Twenty five years ago, Michael Crichton captured our imaginations with the crazy idea that scientists might one day resurrect dinosaurs. But on the eve of Jurassic World‘s release a quarter century later, the prospect of bringing back extinct creatures is looking a lot less science fictional.
We’ll probably never bring back Tyrannosaurus rex. (Mosquitos with perfectly preserved dino DNA in their guts are a bit like magical leprechauns, though scientists did recently discover what they believe is dinosaur blood in fossils). But for species we’ve driven extinct in recent history, from the passenger pigeon to the Chinese river dolphin to the gastric brooding frog and even the woolly mammoth, we may yet be able to reverse time, thanks to incredible advances in genomics and synthetic biology.
In tribute to our undying love for massive reptilian killing machines, and the impossible dream that they will one day rule the Earth again, let’s explore the science of de-extincting life.
Awakening the Dead
On a midsummer’s day in 2003, a group of Spanish and French scientists helped a goat bring a 4.5 pound kid into the world. Normally, a goat birth wouldn’t be worth noting in the history books, but Celia was no ordinary baby goat. In fact, she wasn’t a baby goat at all. She was a Pyrenean ibex, and her kind had gone extinct three years earlier.
Ten minutes after her birth, Celia died, and the Pyrenean ibex was pronounced extinct once more. A necropsy revealed the cause of death: There was an extra lobe in Celia’s lungs, and it was solid all the way through.
Celia’s time in the world was brief, but to the scientific community, the significance of her birth can’t be overstated. With Celia’s birth, the notion of de-extincting life was no longer a pipe dream — suddenly, it seemed very much within reach.
In somatic nuclear transfer, a donor nucleus is injected into an egg emptied of its genetic material.
In many ways, the Pyrenean ibex was a natural de-extinction guinea pig. Hunters had driven the large, mountain goat-like animal to its demise a mere decade earlier, and when the last wild individual (also named Celia) died, samples of her tissue were preserved frozen in laboratories. All scientists had to do was transfer the DNA contained within Celia Sr’s cells into goat eggs emptied of their own genetic material, implant the chimera eggs into a surrogate mum, and hope one would grow and come to term.
They tried over 400 times. Celia Jr’s 10-minute life was the furthest they got.
Halfway across the world, a group of Australian researchers who call themselves The Lazarus Project are now using similar methods to try and restore two other casualties of the human race: Rheobatrachus vitellinus and Rheobatrachus silus, the northern and southern gastric brooding frogs. First discovered in the 1970s, these two species of frogs inhabited tiny patches of pristine rainforest in eastern Australia. But by the early 1980s, both species had vanished, probably due to habitat loss and the introduction of a pathogenic fungus.
During our brief time studying them, scientists learned that gastric brooding frogs have a fascinating reproductive cycle. After her eggs are externally fertilised, the female gastric brooding frog will swallow her embryos whole. A hormone in the eggs triggers the mother to shut off stomach acid production, effectively turning her gut into a womb. After a few weeks of gestation, she regurgitates a slew of tadpoles. The disappearance of this unique mode of reproduction was a major loss to the scientific community — and to natural diversity.
That’s why the Lazarus crew, led by University of New South Wales professor Michael Archer, have spent the last six years trying to bring the frogs back. Similar to the earlier (and cruder) Pyrenean ibex de-extinction effort, Lazarus scientists are attempting somatic nuclear transfer, sucking the nuclei out of gastric brooding frog cells and transferring the genetic material into the live eggs of distantly related barred frogs. The work is slow going, as frog eggs lose their potency after a few hours and can’t be revived. And because of the barred frog reproductive cycle, the scientists effectively have a single week every year to make a real go of it.
In 2013, the Lazarus team announced that they had successfully grown embryos containing DNA of the extinct frogs. But so far, none of the embryos have developed properly. As the Sydney Morning Herald recently reported, Lazarus scientists are finding traces of the host frog’s DNA in embryos where it should have been removed. Archer suspects these two sets of genetic instructions are confusing the embryos and holding back development. Still, the fact that gastric brooding frog DNA is replicating at all inside host eggs is exciting progress, and the Lazarus team isn’t giving up.
Our attempts to bring back the Pyrenean ibex and gastric brooding frog highlight the enormous technical challenges of cloning and reviving lost organisms. And yet, both efforts have focused on a very recently extinct animal, and have been blessed with cryopreserved cells containing high-quality copies of the organism’s DNA.
But others are setting their sights further back in time, hoping now to revive animals that were lost hundreds or thousands of years ago. In these cases, before they can even attempt cloning, scientists face a radically different challenge: Stitching together the lost organism’s genome from ancient, decayed copies.
Passenger Pigeons and Woolly Mammoths
Much as an architect would need floor plans and renderings to rebuild a historic structure, a scientist wishing to revive an extinct organism needs genetic blueprints, in as much detail as possible.
But for creatures that disappeared hundreds or thousands of years ago, finding a perfectly preserved copy of the animal’s genome is nigh impossible. After death, DNA begins to decompose and degrade almost immediately. Even if an creature freezes shortly after dying — one could imagine, for instance, a mammoth in the Siberian permafrost — its DNA will, over time, crack and splinter. (A recent study predicts that even at the ideal preservation temperature of -5C, every bond in a DNA molecule would effectively be destroyed after 6.8 million years, setting a firm upper limit on the ancient organisms we can hope to revive).
Inevitably, paleogeneticists are left with the onerous task of reconstructing the extinct creature’s entire genetic library from fragments, which is essentially analogous to piecing together a book from a copy that went through a paper shredder. How do we even begin to do so?
To find out, I spoke with Ben Novak, a paleogeneticist at Revive and Restore who is currently leading up the effort to de-extinct the passenger pigeon, a famous North American bird whose populations numbered in the billions before humans shot them all from the sky in the 19th century. As a first step, Novak and his colleagues have spent the last few years reconstructing the extinct bird’s genome. Since we don’t have any frozen specimens at all, scientists have had to rely on tissue samples from taxidermy animals housed in museums.
“Passenger pigeon DNA is really fragmented,” Novak told me. “The pieces we get are anywhere from 30 to 150 base pairs in size.” To give you an idea of what this means, a base pair represents a single letter in the DNA code. The entire passenger pigeon genome contains 1.3 billion of them.
“We don’t get anything big, and it’s very, very difficult to piece any of that together, because not only is it short, it’s riddled with false mutations from damage,” he added.
And yet, the speed and accuracy of our DNA sequencing technology has advanced to the point where we’re able to take the many reads needed to spit out all the sentence fragments in a broken genome. But to put the pieces back together, scientists need a reference genome — a very similar book that will serve as a guide. This past March, Novak and his team completed genomic sequencing for the band-tailed pigeon, a close living relative of the passenger pigeon that differs in roughly 3 per cent of its DNA. Using the band-tailed pigeon as a map, they have successfully reassembled several complete passenger pigeon genomes.
Getting the passenger pigeon’s genetic code written and pieced together was an enormous achievement, but still, it’s only the first step toward a much larger goal. To find out what parts of the genome encode for meaningful passenger pigeon traits, the team’s next goal will be to look at RNA — transcript copies of genes that cells use to make proteins. Once they have sequenced the band-tailed pigeon’s entire RNA library, or transcriptome, they can use to the information to identify important genes within the passenger pigeon genome.
“That’s when we start doing the fun preparations for trying to make a bird,” Novak told me.
Unlike the Pyrenean ibex or gastric brooding frog, scientists aren’t going to be able to stick the entire passenger pigeon genome inside a host egg. Bird eggs are enormous, not to mention that they’re enclosed in a hard outer shell. Novak compares removing the tiny, DNA-containing nucleus from a bird’s egg to finding a white marble in a vat of milk. And inserting a new nucleus containing other genetic information is another can of worms entirely.
The process Revive and Restore plans to use to make hybrid birds with passenger pigeon traits
Instead, the current plan is to use CRISPR gene-splicing technology to cut out pieces of band-tailed pigeon DNA from germ cells and hack in the corresponding passenger pigeon traits. In this manner, scientists can create hybrid cells containing all the important genes that distinguish the passenger pigeon from its close cousin. Hybrid cells cooked up in petri dishes will then be injected into the bloodstream of developing band-tailed pigeon embryos, where they will eventually migrate to the gonads. After the eggs hatch and the squabs mature, some of their eggs or sperm will contain the instructions for an animal that looks a lot like a passenger pigeon. Another generation of captive breeding, and a small number of passenger pigeon-like individuals could be born.
Nothing like this has ever been done before, and nobody’s quite sure how it will all go down. But the passenger pigeon isn’t the only animal we’re trying to hack back into existence one gene at a time.
Similar efforts to revive the wooly mammoth are moving full steam ahead. In April, a team of researchers at McMaster University’s Ancient DNA Center published the most complete wooly mammoth genomes to date representing two individuals whose remains were buried in the Siberian tundra 40,000 years apart. Meanwhile, Harvard geneticist George Church and his colleagues are busy using CRISPR to splice genes for mammoth ears, subcutaneous fat, hair length and colour into the DNA of elephant skin cells. These chimera cells, while a far cry from a bonafide mammoth, show that the dream of recreating the iconic Pleistocene elephant is very much alive and kicking.
We Can De-Extinct, But Should We?
Worst case scenario. Worst case.
Bringing back a single individual from an extinct species would be an incredible achievement. Our course, at least two animals are needed to breed, and in theory, we’d like to have many more, each contributing some amount of genetic diversity to the population. The fewer unique individuals we start with, the more likely we are to end up with a race of genetically-impoverished clones.
Scientists in the de-extinction game are not insensitive to this problem, but the amount of genetic diversity we can theoretically infuse depends on a number of factors, including how many unique versions of the extinct organism’s genome we have access to. For the passenger pigeon, several complete genomes have now been sequenced, which scientists can scour for genetic mutations. When creating hybrid germ cell lines, they can intentionally introduce different versions of genes where diversity exists. Novak is hopeful that Revive and Restore can create an initial breeding stock with enough diversity to eventually produce a healthy passenger pigeon population.
For other extinct creatures, a single clone, or a handful of very genetically similar individuals, might be all that’s in the cards. Which begs another question that every scientist involved with de-extinction efforts today has to grapple with: Is all of this effort really worth it?
Why bother to bring Celia’s clone back into the world, when she’ll never have a male Pyrenean ibex to breed with? Why go to pains to reconstruct a mammoth gene by gene, if the chimera population is doomed to be a shadow of its former self?
Critics of de-extinction often argue that reviving lost species takes money and intellectual resources away from efforts to save those we’ve still got. Fair point, especially given the depressing truth that human activity has driven the rate of species disappearance a thousand times above background, pushing us headlong into a sixth mass extinction.
But Novak and his peers counter that some of the methods they’re honing through de-extinction efforts, including cloning and infusing cell lines with gene diversity, might be co-opted to help restore genetically impoverished populations. Indeed, along with its efforts to bring back the passenger pigeon, Revive and Restore is researching black footed ferret genomes. In the future, the company hopes to use “genetic rescue” techniques to help fortify the black footed ferret with mutations that were lost when the population dwindled to a mere seven individuals.
What’s more, many of the species that have gone extinct in recent human history provided vital ecosystem services while they were living. Bringing them back might be an important step toward restoring human-altered ecosystems to something akin to their natural state.
“All of the biodiversity in forests of North America co-evolved with huge flocks of billions of passenger pigeons over thousands and thousands of years,” Novak said. “Getting these birds back into the forest is going to be a part of making productive, bioabundant ecosystems that are more adaptable to climate change. It will make the management and conservation of other species easier for human beings.”
More saliently to the Jurassic Park-loving public, the idea of de-extincting life inspires wonder and awe. We may never see live herds of brachiosaurus stampede across a tropical island, but the technology to reproduce a 40 thousand-year-old Pleistocene mammoth is now within reach.
I don’t know about you, but I think a herd of mammoths stamping across snowy northern Canada would be a pretty cool thing to see.
Picture: Wikimedia, Shutterstock, Universal City Studios, Amblin Entertainment