Reacción a "Mice with fur reminiscent of extinct woolly mammoth created"

While we wait to de-extinct a woolly mammoth, we already have a woolly mouse. Some researchers never miss a trick. They are capable of carrying out and completing the most fantastical and extravagant ideas we can imagine. Ideas that the rest of us dismiss as impossible or unfeasible. For these researchers, nothing is impossible. Their conviction that they have the answer to problems, their perseverance and stubbornness usually bring them successes that the scientific community applauds with a mixture of surprise and bewilderment. This is the case of George Church, Harvard geneticist, founder of numerous companies and visionary.

Church was the one who, in 2015, managed to eliminate each and every one of the 62 porcine retrovirus integrations in the pig genome that limited its use for xenotransplantation, using CRISPR gene editing tools. Church was also the one who, in 2017, encoded and stored five frames of the first film ever shot at the end of the 19th century (a galloping horse) in the genome of bacteria, also using CRISPR. And Church is also the one who, together with Ben Lamn, founded a company in 2014 with a name as overwhelming (Colossal) as the objective they set themselves: the de-extinction of the woolly mammoth, a pachyderm whose last individuals disappeared some 4,000 years ago from an island in northern Siberia. And with a justification no less surprising: to combat climate change.

And now he is announcing the creation of a woolly mouse with some of the mammoth's characteristics, detailed in a preprint not yet published in any peer-reviewed scientific journal. Church may surprise us again with this experiment. However, it has its logic, as I will try to explain below.

The closest living animal, evolutionarily speaking, to the woolly mammoth is the Asian elephant. Using DNA obtained from various mammoth carcasses that have remained frozen and relatively well preserved for thousands of years in the Siberian tundra, the company Colossal has been able to obtain a high-quality mammoth genome to compare with that of the Asian elephant. There are around 500,000 changes between the two genomes that Church and his colleagues want to incorporate, one by one, using CRISPR tools, using cultured Asian elephant cells as starting material. This will take some time, and it is only the first of the technical challenges they will have to solve. Then they will have to reconstruct mammoth embryos using Asian elephant eggs and nuclei from the edited cells by means of nuclear transfer (cloning) and gestate them, probably in some extra-uterine system that has yet to be invented, improving on the existing systems that allow gestation and growth to be maintained outside the maternal uterus in lambs and premature babies. All this is going to take a long time, impossible to predict. And that is why they need intermediate successes that justify their project and allow them to move forward, demonstrating, with much simpler experiments, that it is possible to edit the genome of an animal to incorporate selected characteristics.

Church, together with the Colossal researchers, has applied different versions of CRISPR gene editing technology (both the first-generation tools, initially described by Emmanuelle Charpentier and Jennifer Doudna, as well as second-generation tools, the base editors, described by David Liu) on various mouse genes (up to 10), modifying or inactivating them, reproducing some of the genetic variants found in the mammoth that allowed it to withstand the freezing temperatures of its time. They have also resorted to a classic strategy of gene inactivation in embryonic pluripotent stem cells. All these approaches, in parallel, have allowed them to generate numerous mice, with different combinations of edited genes (the mouse that accumulates the most mutations has seven edited genes), which show an appearance and characteristics reminiscent of the woolly mammoth.

Thus, the inactivation of the Mc1r gene changes the dark color of the hair and turns it yellowish, reddish, like red-haired people and animals, like the mammoth had. Inactivation of the Fgf5 gene causes hair to grow up to three times longer than normal. Inactivation of the Fam83g, Fzd6, Tgm3, Astn2, Krt25, Tgfa and Krt27 genes alters the pattern of hair growth, which begins to curl and become thicker, as it did in the mammoth. The final appearance of the mouse thus edited is that of a woolly mouse, with thick, long, curly, red hair, similar to that of the mammoth, and surely much better prepared to withstand low temperatures than unmodified wild mice.

They have also edited the Fabp2 gene, which is involved in lipid metabolism and is thought to contribute to the storage of enough body fat to insulate and nourish the mice during the long winters. So far, the furry mice with this latest gene do not yet accumulate more weight than their unmodified siblings, which suggests that other gene modifications will be necessary for them to acquire this characteristic.

Naturally, each editing experiment carries a certain risk of uncontrolled genetic modifications in other similar places in the genome, a problem that these researchers have tried to limit as much as possible by selecting very specific RNA guides that only direct CRISPR editing in the intended genes. However, when editing many genes at once, these risks are also multiplied. Something they will have to take into account when they have to tackle not a dozen but thousands of genetic edits, to convert the genome of an Asian elephant into that of a mammoth.

In short, this experiment reported by Church and the researchers from the company Colossal demonstrates their ability to introduce precise genetic changes in a mouse, derived from the genetic differences found in the mammoth genome. No, they haven't yet de-extinct any mammoths, but they have shown the effect of some genetic variants found in the mammoth genome using mice as an experimental system to validate the effects produced by these mutations. A new indisputable success for Church that once again demonstrates his technical excellence, leaving both his followers and his critics speechless.