Return From Extinction

The prospect of "reviving" an extinct species – or a, genetic hybrid version of it – is moving closer to reality thanks to the sophistication of genome engineering technologies coupled with our ability to extract and sequence archaic DNA samples.

In September, the biotech/genetics company Colossal – co-founded in 2021 by renowned geneticist Professor George Church and serial entrepreneur Ben Lamm – announced it had raised $15 million in funding for a project that aims to "de-extinct the woolly mammoth".

The company's mission is not to engineer a complete replica of the woolly mammoth in a laboratory. Rather, it is to create a genetic hybrid that combines woolly mammoth genes with the DNA of an Asian elephant.

Professor Church joined Technology Networks in an exclusive interview for The Scientific Observer, exploring the backstory of Colossal, his aspirations for the project and why "mammoth-sized" interventions are needed to combat climate change.

De-extinction: The backstory

Before looking at the how of de-extinction, let's first ask: why? What inspired Church and colleagues to focus on the woolly mammoth? "This project has really been in the making since 2006/2007, when two journalists asked me about the movement to read the Mammoth genome," Church explained. The journalists asked him whether it would be possible to use synthetic biology approaches to read and then re-build the Mammoth genome. "Their enquiries made me start to think seriously about it. When I came to the answer that, hypothetically, we could do it, I then thought well – should we do it?" Church pondered for some time over which species would be the most appropriate to test the hypothesis. "I thought about many different species and kept coming back to the mammoth, largely because of the work of the Zimovs that had indicated the loss of a whole ecosystem and the conversion of grass to mostly trees and moss." The Zimovs that Church refers to are Sergey and Nikita Zimov, the father and son duo that founded, and now direct, the Pleistocene Park in Siberia.

The park is an initiative that aims to restore the Mammoth Steppe, a region that dominated parts of Europe and Asia over 50,000 years ago. The Mammoth Steppe was rich with biodiversity – including, as the name suggests, the woolly mammoth. The Steppe had a high biomass and ecological productivity until it diminished approximately 10,000 years ago; the cause continues to be debated. Now, the Steppe is Arctic tundra; a stark landscape covered in permafrost that contains trapped carbon. As the Earth's temperature rises and the permafrost melts, greenhouse gases are released into the atmosphere, exacerbating climate change.

The melting of permafrost also reveals archaeological samples that have been buried for thousands of years, including the ancient bones of woolly mammoths from which DNA can be extracted, sequenced and analyzed. Through reading the genome, scientists are able to reconstruct it. This does not mean they can create an exact replica of the woolly mammoth from scratch; rather, they can take its genes and insert them into another living species using genome engineering, such as the Asian elephant – the mammoth's closest living relative. The outcome? A hybrid creature that possesses specifically selected woolly mammoth and Asian elephant genes.

Beyond a flex of scientific curiosity, why would we want to create mammoth–elephant hybrids? Colossal's website outlines 10 core motivations for its "de-extinction project":

Several of these goals are linked to climate change and helping endangered species. Church and his colleagues at Colossal believe that by reviving a hybrid version of the woolly mammoth and introducing it into the Arctic tundra, the habitat can be re-established, restoring the rich biodiversity and ultimately preventing the release of harmful greenhouse gases into the atmosphere from the melting ice.

"Elephants are the only animals which efficiently knock down trees and the resulting increase in grass yields three favorable outcomes: higher photosynthesis – hence new carbon sequestration, higher reflectance (albedo) – hence less solar warming, and more trampled snow – hence higher cold conductance to help freeze the ground and keep methane from escaping," Church said.

Protecting Asian elephants – which are an endangered species – is also a priority for the biotech company, Church explained. By genetically engineering beneficial traits into the Asian elephant, he hopes that the company can help to promote their survival and reproduction. This brings us to the how of Colossal's de-extinction agenda.

The concept of de-extinction is not a novel phenomenon, and several methods for reviving a "proxy" version of an ancient species have been proposed in recent years. Colossal's strategy revolves around the genome engineering techniques that have been refined in Church's lab over recent years, utilizing CRISPR-Cas9 technology.

The woolly mammoth genome has been obtained from ancient archaeological samples revealed by the melting permafrost. Next-generation sequencing technologies allow Colossal to read the genome and compare it to the Asian elephant. Using this sequencing data, the scientists can identify which genes are mammoth-specific and encode the traits that Colossal wants the mammoth-hybrid to bear. These features include fat "clumps" on the mammoth's back that provided insulation, long shaggy hair and its short compact ears.

Skin cells – extracted from the Asian elephant – will be edited using CRISPR-Cas9 methods to insert the mammoth-specific genes into the nucleus. This nucleus will then be inserted into an egg that has been generated from stem cells in a lab. The egg will be encouraged to divide via artificial means before being inserted into an African elephant surrogate mother, which will then carry the calf to term. While Asian elephants are an endangered species, African elephants are classified as a "threatened species". That is Colossal's reasoning behind using the latter species as the hybrid's surrogate parent, to avoid placing any further pressures on the remaining Asian elephant populations.

Colossal is also considering whether an artificial womb could be used to carry the hybrid to term. Scientists at the Children’s Hospital of Philadelphia have worked on several different prototypes of an "extra-uterine support device" that they tested using lamb fetuses. However, these pre-clinical studies have been several weeks in duration, whereas the gestation period of an elephant is two years. Furthermore, there is a notable size difference between a lamb fetus and an elephant fetus; thus, while the results from pre-clinical studies have been promising, it's not clear – for now, at least – whether the technology could be translated for use in this project.

How will an extinct species find a niche in modern life?

Colossal's vision is to create a cold-resistant elephant that can thrive in the Arctic tundra. But the complex relationship between genotype and phenotype means that it is impossible to say with exact certainty exactly what the mammoth–elephant hybrids would look, behave and interact like. In a 2016 paper published in Functional Ecology, Professor Beth Shapiro, evolutionary molecular biologist at the University of California Santa Cruz, wrote, "Genome editing guarantees that the same gene is responsible for the phenotype. However, that gene will be expressed as part of a different genomic background, the consequences of which cannot be known until the organism is born."

Nathaniel Kitchel is an archaeologist at Dartmouth University, where he specializes in the study of the Late Pleistocene and Early Holocene populations. When asked for his thoughts on how mammoth–elephant hybrids might interact with modern animals – and humans – he told Technology Networks that it is "deeply" unclear.

"While some behaviors would likely be instinctual, many others would have been learned through socialization. Modern elephants are highly intelligent and highly social animals, where the young animals learn a great deal from older members of their group," Kitchel said. "Without the process of social learning, it may be that the behaviors exhibited by any recreated version of a mammoth would diverge considerably from now extinct populations." He emphasized that without the benefit of a social group, elephants could face substantial barriers to neurological development, which would subsequently impact their behavior.

Church is not ignorant to the potential issues surrounding socialization and emphasized that Colossal will be paying extremely close attention to this aspect of the project. "We think that there are ways we can use both natural elephant herds and also surrogates that are electromechanical – this is to be determined – but the idea is that we could train them to be even more well adapted than by natural means alone, in terms of socialization."

Ben Lamm (left) and Professor George Church (right), co-founders of Colossal. Credit: Colossal.

What technologies will be born from the project?

Should its de-extinction endeavors prove successful, Colossal will not be profiting from the mammoth–elephant hybrids. Rather, it's the cutting-edge technologies expected to be conceived through the project that will provide investors with monetary return.

However ambitious some of the new techniques may seem, if Church’s track record is anything to go by, their successful development shouldn't be ruled out. Over the last few decades, his lab has either produced or contributed to the development of an array of technologies that are integral to modern genomics research and beyond; be it multiple methods for next-generation sequencing (from nanopore to fluorescent techniques), novel approaches for the enzymatic synthesis of DNA or techniques for editing genomes.

According to Church, his lab can advance a new technology from concept to "industry-ready" with a budget of $1-2 million dollars. With $15 million dollars in Colossal' s funding pot, what technological fruits can we expect its de-extinction project to bear? "In principle, that [funding] could help us create seven new technologies, but nothing is perfect," he said. "We'll be lucky if we get one technology out of that first set [of investment]."

These methods, Church described, can be allocated to one of two categories: "inevitable", or being "intentionally aimed at serendipity". “Inevitable” means that their coming to fruition is a pretty sure thing. Those aimed at serendipity – including artificial endometrial implantation, methods for making gametes for endangered species, reproductive technologies and possibly behavioral technologies – are amongst the more challenging aspects of the project.

Colossal's business leaders have set aggressive goals for the project: they predict the first calf will be born in six years' time. This timeframe incorporates two years for initial mouse experiments, two years for "debugging" the transition to elephants and the two-year gestation period, Church explained.

One of the potential barriers to this timeframe is fine-tuning the genome engineering process. Inserting genes from one species into the genome of another – successfully – is no easy feat. But the Church lab has a lot of practice: "We've already successfully put 42 changes into the pig genome. They are healthy, breeding and are producing organs that can be used for clinical trials in hospitals. This shows us that we know how to go from an idea to a very complicated set of [genetic] changes, and make it work," he said.

What the team aren't certain of right now is just how many changes will need to be made in the Asian elephant genome to create the elephant–mammoth hybrid. The Church lab is a frontrunner in multiplexed genome editing – the process of introducing multiple changes in a genome simultaneously; its record number of successful changes made is 22,000. "If [the number of changes] is 42, then it doesn't require a lot of innovation. Of course, we're prepared for it to be a lot more than that," Church said. The magic number is yet to be revealed, but he anticipates that it is likely to be somewhat more than 42, but considerably less than 22,000.

Criticisms of Colossal "out of date"?

Regardless of the motivations behind its application, genome engineering is often subject to close scrutiny and debate, both within the scientific community and throughout society. The response to Colossal's mammoth project has been somewhat polarized.

Kitchel said that, while he finds the science behind de-extinction projects "fascinating", and potentially important in terms of the development of new technology, his feelings towards returning a particular species from extinction are somewhat mixed. "I am not convinced that the reintroduction of these animals to northern regions will have much impact on the climate crisis, as some have suggested," he said. "Personally, I think we are best served by protecting endangered species from becoming extinct, rather than trying to bring them back after they have disappeared. This obviously does not preclude working on the science of de-extinction, it is only to say that given the challenges and uncertainty of these techniques, I would rather we continue to work towards maintaining biodiversity instead of trying to reverse-engineer ecosystems after destroying them."

Technology Networks asked Church for his thoughts on the negative attention Colossal's de-extinction project has received. He argued that some criticisms of Colossal's efforts are "out of date" and "not in touch with what the project is actually doing".

"The most common question we encounter is: Well, aren't you forgetting about the endangered species? To which the answer is no, the project is specifically focusing on the Asian elephant. It is an opportunity to give them a chance. The question is often an innocent error, but it doesn't require much digging to find out that endangered species are a priority for us," he explained.

Church expanded on the two main reasons as to why the Asian elephant is endangered: 1) interaction with the herpes virus – which his lab has been researching for several years, and 2) interaction with humans. Sadly, Asian elephants are a target for poachers that kill the mammals to extract their valuable tusks. Exposure to poachers, Church said, is a result of Asian elephants living near human population centers throughout Asia. "We think we can solve the high population density by moving them into an 'ancestral stomping ground' where their distant relatives used to hang out and where there are potentially zero human inhabitants," he said. Colossal is also considering genetically engineering the mammoth–elephant hybrid to have smaller tusks. "Plenty of elephants in the wild do not have tusks, and so we can engineer this to be standard, or it could vary depending on whether the hybrid is under intense guard or not."

While many aspects of the project are under Colossal's control, the influence that mother nature could have on the wellbeing of the hybrids cannot be fully determined. Some argue that the optimal environment and climate for the woolly mammoth no longer exists. Church's response to such critique focuses on the adaptability of Asian elephants, which he anticipates would likely raise the first generation of calves. "Asian elephants adapt over a very wide range of temperatures – they can survive in very hot, humid Asian summers and also in cold, snowy environments," he said.

Bigger solutions are needed for the climate crises

Despite the "hype" that has stirred since Colossal initially announced its $15 million round of investment, Church is humble in his discussion of the woolly mammoth project throughout the interview. When questioned on what it means to him in the context of his career, he said: "I don't want to over or understate it," adding that, "While it is wonderful to receive the investment and reassurance of a broad range of investors, the funding is ultimately bringing the project up to scale [in financial terms] with our other projects."

Colossal's revival of the woolly mammoth isn't the only work Church is pursuing on carbon sequestration, but it's arguably the most ambitious. In his opinion, the current crisis our planet is faced with calls for mammoth-sized interventions. "Most of the [other] suggestions I hear seem very feeble," he said. "This [de-extinction] may not work. Other options might work, but not actually have any impact at all [on climate change]. For example, you could turn off your LED lights, or the whole human race could stop burning carbon completely. The latter would save 10 gigatons [of carbon] a year, but we have over a hundred gigaton-sized issue already."

It's speculative whether de-extinction approaches could realistically be scaled-up to the extent that Colossal achieves its ultimate goals for the project and the planet. Nonetheless, Church argued that he would rather try than never know: "If you have a better idea, I'm all ears. I'm all for turning off your lights, but we need some bigger solutions as well," he concluded.