GESDA Anticipation Workshop - Human Applications of Genetic Engineering

Robin Lovell-Badge

Reading and interpreting the genome — whole genome sequencing of patient DNA — is increasingly common in medical practice for developing and adequately deploying therapeutics. Better reading technologies have already helped to diagnose disease, genetic predispositions to disease, and even infections. For example, the CRISPR-Cas system is enabling the fast detection of pathogens; Cas12a has detected Hepatitis B in less than 30 minutes. More typically, sequencing is now possible in days to weeks. Costs are also falling.

Faster, better, and cheaper diagnostics coming into the mainstream will act as a fact checker on the new generations of genome editors, detecting and preventing DNA editing errors. These technologies need to be further refined to ensure every laboratory can easily adopt them when in vivo editing becomes mainstream

CRISPR-Cas9 is now the most widely used gene editing technology in the world. It is not only powerful, allowing multiple edits with a single manipulation, but also widely accessible. CRISPR has been successful in trials treating blood diseases, cancers, and eye diseases. It is not clear that these successes will transfer to other tissues, however. Because muscular diseases, for example, are system-wide, treatment requires very high doses of the editor in order to reach all the relevant tissues. Though the traditional viral delivery method is typically safe, the high dose of AAV could increase the chance of an immune response or other adverse reaction. Additionally, CRISPR is best deployed against single genes, and most diseases are polygenic. Furthermore, the use of CRISPR platforms can result in off-target modifications — where edits happen at the wrong locations — in addition to unwanted on-target modifications, genomic rearrangements and problematic immune reactions. Consequently, research is evolving CRISPR platforms to be more precise. Cas12a, at one third the size of cas9, promises greater precision compared to Cas9. Ultimately, however, Cas12a is still experimental, and Cas9 remains too large to be fitted into today’s genome therapy vectors, and so its use will remain primarily ex vivo, making it a less attractive prospect for future therapies.

Synthetic organisms and AI will help advance genome editing for human applications in several crucial ways. For starters, synthetic organisms will provide improved ways to deliver the editing payload to the cell and experimental organisms that provide a better proxy for human testing; AI will help identify complex links between multiple genes and disease. Recent rapid advances in stem cell engineering, synthetic embryos, organoids (artificial and simplified versions of an organ), and tissue engineering are helping research move towards providing experimental organisms based on human physiology that will help predict the functionalities of genome editors outside the human body and before clinical applications. ,

GESDA Anticipation Workshop - Human Applications of Genetic Engineering