World first as scientists get the “Extinction Gene” to work in mammals

The phrase Gene Drive often sends a shudder down a scientist’s spine, one of awe and dread, and that’s because not only is it one of the most powerful and beneficial genetic technologies we have ever discovered, but, according to the UN it could also the world’s most powerful bioweapon, hence it being called the "Extinction Gene," even outstripping nuclear weapons for the title of “world’s most lethal” weapon. And that’s big.

Tiny snippets of engineered DNA, gene drives are nuclear-grade powerhouses that utterly destroy the rules of inheritance. Rather than the classic 50/50 coin toss, a gene drive can rapidly push inheritance rates to over 95 percent, forcing a new trait down entire generations and irreversibly changing an entire species forever – including in humans. Hence the world’s most powerful weapon title, especially if, for example, it’s used to do harm such as make an entire category of humans infertile, or worse.

So far, scientists have only dabbled with this “God” like technology of inheritance in insects and rats, with the hope of eventually wiping out mosquitoes that carry malaria and other transmittable diseases, and wiping out colonies of invasive rats on islands. Part of this handcuffing stems from bioethical and ecological concerns. The other part is purely technological - it’s really hard to get gene drives to work in mammals. But that’s about to change.

In a paper published last week in Nature, a team from the University of California, San Diego described the first rudimentary gene drive that works in mice, with a large caveat - only females are susceptible, and even then, inheritance rates are “only” pushed to the high 80s.

“Our findings suggest that doing this in mice is more complicated than it was in insects and that does raise questions about whether this will ever be as efficient as you’d need for wild release,” said Dr. Kimberly Cooper, who led the study.

Conservation groups have previously considered using gene drives to reduce the population of invasive rodents in New Zealand, Midway Island, and other regions. By pushing an “infertility gene” through a population, for example, countries plagued by rodent invasions could solve their problem without resorting to deadly poisons.

While Cooper’s results potentially throw a wrench into these plans, in the short term anyway, they do offer a large spark of hope - we now have conclusive evidence that gene drives work in mammals.

“It seems certain that the promise of continual improvements in gene drives will be matched with even more discussion of how to move forward. The development of this technique to generate a mammalian gene drive is another milestone in this exciting area of research,” said Dr. Bruce Conklin at Gladstone Institutes, who wrote an accompanying commentary but was not involved in the research.

This point is made even more salient when you realise that gene drive technology would be the perfect companion for scientists creating human designer babies, something that caused uproar around the world recently when a Chinese scientist showed off two genetically engineered twins who he’d engineered to be resistant to HIV and other diseases.

Cooper, however, had no intention of remaking nature when she decided to look into gene drives. Rather, her jam is evolution. Cooper studies the Jerboa, a hopping dessert rodent with springs for legs. Her lab was trying to tease out the set of genes that could transform the genetic profile of ordinary lab mice towards that of a Jerboa. And it turns out, it’s an extremely time-consuming task.

Inserting genes into mice and waiting for them to “stick,” so that a mouse carries two copies of the desired gene, takes generations of breeding. A three-gene edit, for example, could take thousands of mice before obtaining one with the desired genetic makeup. Similarly, scientists trying to engineer genes relevant for human diseases into mice to make model animals face the same roadblock.

“Our motivation was to develop [a form of gene drive] as a tool for laboratory researchers to control the inheritance of multiple genes in mice,” she said.

Rather than brute-forcing the problem, Cooper contacted her colleagues who had recently described this type of “active inheritance” in flies, and here’s the recipe.

The DNA letters needed for a gene drive, dubbed a cassette, contain instructions to make the CRISPR machinery. Once scientists stick the cassette into a chosen site on one chromosome, we have two in each pair, it churns out Cas9 “scissors” that cut the other sister chromosome.

The cell, sensing DNA damage, ends up repairing the cut using the gene drive-containing chromosome as a template. Voilá, both chromosomes now have the gene drive, the nerdy term is “homozygous,” ensuring that the drive will make it to subsequent generations.

Cooper took a different approach. Her team first made a half gene drive called CopyCat, which contained instructions to make the guide RNA, the “bloodhound” component of CRISPR that targets specific DNA, and stuck it into a gene called Tyr.

These mice were then bred with mice containing the other half of the CRISPR machinery, called Cas9. In this way, only mice that inherited both CopyCat and Cas9 will essentially have the complete gene drive within their DNA.

Why Tyr? The gene controls the production of an enzyme called tyrosinase that makes pigments, including those in the fur. This gives the researchers an easy readout - black mice didn’t inherit either component, whereas gray ones only got a half dose. White ones got the full toolkit on both chromosomes.

To be fair because the mechanism is spread across two animals, it isn’t technically a “gene drive.” Cooper went with this route because it lowers the danger of a gene drive escaping into the wild. With only half the mechanism, an engineered rodent wouldn’t be able to spread the trait like wildfire through multiple generations.

Surprisingly, several rounds of testing showed that the drive only worked in females, pushing white fur inheritance to roughly 86 percent. While that’s a big jump from the usual 50-50 split, it’s still a far cry from the 95 to 100 percent copying rate seen in mosquitoes.

Cooper thinks the failure in males could be due to bad timing. When the body generates reproductive cells, it splits up its chromosomes into two packs. Before this process happens, the sister chromosomes physically pair up to swap DNA, something called “recombination.”

Recombination happens to improve the odds of inserting a gene drive, if one chromosome gets cut, its paired partner will repair it with the desired DNA. This pairing up process is a lot shorter in sperm than eggs, and if a cut occurs when the chromosomes aren’t paired, it ends up destroying the Cas9 cutting site.

“We might be able to improve the efficiency and make it work in males if we can get the timing right,” said Cooper.

Conklin agrees: “[The study] is an important proof-of-concept that will surely be followed by modifications that might lead to improvements in future mammalian gene drives.”