It’s almost been a decade since Harvard geneticist George Church first talked about using synthetic biology to bring woolly mammoths back to life. Now, his idea to reverse history is pressing forward.
Today, Church and software entrepreneur Ben Lamm announced the launch of their biotech startup, Colossal, with seed funding of $12 million. The mission of the company is two-fold: to preserve endangered animals (and someday plants) with gene-editing technology, and use those animals to reshape Arctic ecosystems to fight climate change.
The plan is to use CRISPR to add 60-plus genes from the extinct woolly mammoth into the cells of an embryo of an Asian elephant, which is its closest living relative. The two species share 99.6 percent of their genome, Colossal claims.
In 2015, Church’s lab successfully integrated mammoth genes for small ears, fatty tissue, and shaggy brown hair into the DNA of elephant skin cells. “Just making a DNA change isn’t that meaningful,” Church told Popular Science back then. “We want to read out the phenotypes.”
Colossal will help fund Church’s mammoth research in the long term, while partnering with Arctic researchers to set the stage for rewilding. “We’ve sequenced multiple genomes from frozen tissues that have been recovered from Siberia of the woolly mammoth,” Lamm tells Popular Science of the startup’s progress so far. The team has also sequenced multiple Asian elephant genomes to compare the differences between the two species. “George Church and his lab have actually identified genes that make up the phenotypic traits that we’re looking to express that makes an Asian elephant a functional woolly mammoth,” Lamm adds. But their undertaking has only just begun. © Provided by Popular Science This CRISPR startup thinks that mammoths can save the Arctic. Is it right?
Lamm and Church plan to make mammoth de-extinction a reality. Colossal
First discovered in bacteriophages in 2011, CRISPR/Cas9 is an enzyme that can bind and cut specific sites on a strand of DNA. Church’s lab will pair the rapidly developing tool with other DNA-editing enzymes like integrases, recombinases, and deaminases to splice genes from the woolly mammoth into the Asian elephant to help it adapt to the cold Arctic, where Colossal says it would help sculpt the landscape to better sequester carbon.
The team is still in the early days of the process. Right now they’re trying to make working mammoth genes manifest in live Asian elephant cells. If they succeed, they’ll have to verify that the genes correspond to the traits they want, first in pig and mouse models, and then in elephants.
Church has already demonstrated that his technique can change a mammal’s development. In a proof-of-concept study published 2017 in Science, his lab used CRISPR to edit out 62 genes for the porcine endogenous retrovirus—remnants of an ancient zoonotic infection that can transmit to humans—and produce a live pig carrying those gene edits through somatic cell nuclear transfer, or cloning. The process involves taking the nucleus out of a genetically edited body cell and putting it into an egg cell to create an embryo.
Chuck is preparing to repeat this trick again with the elephants. But grafting in another species’ essence is leagues different from editing out a virus.
“This is something that George and team have been working towards not just in their work on pigs and other species, but specifically with elephants, for the last five years,” Lamm says. “For Colossal, it’s leveraging the research they’ve already done. We’re not a new step in the process.”
If the feat to create hybrid embryos succeeds, they can either be implanted in elephant surrogates or be grown to full term in artificial wombs (which are still being engineered); the latter will probably work better for producing new elephants at scale, Lamm notes. The first set of cloned calves is expected to arrive in the next 4 to 6 years. Based on the life cycle of Asian elephants, it would take 13 more years for the pilot generation to reach sexual maturity.
“This is not a short timeline,” Lamm says. “Our goal at the company is not just to bring back a successful small herd of woolly mammoths. The goal is for successful rewilding of the mammoths back into the Arctic. That means large populations with genetic diversity that can interbreed.”
While the group is aiming for a small herd of five calves to start so they can study population dynamics, Lamm estimates they’ll need tens of thousands of CRISPR-ed mammoths to achieve their desired effect on the Arctic ecosystem.
Though the births of the first elephant hybrids are years down the road, Colossal already has plans to set them free in the wild. The company wants to start with a limited release: restore a small herd of these franken-elephants into a reserve-like ecosystem in the Arctic tundra where mammoths once ruled. The team will be working with Arctic rewilding scientists, Sergey and Nikita Zimov, to bring mammoths to Pleistocene Park, located in northern Siberia.
Pleistocene Park began as a backyard Ice Age experiment in 1996 by the father-and-son Zimov duo. They’ve introduced bison, musk oxen, and wild horses to roam on the 90-square-mile plot; but they’ve been waiting for the mammoths. Until Church’s herd is ready, they’re using tanks as stand-ins to plow down aberrant trees.
As Crichton-esque as it all sounds, the reserve has allowed the Zimovs to make foundational discoveries about the Arctic ecosystem, including its incredible capacity for storing carbon and methane. In 2006, Sergey helped publish a paper that put the Siberian permafrost’s carbon reserves at approximately 450 gigatons. Global warming, however, could cause this frozen pool to break down and enter the atmosphere as carbon dioxide.
“The Zimovs are doing a lot of modeling on the impacts of rewilding, specifically mammoths and other species,” Lamm says. “We’re not trying to reintroduce mammoths into areas where they’re going to be competing for resources with existing species in an area they weren’t originally in. We’re restoring them to the locations and the environments where they lived and thrived.”
About 13,000 years ago, woolly mammoths and other cold-tolerant megafauna were critical in paving an ecosystem called mammoth steppe, a vast glacial grassland that helped to temper the world’s climate. The grasses not only sequestered carbon, but also carved out a landscape that reflected light and heat from the sun via a phenomenon called the albedo effect. Large animals like mammoths and woolly rhinos did the groundskeeping, trampling shrubs and uprooting trees. They ate the grass and pooped the nutrients back into the ground, closing the loop on the steppe’s carbon-nitrogen cycle.
This landscape was likely a lot better at storing carbon than the tree-covered swathes of the Arctic. A recent study from UC Davis researchers found that grasslands tend to be a more reliable source of carbon sequestration than forests, as they’re less impacted by extreme heat and fires—events that could release carbon back into the atmosphere. What’s more, coniferous canopies, by nature of being darker than ice, absorb more light and heat than they reflect.
Many experts say that the Siberian tundra has lost its luster since its Ice Age heyday. Once-green tree tops are browning, the diversity of herbivores in the Arctic is falling, and scientists are scrambling to figure out why. Colossal has a guess. The extinction of the woolly mammoth created an ecological void in the Arctic landscape that has never been filled by another species, the company said in a statement: All that’s left are the yak and reindeer herds that support local villages.
Outside of the Arctic, Colossal wants to ensure they’re setting up the re-engineered elephants to last. The company will continue sequencing both elephant and mammoth samples to identify key genes in both species’ populations to contribute to population diversity. This, they hope, will prevent a rogue mutation from dooming the whole herd. As Church’s lab works through the frozen mammoth samples collected from Siberian permafrost, the startup is also funding work on Asian and African elephants by the Vertebrate Genome Project to gain insights into the biodiversity of elephant populations at large.
Colossal is hopeful that its efforts will give endangered species like Asian and African elephants a second life through a genetic time machine. By creating a franken-species that mashes together DNA from across millennia, it’s proposing a way to make a living archive of the giant tusked mammals.
“If we can give the Asian elephant and African elephant and the entire lineage the ability to survive in a new ecosystem and climate by instilling the genes in them that existed in their previous ancestors,” Lamm says, “then we have this concept of species extension where we have these entire ecosystems that can not only be rewilded from an Arctic grasslands restoration perspective, but also from a perspective of keeping that population and that diversity alive. It’s not just hunting and poaching. Part of that is actually competing with urbanization and lost habitat.”
If the effort works, Colossal thinks it can apply the same model to other species, like the Sumatran rhino.
It’s a radical take on conservation. But experts such as Jesse Reynolds, who was recently a researcher at the Emmett Institute on Climate Change and the Environment, University of California, Los Angeles School of Law, are on board. “If environmentalists are serious about conserving biodiversity,” Reynolds wrote in an email statement, “they should overcome their widespread aversion to biotechnology. It’s no longer enough to merely preserve some land and hope for the best.”
But there should be some precautions when it comes to testing out de-extinction. In a paper in Current Opinion in Environmental Sustainability in April, Reynolds noted that some “conservationist synthetic biology” could pose environmental risks, and that both domestic and international regulations governing how these biotechnologies are used need to be updated. So far, CRISPR has mainly been applied to small groups of organisms in controlled settings, according to a 2019 UNEP paper. A small field study involving mosquitoes edited for disease control against malaria launched in 2019 sparked arguments, despite the fact that the subjects were sterilized to prevent interbreeding with wild insects.
Concerns like this are why Lamm thinks that starting with the mammoth makes a lot of sense. “We’re not genetically modifying an insect like a mosquito and releasing it into the wild where we can’t track it,” he says. “Having a species like the mammoth where they are large enough to have radio and different tracking mechanisms on them, if there is an issue, we can always roll it back.”
Just as the launch of Colossal gives Church’s experiment new legs, the benefits of the project are still subject to debate. Those for it say de-extinction is necessary to undo human mistakes; those against it say it’s too little, too late, and more showy than practical.
James Bull, professor emeritus in the department of integrative biology at The University of Texas at Austin, says that he doesn’t see any major objections to the mammoth rewilding plan, but notes that there will definitely be uncertainties to watch for, as well as interesting science to discover. “Moving genes of one species to replace parts of another’s genome may encounter many incompatibilities—at the level of entire genes down to single-base differences,” he writes in an email. “There are studies showing that human genes can substitute for homologous yeast genes, so there could be many pathways to success. But it may not be straightforward.”
Even if Church proves that mammoths can be mashed up with Asian elephants, it could be a challenge to keep the hybrids from going extinct again, “whether from extreme events, disease, mis-aligned mating behavior, or bad genetics,” Bull explains. Some hypotheses of why mammoths went extinct in the first place include inbreeding, hunting, and warming temperatures. “For precedent, introductions of wild species into new habitats and environments often fail,” Bull writes.
But Colossal is intending to play the long game—and learn from the many failures that may come with it. Lamm says he can see the company “working on other species to balance that ecosystem over time,” including possibly introducing a predator to keep the population in check. “But that’s quite a ways off,” he adds.
The startup is aware of the controversial minefield it’s stepping into and plans to continue addressing skepticisms about de-extinction. Its advisory board is stocked with bioethicists, conservationists, animal trafficking researchers, elephant specialists, chemists, and geneticists in preparation. “We want to make sure we’re doing this in the most transparent and ethical way possible,” Lamm says. “We want to have those conversations with the general public.”
Assuming that the first generation of the hybrid herd endures, both in the faux womb and the Arctic, “it could easily be more than a century after the first mammoth is born before there is a strong enough population that there is any ecological impact to measure,” Bull writes. “I don’t see the possibility of a negative ecological impact as anything of concern now,” he continues. “It’s too far into the future.”
Original Article: This CRISPR startup thinks that mammoths can save the Arctic. Is it right? (msn.com)
Don’t fuck with mother nature