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{shortcode-a0fafb3727a5405eac46bd1741f1eafab86bbf7e}arvard Medical School professor George M. Church didn’t think that by the end of his breakfast in Harvard Square, he would have $100,000 to bring back the wooly mammoth.

In 2011, Church was meeting with Peter Thiel, the billionaire venture capitalist known for his early investment in Facebook and co-founding PayPal. Thiel offered him $100,000 and asked him what he would do with it, and Church mentioned aging, a field he knew Thiel had been interested in.

“And I mentioned mammoths as like, ‘here’s a control, this is something he couldn’t possibly be interested in,’” Church said. “And that’s what he gave it for.”

Over the course of his career, Church has made a major impact on genomics — his work laid the foundation for CRISPR and gene-editing — and he has been working on resurrecting the mammoth for around a decade.

After starting his work through the biotech non-profit Revive and Restore, Church co-founded Colossal Biosciences when the entrepreneur Ben Lamm decided to help the Church lab raise $225 million to support the mammoth project. Upon the company’s 2021 founding, Colossal said it aimed to bring back the animal, which had been extinct for 4,000 years, within the next six years.

But the effort is not restricted to the labs of the Texas-based Colossal. Harvard is deeply intertwined with the project — it’s listed as one of eight university partners on Colossal’s website. Church’s lab at HMS and Colossal have a deeply close relationship: Colossal pays some lab members’ salaries, and some lab researchers also work for Colossal.

‘Don’t Have That Many Shots On Goal Left’

Church, who says he’s been experimenting with “crazy ideas” since his time in graduate school at Harvard, said that the initial inspiration for the idea of bringing back extinct species, at least in part, came from the book Jurassic Park, which the author Michael Crichton ’64 published in 1990.

Since then, the Church lab has focused on developing broad technologies that can be applied to many species, including humans.

Much of Church’s research has focused on using cells to provide assisted reproduction for many endangered species. Church says he finds the task increasingly compelling because “we really don’t have that many shots on goal left” to save species like rhinoceroses and whales.

Colossal frames their effort to resurrect the mammoth — and the dodo bird and Tasmanian tiger — as a crucial step in environmental protection. For Church, that’s a primary goal of the relationship between his lab and his company.

“The main thing for the lab’s interface with Colossal is endangered species,” Church said. “Not de-extinction despite the fact that that's often the associated terms. That's not our primary goal and work.”

The Church Lab has also been focused on the Asian elephant, which faces numerous threats to its population numbers, including poaching and disease. Church says that the lab is “trying to make something that’s more well adapted to the realities of human conflict, the realities of poaching” and “more adapted to their Herpes virus.” A newly-created mammoth-elephant hybrid in the Arctic could have positive “cascade effects” in the fight against climate change, he said.

The process, though, will not be quick — and its benefits are unclear. Church acknowledged that the climate goals of the work are “a little more speculative than the endangered species part.”

In the past, it has taken up to 10 years to get a clinical trial, and Church said that some of the timelines put forward, specifically Colossal's stated goal of having the first mammoth calf be born within four years, is “rather aggressive.”

Church added that he is still hopeful that the research will succeed soon enough to make a difference in the fight against carbon in the atmosphere.

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Hashem H. Abdou ’24, a previous undergraduate research assistant in the Church Lab, said that the lab does not actually have any wooly mammoth cells.

“We do know, though, that the wooly mammoths had certain traits and characteristics that are no longer present in current existing elephants today,” Abdou said, adding that the work of the lab was about “making the elephant genes” emulate specific mammoth characteristics.

“It’s not necessarily about bringing back the wooly mammoth and having him walk around the earth right now,” Abdou said. “It’s a lot about, ‘how do we make species that exist today look and act more like species that existed in the past that made them stronger and more adaptive.’”

‘We’re Going For What Makes a Mammoth a Mammoth’

Church’s work led to the founding of Colossal in 2021, and with it, a sprawling corporate apparatus dedicated to bringing back long-extinct animals.

The company came out of a conversation Church had in 2019 with entrepreneur Ben Lamm, who had no experience in synthetic biology when he reached out to Church to meet to “ask some advice on building software around computation analysis,” Lamm said, before the conversation turned to mammoths.

“I definitely didn't sleep after the first night I talked to George,” he added. “A week later I was in the lab and at that point, I was pretty excited that, you know, thought we could go build the world's first de-extinction and species preservation company.”

While the company also has projects in progress to resurrect both the dodo bird and the Tasmanian tiger, the focus of their work — and the focus of the media — seems to be on their effort to bring back the mammoth.

Officials at the company talk about their project in similar terms to the research at the Church Lab, but say that their company is leading the charge.

“We want to capture all of the phenotypes for cold-adaptation and engineer them onto an elephant,” Eriona Hysolli, the head of biological sciences at Colossal, said. “So absolutely, we’re going for what makes a mammoth a mammoth and engineering that onto its closest living relative.”

Church “was really the pioneer,” Hysolli added, but de-extinction “only started when Colossal came into play.”

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The relationship between the two remains close, but not exactly clear. Dorothy D. Majewski, a research fellow at the Church Lab, said that the lab and Colossal have a “sponsored research agreement,” where they hold quarterly meetings and “share data.” The company funds both research supplies and some of the lab’s postdocs, Majewski said.

“We’ve collaborated a bit with Colossal on it and they’ve helped us with cell lines and with getting the genome as well,” Majewski said.

The project involves sequencing the genes of ancient mammoths and their closest living relative, the Asian elephant. The elephant genome, which is 99.8 percent similar to that of the mammoth, can be genetically modified using various techniques. Hysolli underscored the role of synthetic biology, noting that ancient DNA is often too fragmented to be used.

“When we talk about the resurrection of genes, we definitely mean it in the way of using synthetic biology, whether through genome engineering or DNA synthesis,” she said.

After sequencing and editing the genes, scientists can use stem cell technology to insert the edited genes into healthy elephant cells.

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Last month, Colossal reported a breakthrough in stem cell technology involving the biology preprint server BioRxiv. They generated Asian elephant stem cells from their mature counterparts. These cells, called induced pluripotent stem cells, have the potential to give rise to any other cell type. If they are successfully converted into sperm or eggs, Colossal will be able to reprogram an Asian elephant to be functionally like a mammoth.

The final step involves fertilizing the cells via nuclear transfer and implanting them into a surrogate elephant. By 2028, Colossal plans to observe the birth of the first mammoth calves.

“That timeline hasn’t changed,” Hysolli said. “We believe that it’s absolutely feasible to achieve with the current technology.”

Ultimately, the company’s goal is to produce a number of mammoth-elephant hybrids and re-introduce them to the Arctic tundra.

“When people get word of rewilding, I think they just think, ‘Oh, you make mammoths or other species, and you open up the gates and they run amongst their way.’ And that’s not how it works. It’s actually a very staged process,” said Lamm.

The process of rewilding involves collaboration with private landowners, local governments, Indigenous communities, and the public at large.

Even though Colossal, like the Church Lab, doesn’t have mammoths today, “we’ve started all of those conversations,” Lamm said.

‘A Really Awesome Partnership’

For Colossal, its relationship with Harvard is vital to its work — and affiliates at both institutions say the dynamic between the two institutions help keep the project going.

Lamm said that the distinct roles of universities and corporations allow for a mutually beneficial relationship, saying that Colossal holds Harvard “in high esteem as a university partner.”

“Academia and a corporate partner work very, very differently. We have different goals and different methods,” he said. “But I really think that working with academia, in partners like Harvard, and in many of the other universities that we work with, we kind of get the best of both worlds.”

“We get to run at our pace, and really advance the project, while we have these incredible academic collaborators that are coming up with new ideas — some of those are going to work, some of those that are not going to work, and then we can integrate them where we see fit,” he added.

Church agreed, saying that while his lab is about “crazy ideas, things that are disruptive, transformative,” his “companies tend to be much more pragmatic, they’re focused on product.”

But despite the Church Lab and Colossal’s “different priorities,” Anna-Thérèse Mehra ’24, an undergraduate researcher in the Church Lab said it is a “nice interface to get things done, because everybody wants to move things along.”

“Continuing on, I’m sure this will be a really awesome partnership between the two – the Church Lab and Colossal – because there’s plenty to go around to study and research,” Mehra said. “So everybody’s plenty busy for the next, at least, five, 10 years.”