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New genetic systems created by biologists to neutralize gene engines



Active genetic systems

Scientists at UC San Diego and their colleagues have developed two new genetic systems that stop or eliminate genetic devices after release. Credit: Anna Silva

Two active genetic strategies are helping to address concerns about the release of gene engines in the wild.

Over the last decade, researchers have created a number of new tools that control the balance of genetic inheritance. Based on CRISPR technology, such gene devices are poised to move from the lab to the wild, where they are designed to suppress devastating diseases such as mosquito-borne malaria, dengue, zika, chikungunya, yellow fever and West Nile. Gene drives have the power to immunize mosquitoes against malaria parasites or to act as genetic insecticides that reduce mosquito populations.

Although the latest gene devices have been shown to propagate efficiently as designed in the laboratory, concerns have been expressed about the safety of placing such systems in wild populations. Questions have been raised about the predictability and controllability of gene devices and whether, once released, they can be called into the field if they spread beyond the intended region of application.

Now researchers at the University of California, San Diego, and their colleagues have developed two new active genetic systems that address such risks by stopping or eliminating genetic devices in the wild. On September 18, 2020 in the magazine Molecular cell, research led by Xiang-Ru Xu, Emily Bulger and Valentino Ganz of the Department of Biological Sciences, offers two new solutions based on elements developed in the common fruit fly.

New genetic systems

“One way to mitigate perceived risks from genetic drives is to develop approaches to stop their spread or erase them if necessary,” said respected professor Ethan Bier, senior research author and research director at the Institute of Genetics. and the Tata Society “There was great concern that there were so many unknowns about genetic devices. We are now saturated with opportunities, both genetically and at the molecular level, and we have developed mitigating elements. “

The first neutralization system, called e-CHACR (hitchhiking constructions by autocatalytic chain reaction), was designed to stop the spread of a genetic device by “shooting it with its own pistol.” e-CHACRs use the CR9PR enzyme Cas9 carried on a gene device to copy while mutating and inactivating the Cas9 gene. Xu says e-CHACR can be placed anywhere in the genome.

“Without a source of Cas9, it is inherited like any other normal gene,” Xu said. “However, once e-CHACR confronts a gene device, it deactivates the gene device in its tracks and continues to spread for several generations,” chasing “the drive element until its function is lost by the population.”

E CHACR and ERACR

The second neutralization system, called ERACR (Element Reversing the Autocatalytic Chain Reaction), is designed to completely remove the gene device. ERACRs are designed to be inserted at the site of the gene device where they use Cas9 from the gene device to attack both sides of Cas9 by cutting it out. After the gene device is deleted, the ERACR is copied and the gene device replaced.

“If ERACR is also given an advantage by carrying a functional copy of a gene that is disrupted by the genetic device, then it is competing across the finish line, completely eliminating the genetic device with a fixed solution,” Bier said.

Researchers rigorously tested and analyzed e-CHACR and ERACR, as well as their results DNA sequences, with detailed details at the molecular level. Bier estimates that the research team, which includes mathematical modelers from UC Berkeley, has spent about 15 years working hard to comprehensively develop and analyze the new systems. However, he warns that there are unforeseen scenarios that may arise, and neutralization systems should not be used with a false sense of security for gene devices implemented on site.

“Such braking elements simply need to be developed and kept in reserve in case they are needed, as it is not known whether some of the rare exclusive interactions between these elements and the gene drives for which they are intended may have unforeseen activities,” he said.

According to Bulger, genetic devices have a huge potential to alleviate suffering, but their responsible deployment depends on the availability of control mechanisms in the event of unforeseen consequences. ERACRs and eCHACRs offer ways to stop the spread of the gene device and, in the case of ERACRs, can potentially return the engineered DNA sequence to a state much closer to the natural sequence.

“Because ERACR and e-CHACR do not have their own source of Cas9, they will only spread to the gene disk itself and will not edit the wild-type population,” Bulger said. “These technologies are not perfect, but we now have a much more comprehensive understanding of why and how inadvertent results affect their function, and we believe they have the potential to be powerful mechanisms for controlling gene drive if the need arises.”

Reference: “Active Genetically Neutralizing Elements for Stopping or Deleting Gene Devices” by Xiang-Ru Shannon Xu, Emily Bulger, Valentino Gantz, Carissa Klanseck, Stephanie Heimler, Ankush Auradkar, Jared Bennett, Lauren Ashley Miller, Sarah Leahy, Sara Sanz Jus , Anna Buchman, Omar Akbari, John M. Marshall and Ethan Bier, 18 September 2020, Molecular cell.
DOI: 10.1016 / j.molcel.2020.09.003

Support for the study included: National Institutes of Health (R01 GM117321; DP5OD023098); Paul G. Allen Frontiers Group Award for Distinguished Investigator; DARPAthe Safe Genes program (HR0011-17-2-0047); and a gift from Tata Trusts in India for TIGS-UC San Diego.

Bier and Gantz state-owned and serve on the board of directors and scientific advisory board of Synbal Inc. State-owned equity Bier, Gantz and Akbari and serves on the scientific advisory board of Agragene Inc. Akbari also receives revenue from Agragene. These companies can potentially benefit from the research results.




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