New Excising Protein Inserts Hope Into CRISPR And Its Industry
Over the past year, the CRISPR/Cas9 gene editing system has fallen from buzzword status as studies corroborated potential toxicity issues. New research has suggested the replacement of Cas9 with Cas12a may avert these issues, bringing hope to CRISPR applications in humans.
Naturally, the CRISPR/Cas9 system acts as a prokaryotic immune system to grant acquired resistance to foreign genetic elements. It stores remains of these genetic elements in CRISPR spaces after an infection. When the bacteria are under a second threat, Cas9 enzymes carry guide RNA sequences to cut present DNA at a complementary site to irreversibly damage the invading virus.
In 2017, there were more than 14,000 published papers referring to CRISPR. Researchers have evidenced its efficacy in nearly every organism, significantly lowered its cost to be commonly used in any lab, and engineered new applications including knockdown/activation and RNA editing. Vox has a comprehensive guide to CRISPR if you’d like to learn more about the history or its applications. (https://www.vox.com/2018/7/23/17594864/crispr-cas9-gene-editing)
Recently, however, researchers have been agreeing on issues that make the CRISPR/Cas9 system a lot more toxic than originally thought. The high specificity of Cas9 initially made the system a lot more attractive than other gene editing systems; the specific Cas9 protein implies a low risk of off-target editing. It was then discovered that Cas9 has a significantly higher amount of unwanted genetic changes than previously thought as well as CRISPR inducing a cancer risk in edited cells. Researchers found that cutting the genome with CRISPR/Cas9 activates tumor suppression gene, p53. As a result, activated p53 enables a pathway that repairs DNA damage, including what the CRISPR/Cas9 system worked on. It also makes further editing much more difficult. Further, it led to a strong editing selection of cells that lacked p53. The absence of p53, however, makes cells much more likely to become tumorous: they report that half of all tumor cells are missing the p53 pathway. Major players in the CRISPR industry such as Intellia Therapeutics, CRISPR Therapeutics, and Sangamo experienced drops in their stock prices as a result of these publications.
One of the solutions may be to replace Cas9. Currently, the Broad Institute works with Cpf1 rather than Cas9 as Cpf1 offers greater flexibility among other differences. A team at the University of Texas believes that replacing Cas9 with Cas12a will bypass the current controversy. (https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30546-X) They report that Cas12a acts like velcro compared to Cas9 acting like superglue; when Cas12a binds weakly to a longer string of genetic code to allow the protein to correct misbindings.
It’s clear that using a variant of the CRISPR/Cas9 system is the best shot we have right now towards error-proof gene editing in humans but even ambitious estimates place it +10 years down the line till it appears commonplace, putting the host of ethic debates it brings aside.
Emory Entrepreneurship & Venture Management
