Source: United Kingdom – Executive Government & Departments
An unpublished preprint uploaded to BioRXiv looks at gene editing in mice to create woolly mammoth-like hair phenotypes.
Dr Tori Herridge, Senior Lecturer, School of Biosciences, University of Sheffield, said:
Woolly Mouse in Context
“Colossal have announced that they have successfully bred ‘woolly mice’, and this is a “water shed moment” in their mission to genetically engineer an arctic adapted elephant, aka “bringing back the mammoth.”
“Colossal’s team made a number of genetic changes known as “knock outs” in lab mice that are already known to produce longer, thicker, wavier — or woollier — coats in mice. They also made a change known to cause blonde hair colouring in mice.
“The result, therefore, of various “woolly mice” from these genetic changes is unsurprising: woolly mice have been produced in labs and by mice breeders many times before.”
Mammoth-like genes?
“Three of the genetic changes made in some of the mice were inspired by woolly mammoth DNA, but they still only show effects in mice. The mice were not edited to have a precise copy of the mammoth genes, but it is possible that these edits may have had a similar effect in both mice and mammoths (either by stopping the gene from working, or by changing the way the gene worked), but we cannot be sure about this.
“It is also not possible to tell what impact these ‘mammoth-inspired’ changes had, if any, in the Colossal woolly mouse owing to other gene edits made at the same time.”
Are we a step closer to ‘bringing back the mammoth’?
“A mammoth is much more than just an elephant in a fur coat. While we know a lot about mouse genetics, we know much less about mammoths and elephants. It isn’t yet known which sections of the genome are vital for achieving the characters need to make an elephant fit for life in the Arctic circle. Genes that are linked to fur and fat in well-studied animals like mice are obvious targets, but the devil is in the detail. And what about other characters that are equally important? Which bits of the genome underpin the teeth and jaw changes that might be needed to accommodate an Arctic diet, for example (mammoth teeth were clearly under strong evolutionary pressure to adapt to their diet)? What about things we haven’t even discovered yet, things we don’t know we don’t know?
“Unless you decide to make EVERY edit necessary to in the genome, you are only ever going to create a crude approximation of any extinct creature, based on an incomplete idea of what it should look like. You are never going to ‘bring back’ a mammoth.
“Colossal’s Woolly Mouse experiments also show that de-extinction attempts are fraught with failure: most gene-edited embryos failed to result in live pups (less than 10%), and very few of those born were successfully edited for all target genes. This is for experiments that made a small number of relatively simple (loss of function) changes in well understood genes, using a ‘model’ lab animal as a surrogate.
“Engineering a mammoth-like elephant presents a far greater challenge: the actual number of genes likely to be involved is far higher, the genes are less well understood (and still need to be identified), and the surrogate will be an animal that is not normally experimented upon. Even if success rates are similar to those observed in the woolly mice (and they may well be lower given the greater number of edits and unknowns), there will likely need to be multiple pregnancies before a “successful” calf is born. This equates to either a very large number of surrogate dams, or – given elephant pregnancies last approximately 2-years – a very long time.
“Mammoth de-extinction doesn’t seem to be on the horizon anytime soon.”
Ethical Considerations
“Colossal’s Woolly Mouse experiments show that the physical effect of genome-editing cannot be observed until the animal experimentation stage. This will also be true in elephants.
“Although it is branded as “woolly mammoth de-extinction”, what is being proposed is an experiment to test the effect of certain gene edits on the appearance of elephants.
“For the mice in these experiments the risk was small: the effect of these gene edits already known, and were not likely to cause risk or suffering to surrogate or pup.
“We do not know the risk involved for elephants, but it could be very high.
“We do know that surrogacy is a burden on the dam, and that captive elephant pregnancies carry risks even under normal circumstances.
“Placing such a burden of risk on an elephant surrogate in pursuit of an experiment that – at best – will produce a simulacrum of a woolly mammoth, is unjustifiable.”
Dr Saad Arif, Senior Lecturer, School of Biological and Medical Sciences, Oxford Brookes University, said:
Is there enough info to comment on the announcement, how well can we judge what has been accomplished and how it has been done?
“The preprint provides enough information on what has been accomplished and how it was conducted.”
How novel is the research and techniques to create the mouse, is it more than just genetically engineered lab animals? Is this something more special?
“One novel element of the work seems to be the use of genome-editing technologies to alter multiple genes at once with high efficiency and speed in mice. Although we have had the ability to alter multiple genes at once for sometime, the efficiency and speed with which these changes can be made could still be improved. Based on the results presented by the authors, their methods for generating transgenic mice with the desired changes appears to be both rapid and highly efficient, which would be extremely desirable when testing for the function of genetic changes in any context, whether it has implications for conservation or disease biology.
“Genome-editing can also lead to unintended edits in non-targeted parts of the genome resulting in unwanted modifications, so-called off-target effects. Although, the authors report no missense mutations (potentially eradicating or modifying an untargeted gene’s function), this is not demonstrable proof that gene function hasn’t been altered. Such off-target effects could be detrimental in real world applications of genome-editing e.g. curing a disease or in trying to turn an ‘elephant” into a mammoth’.
“Another novel aspect of this study is that some of the genes targeted by the authors are based on their comparisons of ancient mammoth and modern elephant genomes. This set of genes (in contrast to most of the others, which are selected based on information from mice studies) comprise those with identified differences between cold-adapted mammoths and their warm-adapted elephant cousins. Hence differences in these genes could potentially be part of the cold adaptation repertoire of mammoths. This really paves the way for exploring the consequences of genomic differences in extinct species or populations.”
How is this proof of principle for the research missions of the company?
“It shows that Colossal have a model system to validate predicted effects of the DNA differences they have identified between mammoth and elephant genomes and which of these differences is relevant for mammoth’s cold adaptations. For example, they identified differences in DNA sequences of a gene that controls hair length both in Elephants and Mammals, they then introduced that difference in their mouse model, via genome editing, and determined that the change does indeed affect hair growth. The ability to edit genomes. rapidly and efficiently, to test the role of DNA changes will help them prioritize which genetic modifications are relevant for cold adaptation.
“However, it is important to note that their ability to predict whether a gene controls hair growth comes from work done in mice, humans and other organisms. Not all genes will have functional effects that are so easy to predict because not all genes are as well studied and screening for the effect of alterations in these genes may not be as straightforward. Many genes, unlike those that control hair colour or some aspect of outward appearance, may not have immediate or directly observable effects. Finally, given the idiosyncrasies of mouse biology, some genetic edits will just not manifest themselves in the same way as they would in mammoths or their relatives. The authors acknowledge this and this is a well-known issue with the use of mice in studying human genetics as well. Hence, being able to test whether a specific difference between mammoths and elephants is related to the former’s cold tolerance is still challenging.”
What are the implications of this research? How close are we getting to the “de-extinction” of the Woolly Mammoth? Does this have significance in conservation biology?
“I think we are still very far from their “de-extinction” goal. The elephant and mammoth genomes are considered to be 96.4% identical, however, that still leaves potentially another ~13 million changes in DNA sequence to consider! It is also still unclear how mammoth cold adaptation phenotypes without a clear outward manifestation, could be identified or screened in mice.
“Additionally, at the moment it is difficult to see how they will “birth” a mammoth-like elephant as that may also require some additional technical advances and ethical considerations as this may require elephant surrogacy. Nonetheless, it still remains a goal worth striving for because of potential technical advances they could be achieved along the way. I wouldn’t mind being proven wrong on this.
“I see this as a fairly small step towards their “de-extinction” goal and I still see us far from any direct impact in conservation biology. Nonetheless, being able to test the genetic effects of DNA differences discovered from extinct species and populations could help us identify the genes and sequence differences involved in making organisms more adaptable to their environments.
“Finally, the efficiency and speed of their multiplex genome-editing technologies is promising and perhaps the most impactful part of their work. These methods could have implications for human disease and biology and help us understand, and potentially treat, complex genetic diseases or traits that are controlled by multiple genes.”
Is there any ethical significance of this research to consider?
“I don’t think the results of the current research are of any ethical significance. However, later down the line, the idea of ‘birthing a mammoth’ via an elephant (an endangered species) surrogacy will surely raise ethical concerns.”
Dr Louise Johnson, Evolutionary Biologist, University of Reading, said:
“Seeing these mice is a bit like looking back at the past, but with a highly selective telescope. This technology offers an exciting opportunity to test some of our ideas about extinct organisms.
“It is an interesting piece of work, but the idea that we could bring something back from extinction is false hope.
“What has been done here is not trivial, but of the ten different mutations engineered into the mice, only a few actually make the mouse gene closer to a known mammoth gene. The result does show that it is possible to genetically engineer many genes at once and still produce some live mice at the end of the process, though. The researchers have succeeded in nudging the mouse genome in the direction of a mammoth genome, which is a first.
“If we have an idea of what a gene might do in an extinct mammal, this technology can produce powerful results by introducing a very similar sequence into a mouse. But in this particular case, most of the mutations are chosen just because they are already known to make mice have longer, coarser, wavier hair. You could, in theory, produce mice like this by just breeding mice with weird hair together.
“In theory, you could introduce a gene for hairiness into an elephant and it would look quite mammoth-like, but it wouldn’t be a mammoth in any meaningful way. Elephants would be a terrible species to do this research with – they are huge, have long gestation periods, and require highly specialist housing and care. The mouse is a brilliant lab animal, and we know a lot about the mouse genome and how to alter it effectively.
“You do have to know a bit about how the extinct genes might work. For example, it was already known that the genes for coat colour and texture were similar in the mammoth and the mouse. Being able to create and introduce a mouse gene that is somewhat the same as the mammoth opens up a new way to look at evolutionary genetics.”
Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:
“Genetic engineering in mice has been performed for a very long time using, developing, and testing a variety of technologies. These modifications include introducing traits from other species, notoriously ‘humanised mice’ that have been used for research related to human traits and disease.
“The decoding of an extinct species genome to identify specific genes associated with particular traits has also been done before, where the physical characteristics of ancient humans have been deduced from their genomic data.
“Perhaps the novelty here is using mice to confirm the assumptions about correlations between genes and specific traits. The press release gives the impression that mammoth genes were introduced to mice but from the preprint, it transpires that the genomic editing in these mice consists of inducing loss of function of several genes simultaneously. The choice of these genes comes from observed spontaneous mutations in mice that impact traits such as coat and comparative analyses of elephant and mammoth genomes that reveal similar loss of function in some of these genes.
“The ability to use mice in order to examine and test gene-trait relationships and hypotheses about physical characteristics specifically using genomes from extinct organisms might prove useful, but overall not particularly novel.”
Prof Dusko Ilic, Professor of Stem Cell Science, King’s College London, said:
“The achievement described in the latest press release regarding “woolly mice” is interesting, particularly in terms of the strategy used to refine the list of genes related to hair growth that were also compatible with their model organism—the mouse. This is indeed a noteworthy milestone.
“Once the gene list has been established, engineering mutations in mice, including those involving seven genes, is a well-established process and not particularly challenging.
“With mice, the process is relatively straightforward. Their gestation period is only three weeks, and they typically give birth to six to eight pups per litter. However, translating this approach to elephants presents significant challenges. Elephants have the longest gestation period of any mammal—approximately two years—and generally give birth to a single calf. Furthermore, it will take 10-14 years for them to be sexually mature.
“Assisted reproductive technologies (ART), including in vitro fertilization (IVF), have seen limited success in elephants. The primary ART method employed in elephants has been artificial insemination (AI). The Indianapolis Zoo achieved a significant milestone in 2000 by facilitating the first successful birth of an African elephant conceived through AI. In 2023, the same zoo announced that a 16-year-old African elephant named Zahara was pregnant via AI, marking the first instance where an elephant born through AI is expecting a calf conceived by the same method.
“This raises critical questions: How many elephant cows would need to undergo experimental pregnancies to give a birth to a “woolly elephant”? And how long would it take before the first such hybrid is born?”
Dr Denis Headon, Group Leader and Senior Research Fellow, The Roslin Institute, University of Edinburgh, said:
“With a long-term goal of advancing the de-extinction of the mammoth, the team have managed to alter several mouse genes in one step. They chose these gene alterations based largely on things that we know about mice, rather than what we know about mammoths. This approach produced very shaggy mice with a coat that resembles that of the woolly mammoth remains we find today. While the mice have a striking golden coat, they are otherwise healthy, indicating that the method used is not harmful. Certainly this is an advance in speeding up the rate of genetic modification towards the many changes that distinguish one species from another, though it’s not clear that these changes alone would alter a relatively hairless elephant into a woolly animal. Further work on either synthesising or understanding the mammoth genome would also be required to go beyond these superficial characteristics to generate an animal that would, for example, have the right behaviour to live in Arctic conditions. This paper reports an important advance not only for de-extinction but for animal breeding in general.”
An unpublished preprint titled ‘Multiplex-edited mice recapitulate woolly mammoth hair phenotypes’ by Rui Chen et al. was uploaded to BioRXiv on 13:00 UK time Tuesday 4 March.
Declared interests
Dr Saad Arif: None
Dr Louise Johnson: None
Dr Alena Pance: I can confirm I have no conflict of interest regarding this story
Prof Dusko Ilic: I declare no conflicts of interest.
Dr Denis Headon: I don’t have any interests to declare on this paper/story.
For all other experts, no response for our request for DOIs was received.
