the gastric-brooding frog.
So far, no team has managed to pull it off.
Research groups like California-based biotech and conservation company Revive and Restore have been working for years to de-extinct the mammoth and passenger pigeon, without yet realising their goal.
In Australia, thylacine de-extinction research has started and stopped, and recently started again with a $5 million philanthropic investment for the University of Melbourne.
Are "de-extinction" projects throwing money at science fiction, or is there genuine hope of being able to see animals like the thylacine once again roaming the wild?
What's the theory behind the science?
There are broadly three approaches to de-extinction — genetic engineering, cloning, and back-breeding.
For cloning to work, you need a preserved cell or full set of chromosomes from the extinct animal, so that's no good for things like the mammoth and thylacine.
Back-breeding is essentially selective breeding like we have done with dogs, where you mate animals to produce certain characteristics — in this case, the characteristics of the extinct animal.
That's only an option where you have a living species that is very similar to the extinct one, so again no good.
Which leaves us with genetic engineering.
The first step in the genetic engineering approach is to sequence the genome of the extinct animal — that means working out the order of the "base pairs", the building blocks of its DNA.
For the thylacine, this was done in 2017 by a team of scientists including Andrew Pask from the University of Melbourne.
"We had one of the [thylacine] babies from the Melbourne Museum that was a baby taken from a mother's pouch and dropped straight into alcohol," Professor Pask says.
When Professor Pask's team sequenced the genome in 2017, it was the most intact genome ever obtained for an extinct species — thanks to the swift preservation of the baby thylacine.
So we've sequenced the genome, what next?
So does that mean we're ready for de-extinction? Not so fast.
When animals die, their DNA becomes fragmented, or broken up, into shorter strands.
The more deteriorated an animal's DNA, the more likely it is to be in many pieces.
Genomics researcher Tom Gilbert from the University of Copenhagen explains it as similar to a book that's been put through a shredder.
Your goal is to put the book back together, but you don't have any reference for what it's supposed to look like when you're done.
"And [then] I ask you to tell me what's going on."
You know the order of the words in the fragments, but not the order of the fragments in the book.
Add in the most recent common ancestor
Researchers think they can use the complete genome of a closely related living species as a kind of template to figure out how the pieces of the extinct genome fit together.
In the case of the thylacine, that living species is the numbat.
It's estimated that 95 per cent of the numbat's DNA is the same as the thylacine, and earlier this year a group called DNA Zoo Australia, based at the University of Western Australia, completed a "chromosome-length 3D genome map" of the numbat's genome.
"We have been trying to build the base which will enable the genetic rescue of existing species," DNA Zoo Australia director Parwinder Kaur says.
The idea is that they can first line up the matching 95 per cent of the two species' DNA, and then try to work out where the remaining 5 per cent of the thylacine DNA fits into the puzzle.
Some of this can be done by finding short lengths of matching base pair sequences, which might indicate a starting point where a longer fragment that has varied through evolution can slot in.
If they can map the complete thylacine genome, CRISPR technology can be used to alter the DNA in a numbat cell, to code for thylacine.
The process is already underway with the mammoth.
American geneticist George Church is heading a team that has identified more than 1,600 protein-coding genes that differ between the extinct woolly mammoth and living Asian elephant.
They've identified the genes they believe define the most significant mammoth traits — like long hair and raised forehead — and have begun the process of alteration.
Last year, they launched a new company with millions of dollars in private backing, and say they plan to birth a mammoth-elephant hybrid by 2027.
Similarly, the Revive and Restore group has set the ambitious target of 2025 to "hatch the first new generation of passenger pigeons".
In the 1800s, passenger pigeons were one of the world's most abundant birds, with flocks in the millions said to have blackened North American skies.
But hunting and habitat loss sent the species crashing. The last bird died in captivity in 1914.
If successful, these will be hybrids though, and critics say while they may look similar, they'll lack the functional traits that made their extinct counterparts valuable to their respective ecosystems.
So what's the hold-up?
Professor Gilbert's team published research earlier this month looking at the potential to use the Norway brown rat to de-extinct the Christmas Island rat, which diverged about 2.6 million years ago.
However, they ran into two key issues.
Firstly, current gene-editing technology is only able to introduce up to a few hundred edits per cycle.
In the Norway brown rat and the Christmas Island rat, there were more than 128 million base pairs (the building blocks of DNA) that differed.
If the idea is to edit every single differing base pair, it would take a prohibitively long period of time with current technology to make all the modifications necessary — tens or even hundreds of years.
The second problem is much harder to overcome, Dr Gilbert says.
When the researchers tried to map the Christmas Island rat genome to the Norway brown rat, they found more than 4 per cent of the genome didn't line up.
Basically, where they had very short strands of the extinct rat's DNA, and it had significantly changed via evolution from the living rat's DNA, there were no common reference points to figure out where things went.
"When we sequence all the short fragments, and computationally compare them to the modern rat genome, we can match [95 per cent] and thus work out what is going on," Professor Gilbert said.
One option would be to simply leave the missing pieces as Norway brown rat genes, and only change the genes that we know are Christmas Island rat genes.
The problem there, according to Professor Gilbert, is the missing pieces are likely to be some of the genes that make the Christmas Island rat unique.
"I would suspect that the parts of the genome that are most divergent, [and] thus have been under the most evolutionary pressure, are those most critical to how it adapted to live on Christmas Island," he says.
"So I would argue that the bits we miss are probably the most important if the end goal is to create the thing that was able to exist in the natural environment on Christmas Island."
On the other hand, the outlook for the thylacine is promising
Like Professor Gilbert's shredded book analogy, Professor Pask likens trying to piece together the genome to doing a puzzle without having a picture on the box as a reference.
But he says the thylacine de-extinction program has a big advantage over the Christmas Island rat research.
"We're different from the Christmas Island rat example because they had very fragmented DNA," he says.
"So that takes it from a million-piece puzzle down to a few thousand [pieces]."
And it's not being done manually. Machine learning can help speed up the process.
If they can successfully map the thylacine genome, the process from there is basically cloning.
Of course that's been done already with sheep, but it's more complicated using a different species as a surrogate to carry the embryo.
Still, Professor Pask says as technology improves, it's a matter of when, not if, we'll see thylacine de-extinction succeed.
"At the moment we're looking to understand the scope of all the edits we'd have to make for our surrogate animals," he says.
"We definitely have all the technology at hand, it's just that it would take a very long time to do it at the moment."
Dr Kaur is similarly upbeat about the prospects for de-extinction.
"[It's] going to become a very routine thing in the next decade or so," she says.
"I can see around me the technology on de-extinction is advancing so fast."
Finding a balance between de-extinction and conservation
But there are plenty of scientists more sceptical about the chances of success, and less enthusiastic about spending money on bringing back species when we're still driving others to extinction.
Professor Gilbert thinks researchers should refer to his work on the Christmas Island rat before they start pouring money into a project, but he's not against the idea in theory.
"I love the idea technically," Professor Gilbert says.
"But if there was only one pot of money and it had to go to either conservation or de-extinction, I'd go conservation."
Professor Pask says de-extinction research can be used to provide resilience against diseases like the Tasmanian devil facial tumour, and can help ensure no living species ever goes extinct again.
"One of the main reasons I really love this project is because everything we're developing to bring back the Tassie tiger we can use to benefit marsupials now."
Dr Kaur agrees, but says funding for de-extinction needs to come from the private sector, and we can't lose sight of the bigger conservation picture.
