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New CRISPR-based technique in mice upends rules of genetic inheritance

January 23, 2019

undefinedA new method using CRISPR-based gene editing allows researchers to change the natural way genes are inherited in mammals. They demonstrated the technique using a genetic alteration that renders lab mice white.

The way we inherit genes is responsible for much of humanity’s incredible diversity. Our randomly scrambled DNA blueprint — half from each biological parent, more or less — is the reason we’re not carbon copies of our parents. It may even keep certain genetic diseases from wreaking more havoc than they do.

It’s also a massive thorn in the side of many scientists.

Humans and mice have more than 20,000 different genes, each present in two different copies. If a researcher wanted to change just 10 of those genes in a single laboratory mouse — say, to create a better model of a human cancer — it would be a Herculean task in terms of time and resources.

With standard techniques, researchers make changes to one gene at a time and then wait through several mouse generations, hoping to get enough offspring who inherit both copies of the engineered gene. That process gets exponentially more complicated the more genes they want to tweak. Now, a research team at the University of California San Diego has adapted the technique known as CRISPR to enable mice to preferentially inherit an engineered gene. The technique thus upends the natural laws of genetics.

The researchers describe their method, which is the first time this technique has been demonstrated in mammals, in a study published today in the journal Nature. Being able to quickly and more economically manipulate laboratory animals’ genes means researchers can make more faithful replicas of human diseases in the mouse — potentially speeding medical research.

“This is changing the rules of genetics,” said Ethan Bier, Ph.D., who is an Allen Distinguished Investigator, Professor at UC San Diego and a co-author of the study. “There are serious restrictions that make certain genetic experiments very difficult. Everything would be different if we didn’t have those constraints.”

undefinedEthan Bier, Ph.D., talks about his recent gene editing research at the 2018 Allen Frontiers Symposium at the Allen Institute.

The researchers used a gene that underlies fur color to show that the method works, introducing a modification that results in albino mice only if the animals inherit two copies of the engineered gene. Using their method, researchers showed that female mice with one engineered and one “normal” gene frequently duplicated the engineered gene to replace the normal copy. Under certain conditions, the animals gave birth to fully white mice 86 percent of the time, far higher than would be expected if the normal version hadn’t been replaced.

The parent technique for pest control

The method, which Bier terms “active genetics,” is the parent technique to a more controversial method known as a gene drive, which uses CRISPR-based gene editing to “drive” an engineered gene or genes throughout an entire population over multiple generations. Researchers have proposed using gene drives to wipe out pest species or make mosquitoes unable to carry malaria, although none have yet been tested in the wild.

The research team hoped active genetics would also work in mammals, but going into it they weren’t sure, said Kimberly Cooper, Ph.D., an Assistant Professor at UC San Diego and senior author on the study.

undefinedKimberly Cooper, Ph.D. (right), and UC San Diego graduate student Hannah Grunwald, authors on the new study describing the active genetics technique in mice.

“When gene drives were first demonstrated in insects and yeast, it was really exciting, but the evolutionary distance between those species and mammals is almost 800 million years,” Cooper said. “It wasn’t obvious that all the relevant machinery inside of a cell would be preserved and that this would work. So the fact that it works at all is really exciting.”

This technique is what makes gene drives possible, Bier said, but to be clear, they haven’t built a gene drive for mammals. If a gene drive is like putting a brick on the gas pedal of a car, this method of genetic tweaking in the mouse is more like a controlled and gentle tap on the accelerator.

“It’s not a gene drive in the sense that the changes are being driven anywhere,” Bier said, “at least, not very far.”

Debates over whether gene drives are ethical to use in the wild arise in part because they could be used to eliminate an entire pest species or, at the very least, permanently introduce a human-made gene into a natural population of animals. The technique Cooper, Bier and their colleagues demonstrated in mice doesn’t have the potential to take over an entire population, in part because it turned out to be less efficient than gene drives in insects.

But the researchers also purposely uncoupled two pieces of the molecular gene editing package so that its action wanes over generations, a method sometimes referred to as a split drive. True gene drives allow both the mutated gene and the gene editing molecules themselves to be inherited together, allowing the engineered gene to be copied in perpetuity.

Active genetics beyond insects

There would be a long way to go before this technique could be used for rodent pest control — for one, it only works right now in female mice — but it has more immediate applications in biomedical research, the study authors said. Lab mice are often used in the early stages of drug discovery or other disease-related studies, but it’s often difficult to faithfully model human diseases in other animals. The ability to rapidly and economically introduce a suite of human-like genes into mice could allow researchers to build better mouse models, potentially both speeding medical research and vastly reducing the number of animals needed for a given study.

Extending the reach of active genetics from insects to other animals was one of the original goals of Bier’s application to The Paul G. Allen Frontiers Group, the division of the Allen Institute that names Allen Distinguished Investigators. The idea was too risky for traditional funding sources to support, Bier said, but since he received the ADI award in 2016, the research team has since received more support for active genetics from other philanthropic sources.

“There are all these things that the traditional funding system doesn’t fund, and it’s exactly that gap that is filled so graciously by philanthropic foundations,” Bier said. “It’s impossible to overemphasize the importance of philanthropic contributions to the advance of science.”

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