Colossal Biosciences responds to criticism of the Dire Wolf “de-extinction”, but not convincingly

Colossal Biosciences®, of course, recently announced the “de-extinction” of the dire wolf, which involved editing a gray wolf genome in 20 places (DNA bases), all edits involving 14 genes.  15 of the 20 sites change apparently involved substituting dire-wolf based for wolf bases, while the other five, mainly involving coat color, were simply mutations already known to lighten the coat color in dogs and wolf, and the edits were based on dogs and wolves. These five edits made the dire wolf pups turn out white, though we’re not sure that the original dire wolves were white.  As for the other changes, well, we’ll have to see how they affect the three “dire wolves'” morphology when they grow up, as they’re just subadults now.

In the end, though—and I think Colossal should agree—they produced three gray wolves (Romulus, Remus, and Khaleesi), each with 15 DNA bases taken from a sequenced dire wolf genome.  This means that, because the wolf genome has nearly 2.5 billion base pairs, and because are over twelve million DNA base-pair differences between the dire wolf and gray wolf genome, there were tons of dire=wolf genome that was not edited into the egg used to produce the three faux dire wolves. A quote from Vox (archived here):

“The grey wolf genome is 2,447,000,000 individual bases (DNA letters) long. Colossal has said that the grey wolf and dire wolf genomes are 99.5% identical, but that is still 12,235,000 individual differences,” Nic Rawlence, a paleontologist at the University of Otago in New Zealand, told me in an email. “So a grey wolf with 20 edits to 14 genes, even if these are key differences, is still very much a grey wolf.”

Those 15 edits, then, constitute 0.0000012 of all differences between dire wolves and gray wolves, or .000012%.  As many science journalists have noted, Colossal has not produced anything close to a dire wolf, but simply a gray wolf containing a tiny, tiny fraction of the genes that differentiate the two species. Some of the genes they used may have been published in Colossal’s new preprint on the dire wolf (see below), but it gives little information about which genes they used. They clearly didn’t use genes that differentiated the physiology, digestion, or any behaviors that differentiated the two species, because those genes can’t be identified.  Yet surely if you want to “de-extinct” a species, you need more than just a few superficial changes in appearance to “resurrect” the extinct one. Well, that is apparently not Colossal’s view.

Much of the press around the Dire Wolf has been critical, with the exception of places like Time Magazine, which put one of the offspring on the cover with a photo and the word “extinct” crossed out (along with a photo saying “This is Remus” He’s a dire wolf”). But genuinely savvy journalists didn’t have to dig hard to find the hype in Colossal’s claims, some of which I myself pointed out at ABC News. I’d say that about two-thirds of the press stories have been sufficiently critical to raise doubts in the minds of readers.

That has clearly upset Colossal, which of course expected huge approbation and thje public’s acceptance that they had truly “de-extincted” the dire wolf. Instead they got the press kvetching about the company’s hype. (Granted, Colossal did accomplish good stuff like sequencing the dire wolf genome and making twenty edits to a gray wolf cell, which is a technical accomplishment although making multiple edits is pretty routine these days). What seems to have most upset Colossal and their chief scientific adviser, Dr. Beth Shapiro, is criticism of the claim that they had created a “new species” in the lab (the “dire wolf”) of course.

To evolutionary biologists who employ the “Biological Species Concept” (BSC)—one of over 20 such concepts, but the one, as I argue in my book Speciation with Allen Orr—the concept that makes the most evolutionary sense—the “dire wolf” is almost certainly not a new species.  If it were, it would be reproductively isolated from gray wolves (and dogs), so that if they were to cohabit in the same place, they could not produce fertile hybrids.  But I bet ten to one that if you put a bunch of grey wolves in the secret hidden pen where the three “dire wolves” are kept from prying eyes and are monitored by drones, they’d all hybridize and produce fertile puppies. End of the “new species” story.

Sadly, Colossal won’t do that experiment. But it doesn’t matter because Colossal has rejected the BSC in favor of the morphological or typological species concept, in which individuals are said to belong to different species because they look different.  This concept is next to useless because it’s completely subjective: how different do individuals have to look before they’re put in different species? (The evolutionist Ernst Mayr discussed the intellectual vacuity of morphological/typological species concepts beginning in 1942.)

Granted the BSC has its own problems (what do we do with geographically isolated populations who do not have the opportunity to interbreed?), but, as we show in our book, it does a lot of biological and evolutionary work, including giving us a research program for how species originate: why nature is lumpy instead of being a continuum. (The question of “What is the origin of species?” becomes “How do reproductive isolating barriers evolve?”, a question that is actually how people approach the origin of species when they do research.)

It’s clearly in Colossal’s interest to adopt the morphological species concept because they say they’ve produced an animal that looks different from gray wolves in a few traits. And so they can shout “We’ve got a new species!” from the rooftops. But many people aren’t buying it, and so this week Colossal sent out a press release to inquisitive reporters, which I quote below. It’s quite defensive! Bolding is mine.

We’ve been hearing critics call us “insane” for labeling Romulus, Remus, and Khaleesi “dire wolves” instead of “designer dogs” or “fancy gray wolves.” While we didn’t anticipate this would become the major talking point for a breakthrough in genetic engineering that will fundamentally transform biodiversity conservation, fine. Let’s go.

So many experts out there are demanding that species are defined solely by their DNA. That’s some version of “insane”. Even evolutionary biologists can’t agree on species definitions. Mammoth species? Defined by teeth ridges. Ancient bison? Horn shapes. And so arbitrarily that someone accidentally mixing up length and width measurements had zero impact on species classification. Brown bears and polar bears, humans and Neanderthals, wolves and coyotes are all different species unless you apply the most commonly taught species concept, which would classify them as the same species because they can interbreed and produce healthy, fertile offspring.

Getting dragged into arguments about species definitions is a distraction from the real achievement. This is the most significant advancement in gene-editing in history. Even our harshest critics admit it. As one of our founders stated, “this is the moon landing of synthetic biology.” Colossal identified 14 genes we could modify to resurrect the key traits that defined dire wolves, and then we did it. Why is the scientific community wasting time bickering about species concepts rather than celebrating this monumental achievement and its implications? It’s obvious most critics would rather complain than contribute. Through our dire wolf and woolly mouse announcements, Colossal has generated more attention and funding for conservation than anyone has in decades. That’s the kind of “insanity” the world needs.

We invested over a year collaborating with academic colleagues to improve the dire wolf paleogenome and decode the dire wolf’s evolutionary history. Our scientific manuscript has been submitted for peer review and posted to the preprint server–please go check it out. We generated high-quality ancient genomes from dire wolves that lived 13,000 and 72,000 years ago. Our analyses show that dire wolves interbred extensively with the lineage that ultimately evolved into gray wolves, suggesting that dire wolves and gray wolves are much more closely related than previously thought. This is contrary to the “scientific fact” that they were closer to jackals, which originated from a science writer’s misinterpretation of the previous paper. Our higher quality genomes allowed us to uncover the evolutionary history of dire wolves and dig more deeply into the genes under selection in their lineage. These discoveries enabled us to resurrect the traits that made dire wolves larger, stronger, and phenotypically unique: traits that are now embodied in Romulus, Remus, and Khaleesi.

Why did we stop at 14 genes and 20 edits? Because we didn’t need more and because we prioritize animal welfare. Every modification carries risk, and our primary goal was creating healthy animals with extinct traits. We meticulously evaluated each edit for safety and successfully birthed healthy animals that both resemble dire wolves and manifest the traits we targeted. Now critics are having meltdowns because we didn’t make hundreds or thousands of unnecessary, risky edits just to satisfy one particular interpretation of what constitutes a species? No thank you.

Yes, dog breeders have been transforming gray wolves into the animals that we rely on for work and companionship for thousands of years. Maybe tens of thousands. But the ability to dramatically alter an animal’s appearance and behavior in a single generation? That’s new. The implications for conservation are immense. This is the future. Show us what YOU’RE doing to ensure a world with wolves, poodles, pandas, whales, and (assuming agricultural advances) billions of humans. We’re convinced our brand of “insanity” is exactly what’s needed to get there.

We get it. We totally understand that some scientists are not comfortable calling these dire wolves because they feel like the wolves are not sufficiently genetically similar to a particular extinct individual to merit that name. That’s ok with us.  This is not a fight that we care about. We’re calling them dire wolves, and if you prefer something else (how about “Colossal’s dire wolves”?) that works too. And maybe also take a breath and think about what the birth of these technologies means to the future of our planet instead of nitpicking terminology.

That last sentence is pretty hostile, but reflects a certain defensiveness of Colossal about its achievements that does it no good. Will people like Paris Hilton, Tiger Woods, and Peter Jackson, who gave big donations to Colossal, think twice about what they funded. (Probably not; they’re rich as Croesus.) Colossal is saying, “we’re helping the environment; what are you doing?”

I’ve bolded two bits above. The first is their paper on the “dire wolf”, submitted for publication, which you can find on bioRχiv by clicking on the title below (download pdf here.) . The paper doesn’t say which edits were made from the dire wolf genome into the wolf genome, but that’s irrelevant when assessing if they’ve “de-extincted” the dire wolf.  It’s largely about phylogenetics, and shows that the dire wolf and gray wolf are separated by about 4.5 million years. It also gives the names of 80 genes whose DNA sequence shows that they seemed to be under positive natural (including sexual) selection in the dire wolf, and perhaps some of these genes were used in producing the faux dire wolf.  Note that they also claim they changed the behavior of the gray wolf through their edits, but I have seen no evidence of  that.

The second bit is their defense of using a morphological species concept. It’s clear that Shapiro and Colossal are buying into a morphological species definition that’s something like: “If we edit the genes of a living species so it superficially resembles an extinct species, having a few of its traits, then we’ve “de-extincted” the extinct species. Below they refer to the IUCN, the International Union for  the Conservation of Nature, a worldwide organization devoted to conserving habitat and species. They say they are using the IUCN’s definition of “de-extinction:, but they leave out the caveats that IUCN attaches to that word (it prefers “proxy”). This is unconscionable cherry-picking in defense of misleading scientific results.

When I posted on Twitter about the critical ABC News piece on de-extinction, because I was quoted, I got a comment from, of all people, the concerned scientists at Colossal:

The IUCN defines de-extinction as, “the process of creating an organism that resembles an extinct species.” That is not our definition, it was written by an international team of scientists in 2016, and it accurately describes the dire wolf project. Read More