CRISPR Active Genetics

Active genetics is a new CRISPR/Cas9 based method that greatly biases transmission of genetic traits, thereby bypassing traditional constraints of Mendelian inheritance. One application of this new technology is to create gene-drive systems for disseminating anti-malarial effector genes into mosquito populations. Active genetics has also been adapted to bacterial systems, with the potential to target and eliminate bacterial virulence factors or antibiotic resistant determinants.

Tata Institute for Genetics and Society (TIGS)

Active Genetics research at UC San Diego is conducted in partnership with the India-based philanthropic Tata Trusts and the Institute for Stem Cell Biology and Regenerative Medicine (InStem) in Bangalore with establishment of TIGS. The investigators of TIGS are deeply committed to the use of Active Genetics for beneficial purposes in a socially conscious, safe and ethical manner. TIGS examines the economic and social impacts of Active Genetics technologies, best practices for their safe use, and participates with international regulatory agencies in guidance on how and when to deploy this technology for highest impact with minimal environmental risks.

Visit the TIGS Webpage

Targeting Mosquito-Borne Infectious Diseases

Pioneering experiments conducted at UC San Diego and UC Irvine demonstrated that the malaria vector mosquito Anopheles stephensi can be genetically engineered using Active Genetics to express genes targeted against the malarial parasite Plasmodium falciparum, and that this new trait is inherited by nearly all of the mosquitoes’ progeny. TIGS and CHARM researchers and international collaborators are expanding on this work with a goal of developing mosquito strains that may ultimately be used to substantially reduce malaria transmission, using a vector replacement rather than a vector-elimination strategy. In addition to combating malaria, a disease that causes an estimated 450,000 worldwide deaths per year, this approach may also be leveraged against other mosquito-borne-disease agents, including Dengue, Chikungunya and Zika virus.

Opportunities and Challenges

In contrast with other genetic modification techniques, which are typically designed to minimize inheritance or transmission of altered genetic elements, the goal of a gene drive is to rapidly spread genetic information throughout a population. This makes it especially important to minimize the potential for unintended consequences. Reducing the potential for unintended consequences will require a combination of confinement and containment strategies. For active genetics to target pathogenic or antibiotic resistant bacteria, technical challenges will include selection of optimal delivery systems, e.g. bacteriophage or conjugal transfer, that can be deployed in environmental or clinical settings.

Active Genetics in Bacteria

CHARM and TIGS investigators targeted bacterial antibiotic resistance genes on high copy number plasmids through "pro-active genetics" (Pro-AG) with 100 to 1,000-fold greater efficiency than current cut-and-destroy methods. The technique involves a self-amplifying “editing” mechanism that increases efficiency through a positive feedback loop, and can also be adapted to deliver functional gene cargos.

Read the paper at Nature Communications

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