Boston, Massachusetts 2021-09-13 10:00:56 –
Harvard scientist George Church, a pioneer of both DNA sequencing and gene editing, has been talking in the press for more than a decade about the possibility of bringing the extinct woolly mammoth back to life. It’s been the subject of magazine articles, books, and, of course, a TEDx talk.
Now, it is the focus of a company. Church and his colleagues announced Monday that Colossal, a startup focused on “de-extinction,” had raised $15 million for a project that involves CRISPR technology to genetically reengineer Asian elephants to be more like mammoths. Billionaire Thomas Tull, best known for founding a film production company that backed the “Batman” movies and “Inception,” and Silicon Valley venture capital firms Breyer Capital and Draper Associates are among the backers.
“Very little has happened directly on the mammoth because we’ve had so little funding,” Church told STAT in an interview. “We had less than $10,000 a year, which is unimaginably small for this kind of project.”
The new funding, though small by the standards of the current biotech boom, is likely to force investors, policymakers, and the biotech industry to engage more directly with what has until now seemed an idea closer to science fiction than reality. But there is, even by Church’s own admission, plenty of time. Despite the bold-type declarations in Colossal’s press release — “woolly mammoths will walk the Arctic tundra again” — the planned project will take years: six years, Colossal guesses, until a calf might be born, and another 10 to 12 for the calf to grow to maturity. The $15 million is probably enough, Church said, to get to an embryo — to get a calf more money will need to be raised.
Church and the team behind Colossal are adamant that the idea is not just to make one mammoth, or to make a zoo, but to release whole herds, so that the large grazing mammals can remake the Arctic tundra, which poses a real threat when it comes to climate change. As the permafrost melts, it will release huge volumes of methane, a potent greenhouse gas, into the air. But by knocking down dark, sunlight-absorbing trees, mammoths, (or even cold-adapted elephants) would transform the tundra into light-reflecting grassland that keeps the ground colder, locking in the methane and creating a lot of plant matter to lock up carbon, too.
Which is a huge, George-Church-sized idea that faces, well, mammoth hurdles.
Outside experts, and even some working with the company, greeted the effort with a mixture of excitement and skepticism about the scientific project, and also about Colossal’s business plan; the company hopes to profit not off the mammoths but off of all the technology that will be created in developing them.
“I’ve got mixed feelings,” said Hank Greely, director of the Center for Law and the Biosciences at Stanford University. “Part of me hates the hype in this. But I do think de-extinction is an interesting idea and may well be a useful and worthwhile thing to do. It’s not the answer [to problems like climate change]. It’s not high on my priority list. But it’s cool. And you know, humans do a lot of things just because they’re cool.”
David DeGrazia, a philosopher known for his thinking on animal ethics, was far more critical, framing it as an issue of animal rights. “Elephants are not just sentient creatures. They’re really smart, they are really self-aware and emotionally complex. I don’t think we should involve them in experiments that are not in their best interest,” he said, though he added he would need more information to be certain in his conclusions about potential harm to the animals.
The woolly mammoth is most closely related to the Asian elephant, differing by about 1.4 million DNA letters. That results in changes to more than 1,600 protein-coding genes, though Church said that he thinks only about 50 of them would have to be edited to get an animal that’s adapted to living at minus-40 degrees Fahrenheit for long periods of time. “We’re prepared to do more,” he said. “We don’t know exactly, frankly, what that [number] is.”
Greely said he was surprised the firm decided to focus first on the mammoth, with its 22-month gestational cycle, rather than a smaller extinct mammal, of which there are dozens of rats, mice, and other rodents to choose from.
But to Church, such a long gestation could be considered a feature. If the project were to end up creating a hairy, elephant-sized invasive species — the equivalent of the ecosystem-wrecking cane toads introduced in Australia to combat cane beetles, or the Galapagos Islands’ goat herds — at least there would be a built-in safeguard against runaway reproduction. Plus, Church pointed out, elephants are hard to miss. Greely suggests that if the animals proved problematic, they would likely end up in zoos or Pleistocene parks — a likelihood anyway, because people would pay to see them.
At this point, if you’ve been doing the math, you may be wondering how Colossal plans to build up whole herds of animals on a time frame that allows its 67-year-old founder to live to see them. For this, Church has a plan. It doesn’t involve shortcutting the gestational cycle, but rather, creating scale by eliminating the need for natural, elephantine surrogate mothers.
Church’s lab recently published a massive library of transcription factors — the recipes for nudging pluripotent stem cells into becoming almost any type of cell. “We’ve now made endometrial cells and endothelial cells, which is enough to get a vascularized landing pad for the embryos,” said Church. The plan is to use these cells as artificial wombs to incubate the embryos through their 22-month development.
“In principle, one could make 100,000 at once over two years,” said Church. “I’m not saying that’s what we’re going to do, but it’s not necessarily a technical barrier, it’s more financial and willful.”
Even getting to the viable embryo stage, though, Greeley noted, will require navigating a thicket of regulatory and ethical challenges. Once the animals are created, there will be new questions. What are the challenges in releasing such animals into the wild? Will countries be OK with that? Church wants to change the tundra to grasslands. Will others oppose the change?
Alta Charo, a noted bioethicist who is serving on Colossal’s scientific advisory board, shared many of those concerns. “There are animal welfare issues running through all this,” she said. “Then there’s a question about the environmental effects of altering an animal.”
Would the edits to make the elephants more cold-hardy cause unforeseen health issues? Would the calf get the kind of social interaction that elephants need? Would the proposed environmental benefits actually emerge?
These are questions a regulatory body somewhere, someday, will have to weigh in on, should Colossal succeed in producing live mammoth-ish calves. In the U.S., the Food and Drug Administration and the Environmental Protection Agency have been tussling over which agency has the authority to regulate such genetically modified animals. Under current law, the FDA treats any genetic changes made to an animal, like gene-edited dairy cows, as a veterinary drug, subject to lengthy testing and field trials. But what Colossal is doing — editing cells and then cloning them into eggs and growing the fetus in an artificial womb — falls into fuzzier territory, said Charo.
“There’s some ambiguity about how exactly this whole thing would be regulated in the U.S.,” she said. And that’s before you consider the eventual goal — to release mammoth herds into the Arctic, which is governed by multiple countries including the U.S., Canada, and Russia. “There are a lot of gaps in the governance system there, so doing this in the Arctic is going to raise much more complicated questions about whose regulatory system, if anybody’s, applies before you can introduce an animal into that environment.”
Charo said that these hurdles make her skeptical that mammoths are any time soon, if ever, going to be roaming the top of the Earth in numbers great enough to fight climate change.
But she said that she sees the real value in the company as a vehicle for pushing forward the development of powerful techniques that could be repurposed for conservation, including pulling endangered species back from the brink of extinction.
“It’s almost inspirational,” Charo said. “It’s the charismatic, marquee project that drives interest in all the other stuff that’s harder to get people excited about.”
So Colossal may turn out to be a Trojan Mammoth, paving the way for more realistic de-extinction projects.
There’s a more immediate question. Investors are giving Colossal $15 million because it’s supposed to be a business. How does a CRISPR mammoth-making company make money?
Church’s lab has already spun out another firm, eGenesis, that is trying to use CRISPR to make gene edits in pigs. But that is both a simpler problem — so far, 42 edits have been made in the pigs, Church said — and it has a commercial purpose. The edits are meant to make pig organs safe for transplantation into humans as a way of combating the organ shortage.
But how does a company make money off bringing back mammoths?
It doesn’t, said Ben Lamm, the company’s CEO and co-founder.
“Along the way we believe there’ll be many opportunities to create innovative technologies, very similar — one of my previous companies does a lot of work in space, so maybe I’m more attuned to this analogy — very similar to the Apollo program, which obviously was a literal moonshot” and helped spawn technologies such as one fundamental the internet and GPS.
The company’s investors are more than on board with this idea.
Tull, who had a background in technology and tech investing before investing in films, said the idea of mammoths walking the earth was not what led him to invest.
“I invested in it because of the technology and the road map ahead that I’ve been shown,” he said.
Tull described the project as “a Bell Labs of biotech,” referencing the legendary research center whose scientists and engineers made discoveries crucial to communications satellites and the computer revolution. He doesn’t expect any particular near-term return, he said, and he intends to give Church lots of “latitude.” What really appeals to him is that he feels he’s getting Church, not just a license to his technology.
Tull added that “we’ve been shown, without question, that other countries are certainly not going to be as responsible as I think they should be with science. And in this case, I think that this work is going to be done and it’s going to be done in some cases by foreign countries who are adversarial to us. And I think somebody with George’s pedigree and ethics is the right person to pursue this.”
Jim Breyer, CEO of Breyer Capital, known for his early investment in tech firms like Facebook, Etsy, and Spotify, acknowledged “it’s highly unusual to back something this early where there isn’t clarity around the business model and the monetization.” Nonetheless, he said he is “making the leap that through the various technology licenses that Colossal has with Harvard and The Church Lab, we will find very interesting technologies along the way that will not only add to the development of the mammoth, but have many other applications.”
He said he believes there will be “objective clear events” that will allow investors and the company’s management to see if Colossal is on track in three to four years.
“There are business model questions we will have to get our arms around, but my checks with Harvard and with a number of other academic medical leaders is when George feels he can head down the path of validating moonshot technologies, he almost always delivers and that’s very compelling to me as a venture capitalist,” Breyer said.
Church has previously founded more than 14 companies, though not all have been successes. For instance, Codon Devices, an early synthetic biology firm, and Knome, which was selling people their DNA sequence for $350,000 back in 2007, both failed to take off.
Other investors include Cameron Winklevoss, of Winklevoss Capital, known for his role in co-founding Facebook; motivational speaker Tony Robbins; former Amazon executive Jeff Wilke; and Tim Draper, the iconic venture capitalist who backed Baidu, Skype, and Tesla but was more recently associated with his investment in and defense of Theranos.
“In the de-extinction process Colossal will build world-class software products for CRISPR and their breakthroughs will have major implications for biotechnology products, treatment of diseases, and genomics,” Draper wrote in a statement.
The company’s leadership team has plenty of experience in technology, Greely noted, but not in biotech. That can be a warning sign. It’s also notable that many of these investors may have put in small sums. The average investment, with 15 investors and $15 million, is $1 million each.
“It’s an arduous path ahead,” Tull said. “If it wasn’t, then it wouldn’t be interesting to pursue or write about because somebody would have done it.”
Colossal launches with $15 million to bring back woolly mammoths Source link Colossal launches with $15 million to bring back woolly mammoths