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Daisy Chain: A Gene Drive System With Built-in Controls

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Posted April 8, 2019

Genetic engineering tools that spread genes within a target species have the potential to humanely control harmful pests or eradicate parasitic diseases such as malaria from a local area.

The tools, known as gene drives, ensure that engineered organisms transmit desired genetic variants to their offspring. These variants could ensure that the organisms only produce male offspring or sterile females, for example.

The mosquito Aedes aegypti can spread several diseases as it travels from person to person. Only the females feed on blood. This mosquito is just starting to feed on a person’s arm. Illustration by Stephen Ausmus, USDA ARS

The mosquito Aedes aegypti can spread several diseases as it travels from person to person. Only the females feed on blood. This mosquito is just starting to feed on a person’s arm. Illustration by Stephen Ausmus, USDA ARS

In this way, gene drives could be used to exterminate insects that carry pathogens, including mosquitoes, which spread malaria and the dengue and Zika viruses. Gene drives could also be used to control invasive species such as rodents that threaten the survival of native animals.

However, previously described versions of gene drives based on the CRISPR genome editing system have the potential to spread far wider than their intended local population to affect an entire species.

They could also spread across international boundaries, potentially leading to disputes between countries if no prior agreement had been made.

Such concerns could significantly delay, or altogether prevent, the safe testing and introduction of the technology.

Now, in a paper published in the Proceedings of the National Academy of Sciences, researchers at Harvard Medical School and MIT describe a gene drive system with built-in controls.

Kevin Esvelt, assistant professor of media arts and sciences and director of the Sculpting Evolution group in the MIT Media Lab, developed the system in collaboration with George Church, the Robert Winthrop Professor of Genetics in the Blavatnik Institute at Harvard Medical School.

Co-first authors Charleston Noble and John Min, both HMS graduate students in the Church lab, led the modeling and the molecular biology experiments designed to ensure the system is evolutionarily stable.

Links in the chain

The CRISPR-based drive consists of a series of genetic elements arranged in a daisy chain.

One link within the daisy-drive system encodes the CRISPR gene editing system itself, while each of the other links encodes guide RNA sequences. These guide sequences tell the CRISPR system to cut and copy the next link in the chain.

Adding more links allows the daisy-drive system to spread for more generations within the population.

“Just imagine you have a chain of daisies and you pluck off the one on the end, and then you pluck off the next one, and with every generation you pluck off a link in the chain, until you run out, and it stops,” Esvelt said.

In this way, a small number of genetically engineered organisms could be released into the wild to spread the daisy drive among the local population and then stop when programmed to, he said.

“We’re just programming the organism to do CRISPR genome editing on its own, within its reproductive cells, each generation,” Esvelt said.

Driving change

“If the world is to benefit from new gene-drive technologies, we need to be very confident that we can reverse it and contain it, both theoretically and via controlled tests,” added Church.

“Many of the applications of gene drives involve islands and other geographical isolations, at least for initial tests, including invasive species and Lyme disease,” Church said. “It would be great if these highly motivated local governments can do tests that do not automatically affect adjacent islands or mainlands. The daisy-chain drives offer this.”

The research suggests that for every 100 wild counterparts, releasing just one engineered organism with a weak three-link daisy-drive system, once per generation, should be enough to edit the entire population in about two generations—roughly a year in a fast-reproducing insect. Most existing systems require the release of at least as many organisms as are already present in a local population, sometimes 10 or 100 times as many.

The process could take several years in species that reproduce more slowly, such as mice, but would be more humane than the existing use of rodenticides, which can also harm people and predator species, Esvelt said.

Responsible use

In 2014, Esvelt and colleagues first suggested that CRISPR-Cas9 could be used in gene-drive systems. As a result, he said, he has felt a moral responsibility to develop an alternative to self-propagating systems.

“Ideally, localization will let each community make decisions about its own environment without forcing them on others,” Esvelt said.

Self-propagating drive systems can spread rapidly through target populations, according to Luke Alphey, head of arthropod genetics at the Pirbright Institute in the United Kingdom, who was not involved in this research but is now collaborating with Esvelt.

Such drive systems, however, are also thought likely to spread to all connected populations of the target species, which is desirable if you want to modify the entire species but undesirable if you do not, Alphey said.

“Daisy drives potentially provide a means to get much of the benefit of this type of gene drive while constraining spread and also limiting persistence of the gene drive even in the target population,” he said.

Alphey is now working with Esvelt on the use of daisy drives in mosquitoes.

Esvelt’s group and collaborators are also beginning to work on daisy drives in white-footed mice, the primary reservoir of the bacteria responsible for Lyme disease in the U.S.; Cochliomyia, known as the New World screwworm, a parasitic fly that produces larvae that eat the living tissue of warm-blooded animals, causing considerable suffering; and fast-reproducing nematode worms, which will allow the researchers to study the evolution of daisy-drive-engineered organisms in the lab to ensure the systems cannot become self-propagating.

Source: HMS

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