With the "woolly mammoth rat", can we really "revive the mammoth"?

On March 4, the US biotechnology company Colossal Biosciences announced that they had created a batch of "woolly mammoth mice", saying that this was the first step in resurrecting mammoths. The company was founded in 2021 with the goal of resurrecting mammoths, dodos, thylacines and other animals that have not been extinct for a long time.

As can be seen in the photos and videos released, these mice have long and thick hair, and indeed have some of the charm of mammoths.

Image source: Colossal Biosciences

The company also uploaded a preprint of a paper that had not been peer-reviewed at the time of the news release. This is undoubtedly an achievement of gene editing technology. But can these so-called woolly mammoth mice really increase our understanding of mammoths?

Are there really mammoth genes in mammoth rats?

Trying to resurrect the mammoth but ending up with the mammoth rat sounds like a joke.

Image source: A social platform

But after laughing, many readers probably think that this mammoth mouse is a hybrid product of mammoths in some sense, or at least uses some mammoth genes. But genes are not Lego blocks, and you can't just move them from one species to another. Is this so-called mammoth mouse really made with mammoth genes?

The biggest problem comes from the main promotional image used in this round of media reports. Comparing it with the preprint paper released by the company, it can be found that these two long-haired mice look most likely to be the two mice numbered 512 and 517 in the paper. This is understandable, after all, other mice are not as good-looking as these two.

Image source: Colossal Biosciences

So how much is the relationship between the mammoth appearance of these two poster girls in this study and their mammoth genes?

It can be said that "not at all".

Researchers edited five genes of these two mice, four of which are related to hair. But these four are genes that the academic community has long been familiar with. For example: Fgf5 is responsible for inhibiting hair growth, and knocking it out will cause the hair to grow longer. Everyone knew this 30 years ago; the "hairy" mutation of Fam83g, as the name suggests, will make the hair more abundant and fluffy; Frzd6 is responsible for the direction of the hair, and after knocking it out, the hair will grow in tufts randomly; Mcr1 is responsible for the color of the hair, and knocking it out will make the hair golden. All four of them contribute to the "mammoth appearance" of the two mice 512 and 517. However, none of them are "mammoth-characteristic genes."

This is not to say that the mammoth's genes do not contain them. All life on Earth is a distant or close relative, and there are some similarities in genes. Mammoths and mice are both mammals, not too far away, and there are many homologous genes, but these genes are also found in other mammals - such as humans. In humans, the FGF5 gene is also responsible for hair length - according to the naming logic of "woolly mammoth mice", they can also be called "human mice".

So what kind of gene can bear the name of mammoth characteristics? Logically speaking, such a gene should be newly born in the mammoth species, or at least have undergone some important evolution in the mammoth.

Scientists already know about similar genes, such as Fabp2, which is responsible for fat transport. In the mammoth genome, it seems to be cut off, and most likely lost its function. If researchers knock out this gene in mice, although it is not literally "transporting" the mammoth gene, it can be regarded as continuing the spirit of the mammoth. In addition, another gene Tgfa does not seem to function properly in mammoths. There is also a gene Krt27 that has an amino acid difference between mammoths and their close relatives, elephants...

The researchers of the woolly mammoth mouse project knew about the genes mentioned above. They also followed suit. The preprint paper mentioned a mouse, No. 571, which has multiple mammoth-inspired genes, making it the most mammoth of the batch.

However, it looks like this:

Image source: Colossal Biosciences

Guess why the "woolly mammoth" project didn't choose it as the exhibit for this project.

Can the mammoth be resurrected through genetic technology?

Although many technology companies and even researchers often talk about resurrecting mammoths, to be honest, it is still a long way from humans to revive a real mammoth. Beth Shapiro, one of the main scientists responsible for sequencing the mammoth genome and chief scientific officer of Colossal Biosciences, asserted in 2015 that humans will never be able to revive a "pure" mammoth.

First, we don’t have any genomic data ready to use. Although the mammoth genome has been sequenced “completely” in name, this is only complete enough “in terms of data processing and research”, and does not mean that we have really obtained a complete set of genes for a living organism. Many studies in recent years have shown that whole genome sequencing methods can easily miss some fragments. If the genome of a complex organism really has so much damage, whether it can survive normally will be a big problem.

Secondly, having data does not mean having physical gene fragments. It is difficult to guarantee the accuracy of artificially synthesized DNA as long as the length exceeds a few hundred. For longer DNA, it can only be pieced together with short fragments, but too much pieced together will also face the problem of accuracy. The current world record length of synthetic genomes is about 4 million words - but the genome of mammoths is about 4 billion. And the 4 million words is the genome of Escherichia coli, which is a prokaryotic organism and relatively simple. Mammoths are eukaryotic organisms, and their genes are combined with proteins in a complex way and folded into chromosomes. It is even more difficult to achieve this artificially.

Third, even if we get a complete genome, it still won’t work. The smallest unit of life is the cell, and we need at least a complete mammoth cell - which is of course impossible, so we can only consider using an existing elephant as a substitute. Not to mention whether the mammoth raised by elephant cells is a real mammoth, it is also difficult to predict whether the cells can accept the mammoth gene and develop normally.

In fact, Colossal Bioscience is very aware of these problems. The company's CEO Ben Rahm said in a recent media interview, "We hope to get the first cold-adapted elephant in 2028... Over time we can produce a whole batch of cold-adapted elephants that can be released back into the wild for reproduction."

In other words, he clearly admitted that the company's goal was not to produce a real mammoth. Such a "transgenic elephant" would be of no help to paleontology and evolutionary biology, and would probably not have any commercial breeding value.

Of course, there is a theoretically feasible goal, which is what he said, "returning them to the wild for reproduction." The goal of this kind of wild release is not traditional ecological protection, but to allow these animals to reconstruct the existing ecosystem. This goal is usually called "Pleistocene rewilding."

Can resurrecting animals save the world?

At the end of the Pleistocene, about 10,000 years ago, large creatures in most parts of the world except Africa experienced a mass extinction. Mammoths were one of the victims of extinction. Although a small number of mammoths survived for thousands of years on remote islands, the overall situation was irreversible.

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The extinction was linked to the end of the Ice Age, but hunting by humans may have been even more important. In the 10,000 years since then, a number of key locations in these ecosystems have remained empty.

The far-reaching consequences of this fact have only been gradually recognized by ecologists in recent decades. For example, North American ecosystems have evolved under the shadow of large organisms. After the disappearance of large organisms such as mammoths, 10,000 years have passed, and the original balance has not been restored here. The goal of the Pleistocene rewilding plan is to reintroduce substitutes for these large animals, graze overgrown vegetation, hunt smaller herbivores, and return the distribution of matter and energy flow in the ecosystem to the pattern of 10,000 years ago. In this scenario, it doesn’t matter if the mammoth is a fake transformed elephant. As long as it can survive in the subarctic zone, it can play a similar role.

The basic logic of rewilding makes sense. But all practical operations face a fundamental question that cannot be avoided: the past may have been good, but can we really go back? In a world of global warming, tundra collapse, and humans on every continent, is there really a place for animals like mammoths?

Moreover, elephants are social animals with a knowledge inheritance. The old patriarch is responsible for leading the herd to find food and water, female elephants and their relatives raise the young and old elephants, and adult male elephants are responsible for disciplining the young elephants approaching the estrus period. For artificially cultivated mammoths, this knowledge and social structure must be built from scratch. How can such a herd face the landscape they have never seen before?

Gene editing technology and genomics are probably the most remarkable achievements in biology in the past two decades, and they are likely to become the "cornerstone" of human progress in the next hundred years. But technology is not magic or a time machine. Every use of technology by humans is forward, not backward. Resurrected mammoths may really save the world, but that road is bound to be longer and more unpredictable than resurrection itself. Today's "mammoth rat" can be regarded as a step in that direction, but this step can only be said to be minimal, not even a "small step for a mouse".

Planning and production

Author: Fang Gang, popular science creator

Reviewer: Huang Chengming, Researcher at the Institute of Zoology, Chinese Academy of Sciences

Planning丨Xu Lai

Editor: Yinuo

Proofread by Xu Lai and Lin Lin