Scientific Resurrection
Even before the dawn of civilization, many species went extinct, usually from a mix of climate warming at the end of the Ice Age, and over-hunting or competition with early human populations.
As this happened “only” 10,000 years ago, this means that these recently extinct species left bodies, especially in cold regions, with still-recoverable DNA. So while the Jurassic Park idea of finding dinosaurs’ DNA will likely remain science fiction, some extinct species could potentially be revived.
And that’s precisely what a biotech company called Colossal Biosciences claimed to have achieved with an extinct species of wolf: The dire wolf.
The animal has been extinct for 12,500 years and became a popular “mythic” animal thanks to its central role in G.R.R. Martin’s fantasy story and the HBO series Game of Thrones.
Of course, Colossal realized the PR potential here and got the freshly “resurrected” dire wolf puppies in a picture with the famous author, as well as naming one of the wolves after a character in the books.
“We’ve made three dire wolf puppies. There’s Romulus and Remus, which are five months old and around 80 pounds. They’re beautiful.
Then there’s Khaleesi, a little over six weeks old. She’s a baby, our first girl.”
But are these animals really dire wolves? And what does this mean for the future of wildlife conservation, as well as other ambitious plans by Colossal to next resurrect the woolly mammoth?
Dire Wolves
Maybe the most surprising thing about dire wolves is that, technically, they are not wolves at all. While part of the Canidae family and Canina subtribe in evolutive classification, it is its own genus: Aenocyon (meaning “terrible dog”), while “normal” wolves are part of the Canis genus.
Source: Thallaso Atrox
The dire wolf was about the same size as the largest modern forms of gray wolf, and sometimes larger, with some unique morphological features: smaller feet, larger head, likely adaptations to hunting the arctic megafauna of the time.
This larger head and larger teeth gave the dire wolf a bite power 20% stronger than even the strongest wolves and dogs today.
Source: The Armory
While the cause of their extinction is debated, the scientific consensus is that it stemmed from a mix of the impacts of climate change and competition with other species, including overhunting by human hunters newly arrived in North America.
Colossal De-Extinction Process
De-Extinction Goals
Bringing back the dire wolf, or a dire wolf-like creature (more on that debate below) is not the first genetic engineering feat for Colossal.
A month prior, the company released news of the newly created “wooly mouse”. These test mice received seven different genes coding for the woolly mammoth’s wooliness through a complex and very advanced multiplexed genome engineering technique.
Source: IFL Science
These genetic manipulations do not cover only the superficial esthetic aspect of the fur coat, but also resistance to cold and change in the animal’s lipid metabolism that will be required to turn a tropical-living elephant into an arctic-living “de-extinct” mammoth.
Source: IFL Science
Colossal was also previously involved in an effort to help prevent the extinction of red wolves, of which only 16 still live in the wild, all in a rural five-county section of northeastern North Carolina. However, the fact that these animals were more coyote-red wolf hybrids than “real” red wolves makes it a controversial take among conservationists.
How It Works
The basic idea of de-extinction is to analyze the DNA of the extinct species and compare it to still-alive species that are closely related.
“Colossal has de-extincted the dire wolf. We took a 13,000-year-old tooth, a 74,000-year-old skull, and made puppies, and then we also used some of that same tech to help save the red wolves, which is really exciting.”
Colossal Biosciences CEO Ben Lamm
The company defines the de-extinction process as the convergence of three ideas at once:
- Bringing back the key genes that gave the extinct species its unique features.
- Helping the brought-back species to adapt and survive to current environmental conditions with other genetic modifications.
- Engineer resistance to diseases and other threats to make the species viable in nature.
Source: Colossal
This requires more than just genetic engineering, even if it is the core of the project, with CRISPR-Cas9 the most important tool for Colossal.
The company also has to properly deploy AI & machine learning to handle very complex biological data, something it expects to be able to monetize in other fields in the future.
In addition, good handling of embryology (the science of embryo development) is required to successfully implant the modified eggs in the “surrogate” mother that will carry to term the new species, be it wolf or elephant.
Does It Reverse Extinction?
Biologists and conservationists worldwide are debating if what Colossal is doing is really useful or even at all bringing back dead species.
The core of the issue is the definition of a species. In the early era of biological sciences, any animal looking like a given species (phenotype) would have been considered as part of that species. However, a modern understanding of genetics makes it clear that the genetic diversity of another species is much greater than just looks.
So while 20 genetic differences identified by Colossal can make the new puppies look like dire wolves, from a genetic point of view, they are just gray wolves looking like dire wolves, not “real” ones.
“Ancient DNA is like if you put fresh DNA in a 500-degree oven overnight. It comes out fragmented – like shards and dust. You can reconstruct it, but it’s not good enough to do anything else with.
The animals are “genetically modified gray wolves. So what Colossal has produced is a gray wolf, but it has some dire wolf-like characteristics, like a larger skull and white fur.”
Zoologist Philip Seddon and Paleogeneticist Dr. Nic Rawlence from the University of Otago in New Zealand for BBC
Still, these criticisms ignore that this is a major achievement and that, ultimately, even more genetic diversity could be achieved through that technology.
Why Attempt De-Extinction?
Colossal is very much looking to draw a parallel to the Apollo mission, claiming their de-extinction efforts are just a stepping stone in a much larger and more impactful revolution from genetic engineering.
Like the Apollo program, the scientific efforts at Colossal make ongoing contributions to the scientific community. Today, we too are within reach of another massive scientific breakthrough, one that will create a positive impact on the long-term health of Earth and its inhabitants, both past and present, as we look forward to rewilding the future.
However, these ambitious goals do not answer the question of what to do with newly resurrected species (or invented depending on the definition you use). Should they be released in the wild, without knowing the benefits or risks it could cause the affected ecosystems and local species?
At least for now, the focus of the company on large animals means that any mistake could likely be solved by hunting them down. However, the same technology applied to insects, marine animals, or plants could cause untold and irreversible ecological damages, akin to introducing invasive species to new habitats.
Another source of ecosystem variety stems from our new technologies to de-extinct lost genes, including deep ancient DNA sequencing, polyphyletic trait analyses, multiplex germline editing, and cloning. The dire wolf is an early example of this, including the largest number of precise genomic edits in a healthy vertebrate so far. A capability that is growing exponentially.
George Church, Ph.D. / Colossal Co-Founder
Future Applications
Resurrected Species
So far, Colossal seems focused chiefly on resurrecting the woolly mammoth as the emblematic project of the company.
Colossal analyzed 59 woolly, Columbian, and steppe mammoth genomes ranging from 3,500 to over 1.2 million years old, and used computational analysis to compare a data set of 121 mammoth and elephant genomes, including the high-quality reference genomes for Asian and African elephants the company previously created.
It could also turn into an interesting business model for the company, allowing it to raise mammoth for tourism or even meat production perspective, a monopoly on which it could likely ask for premium prices.
Source: Colossal
Other species are also in plan, notably the dodo birds and the Tasmanian wolf / Tasmanian tiger / Thylacine.
However, it is likely that, to some extent, the dire wolf and the mammoth projects are essentially just learning experiences and PR for Colossal.
The company’s scientific push is led by George Church, who was a pioneer in genomic sequencing methods, chip-based DNA libraries, genome editing, and stem cell engineering.
Improving Existing Species
The way elephants can be adapted to live in cold climates, cattle, and other farm animals, as well as crops, could be adapted through genetic engineering for higher yields or better resilience.
Colossal’s four primary labs are already working on such themes, as they are targeting “precision livestock solutions” and sustainable agriculture practices.
Source: Colossal
In the long term, this concept could be pushed even further to engineer de-facto new species for specific human purposes. For example, neo-species could produce silk proteins in plants or in animal fur, human medicines in fruits, etc.
Bioengineered Depollution
Colossal is also looking into the potential of plants and other organisms to reduce pollution. This includes environmental remediation, but also plastic-eating bacteria, with a spin-off company previously incubated at Colossal’s labs: Breaking.
In collaboration with Harvard / Wyss Institute, Breaking engineered MICROBE X-32™, which could potentially speed up the degradation of all existing types of plastic.
Biotech Tools
In order to succeed in creating the dire wolf and maybe the mammoth, Colossal needed better bioinformatics tools, notably for processing and interpreting large-scale biological data.
They also push further the technology of DNA barcode multiplexing, which allows for the simultaneous identification of multiple genetic markers.
Medicine & In-Silico Tools
Colossal has applied its expertise in CRISPR-Cas9 gene editing to create better disease models in animals and cell cultures, which are useful for researchers and speed up medicine development.
This includes gene therapy using a virus (AAV) as a vector, with a company spun off from Colossal to commercialize the progress on this technology, FormBio. FormBio uses AI and machine learning for cell and gene therapy candidate validation and makes manufacturing AAV medicine more efficient and accessible.
Regenerative medicine could also benefit from the company’s discoveries in embryology and in vitro fertilization (IVF), which could lead to applications in tissue engineering, stem cell research, and organ transplantation.
Conclusion
Beyond the debate arguing if Colossal’s dire wolves are a true resurrection of an extinct species or the wisdom of releasing such creatures in the wild, the technological achievement of the company is impressive.
Between dire wolves and woolly mice, they seem to be able to somewhat routinely modify the genome of animals in double-digit locations, radically changing their metabolic activity and body structure.
This ability will likely have tremendous applications in other fields, with husbandry and farming the most obvious candidates.
Beyond animal modification, the technology used here can be deployed to bioengineer new plants, microbes, and other organisms to solve specific issues, like, for example, plastic pollution.
In the process, Colossal has also developed a powerful tech stack of viral vectors, bioinformatic solutions, AI & machine learning, and cell manipulation that could be deployed to many other sectors, from gene therapy to disease models and organ transplantation.