A new company co-founded by Harvard geneticist George Church wants to use cold-adapted elephants to transform Arctic tundra, sparking intense scientific and ethical discussions.
Written by Michael GRESHKO
A gilded mammoth skeleton sculpture on Miami Beach, Florida, by renowned artist Damien Hirst titled Gone but Not Forgotten. But if Colossal's plan comes true, dozens of genes from extinct mammoths will be reproduced in cold-adapted hybrid Asian elephants. Photo by JEFFREY GREENBERG, EDUCATION IMAGES, UNIVERSAL IMAGES GROUP VIA GETTY
Colossal, a Harvard geneticist involved in the creation of Colossal, has come up with a bold plan: use mammoth DNA to create a hybrid Asian elephant that can thrive in Arctic climates.
Colossal's long-term goal is to use these "hybrids" to reshape the Arctic tundra, transforming the tundra that is now covered with moss into lush grasslands of the Pleistocene era. Some scientists hypothesize that, on a large scale, this reversal could slow the melting of Arctic permafrost, thereby slowing future climate change. In the process, Colossal wants to create new, lucrative biotechnologies, such as tools that complement traditional conservation methods.
"We're stopping the extinction of genes, not species," Church said. "Our goal is to breed truly hardy elephants that are fully hybridized with the endangered Asian elephant."
The idea of using biotechnology to help endangered or even extinct species is not new. In 2009, researchers successfully cloned a subspecies of wild goats that became extinct in 2000, but the cloned wild goats survived only a few minutes. In April, the San Diego Zoo and the nonprofit Revive & Restore announced that they had cloned an endangered black-footed ferret with the aim of increasing genetic diversity in captive breeding programs.
For years, Church's plan to "resurrect" mammoths using DNA sequences has dominated the headlines around the world.
"Most of the scientific problems have been solved; all that is needed now is funding and attention," said Ben Lamm, co-founder of Colossal. "After two years of hard work, it's exciting to finally be able to tell people what we're doing."
The "stand-in mammoth" isn't coming anytime soon. Colossal's plans rely on several technologies that have not been proven in elephants. Church says that even according to the company's ideal schedule, the first hybrid baby elephant will not appear until 6 years later. A self-sustaining herd can take decades to build.
But even in the current early stages, Colossal's plan raises a series of questions worth pondering about what it means for a species to go extinct, and how biotechnology can address today's species extinction crisis. Tori Herridge, a mammoth biologist at the Natural History Museum in London, says that with the advent of Colossal, the discussion of the "resurrection" of species is no longer abstract. "My first reaction was that things were getting more and more real," she said.
Welcome to Pleistocene Park
In a 2008 interview with The New York Times, Church recounted the sequencing of mammoth genomes, and since then, the idea of breeding hybrid mammoths has become more and more firm in his mind.
At first, the idea was more like an intellectual puzzle that I couldn't get started with. But in the years that followed, Church began working with Stewart Brand and Ryan Phelan, the founder of the nonprofit Revive & Restore. Brand and Phelan's goal is to use biotechnology to help save endangered species and bring extinct species back to life.
"Resurrecting extinct species and what we call genetic salvation is actually a hopeful idea to repair some of the damage that humans have done over the centuries," Phelan said. "It's not nostalgia, it's about increasing biodiversity."
Brand and Phelan invited Church to attend the world's first "de-extinction" conference in 2012 and 2013 at the National Geographic Society headquarters in Washington, D.C.
At the conference, Church met with Russian ecologist Sergey Zimov, director of the Chersky Northeast Science Station in the Sakha Republic. Zimov, who has been studying siberia's permafrost since the 1980s, warns that large amounts of methane and carbon dioxide may seep into the atmosphere after the permafrost is thawed. "It's not nostalgia, it's about increasing biodiversity."
Zimov also proposed a way to leave carbon underground. Since 1996, Zimov and his son Nikita have been working at Pleistocene Park, a fenced tundra near Cherski. The Zimovs introduced Canadian red deer, North American bison, reindeer, Twin Peaks wild camels and other large herbivores to test the effects of these creatures on the landscape.
Tens of thousands of years ago, during the Pleistocene era, much of Europe, Asia, and North America was covered with highly productive grasslands and filled with a wide variety of herbivores. By 10,000 years ago, many herbivores, including mammoths, had gone extinct in much of the world, possibly in part due to human activities such as hunting. With the extinction of these animals, meadows became shrubs, trees, and mosses, forming the tundra and coniferous forests we see today.
The Zimovs speculate that mammoths were crucial in maintaining the productive grasslands of the ancient Arctic. These behemoths can tear down trees, stir up dirt, fertilize the soil with manure, and help the grasslands thrive. Their heavy footsteps penetrate the snow and ice, allowing the Arctic cold to penetrate deeper into the permafrost.
"If you think of ecosystems as bodies," Nikita Zimov said. "That mammoth is the right hand that is indispensable."
While there are no mammoths in Pleistocene Park, the park's current herbivores may already be shaping the soil here. In a study published last year, the Zimovs couple found that in winter, the compacted soil inside the Pleistocene Park was more than 12°C lower than the soil outside the park.
In this aerial view, the lush greenery of Pleistocene Park surrounds the blue lakes of northern Russia. Photo by Katie Orlinsky
Jacquelyn Gill, a paleoecologist at the University of Maine, said the vision of Pleistocene Park's restoration of ancient grasslands is "an exciting hypothesis" in terms of the impact of modern elephants on their habitat. However, she cautions that researchers still don't know the full details of how the mammoth ecosystem works, which complicates today's reinvention efforts.
"As a reason to launch the grassland restoration and resurrection project, it feels a bit of an inversion, after all, this project involves ecological, social, ethical and bioethical aspects."
Whatever the cost
Still, the Zimovs' work inspired Church and The Natural Resource Conservationists at Revive & Restore to get more seriously involved in researching mammoth DNA and elephant cells.
Until now, members of church labs involved in elephant and mammoth research have been part-time volunteers selected from a regularly changing staff. As a result, these findings have not yet been published in the scientific literature, much to the consternation of outside experts. Church said the lab is now preparing to submit two research papers for publication in the coming months.
Church Labs has a budget of only about $10,000 a year for elephant research, funded largely by a $100,000 donation from investor Peter Thiel and support from Revere & Restore.
In contrast, Colossal attracts much larger investment, with as much as $15 million in disposable funds. The funds will be used to support ongoing elephant cell research at Church's lab, as well as the development of the company's in-house lab. The in-house lab will be managed by Eriona Hysolli, a former postdoctoral researcher at Church's lab and the company's current head of the biosciences department.
Beth Shapiro, a paleogeneticist at the University of California, Santa Cruz, said Colossal's funding model could be a revolution for geneticists working on species conservation. "It's a new, huge source of funding that can be invested directly in the things we all care about," she says.
To help guide the work, the company hired a number of scientific advisors, including two researchers with backgrounds in elephant or mammoth research: Michael Hofreiter, a geneticist at the University of Potsdam who works primarily on mammoths and other Pleistocene animals; and Fritz Vollrath, a zoologist at the University of Oxford, who studies the behavior of spiders and modern elephants.
There are also two prominent bioethicists who study genome editing: R. Lee of the University of Wisconsin-Madison. Alta Charo and S. S. of New York University Matthew Liao。
Life scientists have found a way
Colossal's ultimate goal is to transfer enough key genes into the genomes of Asian elephants to create a "proxy" species that adapts to the arctic cold, like the mammoths of the past.
Although the last common ancestor of mammoths and Asian elephants lived 6 million years ago, the DNA similarity between the two species is still as high as 99.9 percent, Herridge said. But the elephant's genome has 3 billion base pairs. This means that there are more than 1 million different differences between the genomes of Asian and mammoth elephants, and scientists must carefully screen them.
So far, Lamm and Hysolli say, Colossal's team has targeted at least 60 mammoth genes, including those associated with their fat deposition, the oxygen-preserving ability of blood at low temperatures and the iconic fluffy fur.
Inserting the associated mammoth gene into the DNA of Asian elephants requires multiple gene edits at the same time, a problem that has been addressed in other species. Church's team used CRISPR-Cas9, a powerful gene-editing technology, to simultaneously edit the pig's genome in dozens of different places with the goal of making the pig's organs safe for transplantation into humans.
At least one of these candidate mammoth genes has been tested in transgenic lab mice. But a single gene can have many potential effects on the entire genome, and the ultimate impact of a gene on an organism's characteristics depends on when, where, and how well the gene is expressed in vivo. This regulation relies in part on fragments of MAmmoth DNA that have not yet been thoroughly studied.
Church said Colossal researchers should be able to screen out many potential problems in the early stages of hybrid embryo development. That said, he acknowledges that some altered genetic traits — such as their ears, which need to be small enough to prevent frostbite — may not be detected until later in development.
For Colossal, the biggest uncertainty is the question of how these embryos develop. Asian elephants are endangered, and to avoid surrogacy, the company claims it will develop an artificial elephant womb.
In the past, when lambs and mice were used as experimental subjects, researchers found that artificial uteruses can support the survival of preterm fetuses for 4 weeks, or support the survival of 5-day-old embryos for 6 days. But So far, Church said, no mammal has used an artificial uterus throughout its pregnancy.
To achieve this, Colossal must first set a precedent among modern elephants. Their gestation period lasts for almost two years, and the cubs weigh up to 100 kilograms at birth.
Colossal also needs an adequate supply of Asian elephant cells. Church said the company in particular needs to develop a series of induced pluripotent stem cells that have been biochemically transformed into multiple possible cell types, such as eggs, Church said. Induced pluripotent stem cells have been used in other endangered mammals, such as the northern white rhinoceros, but not yet in elephants.
Stop and think about whether you should do it
Any experiment involving animals comes with ethical challenges. If Colossal does breed a healthy hybrid elephant, it will only further increase the risk. Elephants are long-lived, highly intelligent creatures that sustain complex and multi-generational matriarchal societies.
Studies of ancient mammoths have shown that they have many of the same social characteristics as modern elephants. So how will the first mammoth and elephant hybrid be properly cared for and socialized? How will these hybrids learn to survive in the Arctic in the future and effectively restart mammoth culture?
"It's not just about letting them exist, it's about making sure that once they exist, they can thrive and live prosperous lives," said Liao, a bioethicist at New York University and a member of the Colossal Scientific Advisory Board. "Otherwise, it would be too cruel for these animals."
Colossal and Zimovs reached a friendly informal agreement that Pleistocene Park could provide home for some of the company's future mammoths. At present, only 20 square kilometers of land have been demarcated, and the final plan covers 144 square kilometers.
Today's migratory elephant herds can travel great distances, as can mammoths. A recent study found that a young male mammoth from 17,000 years ago walked tens of thousands of kilometers during its 28-year life, traveling much of modern-day Alaska. If Colossal is to realize its full vision, it will need to rewild millions of square kilometers of Arctic tundra in order to impact the global climate.
These proposals, if implemented, would bring about a number of significant changes and raise thorny questions about land use, the impact of existing Arctic wildlife, and global governance. What does this mean for the roughly 180,000 Inuit people living in Russia, Canada, the United States and Greenland? They are already facing the most immediate risks in the stressful, rapidly changing Arctic.
"Frankly, I'm quite skeptical when non-indigenous scientists want to reinvent the world in a particular image." Daniel Heath Justice, an Aboriginal studies scholar and historian of animal culture at the University of British Columbia in Vancouver, said. He noted that biotechnology can be a useful tool for protecting the environment, but that work in this area, such as Colossal's research, "cannot be dominated solely by non-indigenous interest groups." ”
Colossal said in a statement that "this will not affect the indigenous tribes currently living in the area" and that the company has pledged to "prioritize environmental protection and the protection of all species, including humans."
Proponents of the company argue that if Colossal can deliver on its promises, living species will benefit even if hybrid offspring of elephants and mammoths cannot be born. With funding from Colossal, Church's lab is working on ways to synthesize elephant endothelial herpesvirus (EEHV). Many young Asian elephants have died from infection with the virus, and it cannot survive laboratory conditions. Therefore, synthesizing the virus will be a key first step in the study of treatments and vaccines.
Shapiro, a geneticist at the University of California, Santa Cruz, said, "The only realistic, plausible argument for this type of technology is to be able to help those living species thrive in rapidly changing human environments." ”
(Translator: Strange Flowers Blossom)