Scientists Are Trying to Revive Woolly Mammoths With CRISPR
In November 2018, Chinese biophysicist He Jiankui gave the worldwide scientific community a severe case of ethical whiplash when he announced that his team at the Southern University of Science and Technology in Shenzhen had edited DNA in human embryos which were later implanted into two women who later gave birth.
In an apparent attempt to duplicate a naturally-occurring mutation seen in roughly 10 percent of Europeans, Jiankui used gene-editing technology to disable CCR5, a gene that encodes a protein which allows HIV to enter cells, according to the journal Nature.
Jiankui was fined three million yuan ($430,000) and sentenced to three years in prison for illegal medical practice by a court in Shenzhen. Smaller fines were meted out to two of his colleagues who assisted him in the work, and investigations are still ongoing to determine how much assistance he received from researchers in the US.
While there is no hard evidence that he succeeded in altering the genes of the three children born of the edited embryos, there is a clear record that He disregarded established protocols of participant recruitment for his research. Coupled with a bold advance into a potentially dangerous territory in genetics, Jiankui’s team, “crossed the bottom line of ethics in scientific research,” the court explained, according to the BBC.
The entire case could easily be the premise of an excellent science fiction novel: A rogue biophysicist takes a god-like swing at engineering an artificial resistance to HIV by throwing medical ethics and convention to the wind, revealing an international network of ethically-questionable collaborators in the process.
It’s also the perfect representation of the exhilarating and dreadful potentials of a technology that could throw open the doors to a legitimate scientific and social revolution unlike any we’ve ever seen.
CRISPR by the minute
That gene-editing technology is called CRISPR, the merciful acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeat. This is the name for arrays of short, exact sections of DNA encoded in microorganisms like bacteria.
"This technology has had a revolutionary impact on the life sciences."
Molecular biologist Yoshizumi Ishino and colleagues first noticed the presence of these odd, repeated genetic sequences in the 1980s while studying E. coli bacteria. The discovery made relatively few waves in the scientific community at the time as nobody knew what function they served. However, a number of researchers started making headway on these observations in the early 1990s and 2000s. In 2005, the microbiologist Francisco Mojica correctly theorized that these DNA arrays were part of a microbial immune system.
When a virus attacks a single bacterium, it inserts its own genetic code into the microorganism to try to take it over and use it as a factory to produce more copies of itself. Bacteria are not always able to repel such a viral attack, but when they do, they store a copy of a section of the virus’s DNA in an archive of their own to aid in future defense efforts. The DNA stored in this archive is used like mug shots to allow the bacteria to identify harmful viruses.
To keep track of this collection of “mug shots” and to keep them separate from the bacteria’s own DNA, the bacteria place repetitive sequences of molecules around each one. When a bacterium comes up against a harmful virus with a genetic “mug shot” in its collection, it sends an enzyme (such as Cas9) to cut apart and destroy anything that matches it.
One of the remarkable things about this system is the ease with which it can be programmed to recognize and alter a huge range of DNA sequences. This revelation was brought to the world’s attention in 2012 when biochemists Jennifer Doudna and Emmanuelle Charpentier published a paper in Science describing a technique for using the enzyme Cas9 to edit the genome of anything from microorganisms to humans.
Being able to reprogram the DNA of living cells involves switching specific genes on and off, an action that can be the difference between the life and death of an organism. If scientists could identify the exact DNA sequence that allows for, say, HIV transmission, they could theoretically turn that gene off, leading to greater resistance to the illness and the increased health of millions of people.
The potential impact on human health is just one of the reasons why Doudna and Charpentier were awarded the 2020 Nobel Prize for Chemistry. In a press release announcing last year’s winners, Claes Gustafsson, chair of the committee that oversees that prize said, “This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies, and may make the dream of curing inherited diseases come true.”
Gustafsson’s mention of life sciences is key here, as the technology can be applied to nearly any living creature. Scientists have already used it to reduce the lifespan of mosquitos and alter cholesterol levels in monkeys, for example. CRISPR’s potential to be a revolutionary technology alongside the best of human achievements in computing power, artificial intelligence, and engineering, is nothing short of thrilling.
Life finds a way
Wrapped up in that potential is the ability to bring extinct species back from the dead. As CRISPR allows scientists to splice individual genes that program for specific characteristics into the genome of living species, it could be used to create new, hybrid animals that exhibit at least some of the physical and behavioral traits of their extinct brethren.
One such species that has been brought into the CRISPR spotlight in recent years is the woolly mammoth. The Woolly Mammoth Project is one of several ambitious plans under the direction of Revive & Restore, a California-based non-profit organization co-founded by the long-time environmentalist Stewart Brand, with the goal of enriching biodiversity by genetically rescuing endangered and extinct species. How exactly might scientists achieve it in the case of the mammoth?
“First, you need to sequence a prehistoric mammoth,” explained journalist Ben Mezrich in a 2017 interview with National Geographic.
In Mezrich’s book, Woolly: The True Story Of the Quest To Revive One Of History’s Most Iconic Extinct Species, he explains how woolly mammoths inhabited huge swaths of grassland ecosystems on the Eurasian and North American continents during the Pleistocene, an epoch that began roughly two and a half million years ago and ended around 12,000 years ago.
Beginning at that time, both the grasslands and the mammoths disappeared. The circumstances of the animal’s demise have been the source of much speculation, but scientists generally credit their end to a combination of environmental changes and overhunting by humans. Countless mammoth skeletons and carcasses are scattered across these frozen plains, trapped in the permafrost in oftentimes excellent condition.
But as the permafrost in places like Siberia slowly melts away due to modern-day global warming, these carcasses have begun to reveal themselves in increasing numbers. This presents scientists with a unique opportunity. Taking samples of the mammoth remains would allow researchers to sequence its genome and investigate exactly what makes the animal unique on a genetic level.
Cloning is off the table—that would require perfectly preserved mammoth DNA, which none of the mammoth carcasses can provide, due to the amount of time they’ve spent in the icy ground degrading. Luckily, woolly mammoths have a close, living relative; the Asian elephant, with which it shares over 95 percent of its DNA. This is where CRISPR could work its magic.
“Instead [of cloning the mammoth],” Mezrich elaborated, “you synthesize the genes, place them into the embryo of an Asian elephant, put the embryo back into an Asian elephant, and the Asian elephant then gives birth to the Woolly Mammoth.”
It’s a tall order, one that conjures up ideas of Jurassic-Park-esque fantasies. Crucially, though, bringing back the woolly mammoth isn’t just about helping right a single human-made wrong of driving a species to extinction, it’s also about how reintroducing the animal can help abate the effects of climate change.
Turning back the environmental clock
For the last few decades, ecologist Sergey Zimov and his son and Nikita have been hard at work knocking down trees in the northern plains of Siberia in one of the largest geoengineering efforts on the planet. The father-son pair have managed Pleistocene Park, a 90-square-mile (144 km) nature reserve and scientific experiment, since its official establishment in 1996.
"We need a sound oversight framework, and it needs to be established globally."
“I am trying to solve the larger problem of climate change,” Nikita said in a 2017 interview with The Atlantic. “I’m doing this for humans. I’ve got three daughters. I’m doing it for them.”
Felling trees seems like an odd way to do that, but research published by both men in the journal Nature has shown the potential for the reintroduction of grassland ecosystems to slow the thaw of the Siberian permafrost. Grassland reflects more sunlight than forests do, and the grazing animals that roam them keep the snow trampled in winter, reducing insulation effects and allowing the Arctic freeze to reach deeper and deeper into the soil.
Maintaining that permafrost is vital to anyone interested in mitigating the effects of global warming. Because of work carried out by scientists like Sergey Zimov, we also know that Arctic permafrost contains roughly four times more carbon than humans have released into the atmosphere since the Industrial Revolution. If that soil warms up enough, the released carbon could exacerbate the effects of global warming to an unforeseeable degree.
So far, Sergey and Nikita have reintroduced Yakutian horses, reindeer, musk ox, moose, yaks, sheep, and bison to Pleistocene Park in an effort to restore an ecosystem that once stretched across the Eurasian continent. And it’s just such an ecosystem that a woolly mammoth would find itself perfectly at home in.
Dr. George Church of Harvard Medical School, the head scientist for The Revive & Restore mammoth project, had a chance meeting with Sergey in 2013 at a de-extinction conference in Washington D.C. Church was so inspired by Sergey’s dreams of using grazing animals to restore the grassland ecosystem that it galvanized his resolve to see through the project of mammoth de-extinction. He is now aiming to deliver one to their park within a decade.
Despite impressive progress, that timeframe may end up being a flexible one. So far, Church’s lab has been able to edit the genome of the Asian elephant to introduce changes like cold-resistant hemoglobin cells, extra hair growth, and a thick layer of fat to insulate the animals from extreme winter weather. And while much work remains to identify and edit for other traits, the genetic work that CRISPR has enabled may actually end up being the easy bit.
“It turns out the genome editing part is pretty easy—we’re getting good at that,” Church told Baku Magazine in 2018. “And reading the ancient DNA turned out to be easy, too; we have now analyzed 24 elephants and mammoths and that’s allowed us to pick the right things to prioritize.”
Inserting edited cells into a mammalian embryo that carries to term is where things get tricky. Doing so artificially is something that no one has ever done before. Asian elephants are already an endangered species—conservationists are less than eager to allow geneticists to use one as a surrogate in pursuit of de-extinction dreams. As it stands, Church’s team won’t be ready to even begin dealing with that problem for some years.
"I worry that we’re going to not do something that could save a lot of lives and improve quality of life."
Despite the challenges, scientists around the world are chipping away at bringing the mammoth back. In 2019, Japanese researchers at Kindai University published the results of an experiment in Scientific Reports in which they took the least-damaged nuclei from bone marrow cells of a 28,000-year-old mammoth carcass and embedded them into mouse oocytes (immature egg cells). Some of those altered cells then briefly exhibited activity that normally precedes cell division. They were effectively alive, albeit fleetingly.
While experiments like these are a long way off from yielding herds of the giant herbivores roaming the Siberian steppe, the technology will almost certainly get better. Given this, a perfectly valid question is whether or not we are capable of using a powerful tool like CRISPR wisely.
The ethics of CRISPR resurrection
The ethics of de-extinction and geoengineering are not straightforward, but neither are they prohibitively dense. As He Jiankui’s case demonstrates, technology can easily outpace the human capacity for caution if the circumstances allow for it.
Regarding animal species like the woolly mammoth, it’s possible there are more reasons for optimism than not. For one, the reintroduction of animal species to an ecology has proven it can engender a wide range of environmental benefits. One of the best examples of this is the reintroduction of gray wolves to Yellowstone National Park in 1995 after a 70-year absence.
As Ben J. Novak writes in Building Ethical De-extinction Programs: Considerations of Animal Welfare in Genetic Rescue, this was one of the best things to happen to the park in decades, as, “a cascade of beneficial trophic and habitat changes ensued, among which was an increase in tree growth, allowing the unassisted recolonization of another locally extinct species, the beaver. In turn, this led to wetland habitat creation and improved stream hydrology.”
Cases like this show that it’s not necessarily a pipe dream to think that reintroducing the woolly mammoth could have similar positive effects on the landscape and the climate.
But what of the animals that come back from extinction? Elephant species, for example, are highly gregarious—there is even evidence of African elephants mourning the deaths of herd members. Take away the context of these social bonds and interactions, as happens when elephants are relocated to zoos or used in circuses, and the animals exhibit what can only be described as a mental breakdown. Would it be right to synthesize a mammoth calf with no herd to support it?
Such questions await practical answers and will need to be addressed when using CRISPR applications on any organism, be it mammoth or human. One of the frightening aspects of the technology is that it’s essentially a free-for-all at the moment, with no single governing body calling the ethical shots on its usage.
Speaking to the Harvard Gazette in 2019 Catherine Racowsky, professor of reproductive biology, highlighted the need for regulation, saying, “We need a sound oversight framework, and it needs to be established globally. This is a technology that holds enormous promise, and it is likely to be applied to the embryo [...]. That means we must have consensus on what applications are acceptable, that we have appropriate regulatory oversight, and, perhaps most importantly, that it is safe.”
Others, like George Church, fear we might sway too far in the other direction and prevent ourselves from enacting real and significant change. “I’m one of the loudest voices about caution. I’m heavily invested in safety engineering, and I’ve written nearly 20 papers on bioethics. I’m an optimist, but it’s complicated—everything worries me. But because people worry so much about new technologies, I worry that we’re going to not do something that could save a lot of lives and improve quality of life.”
CRISPR is too tempting a tool for us not to tinker with. The coming decades will see more experiments, ethical mishaps, and breakthroughs as humanity finds its feet after having built itself a new pair of Promethean shoes. It will be fascinating to see where we choose to walk with them.