CRISPR/Cas technology adapted from the bacterial immune system has received tremendous attention from medical research and technology community.  With the advent of genomic sequencing and subsequent disease predisposition gene discovery, this technology offers enormous opportunities to correct genetic defects for patients suffering from rare hereditary diseases currently with no effective therapy.  Although CRISPR/Cas technology is capable of precise genome editing, it is also well known for its low efficiency.  Recently, a report published in the latest issue of Cell Stem Cell from the laboratories of Dr. Ding Sheng, and his collaborator Dr. Lei Qi, co-senior author from the Stanford University,  have discovered a way to enhance the efficiency of CRISPR with the introduction of a few key chemical compounds. Dr. Sheng Ding is current the William K. Bowes, Jr. Distinguished Investigator and Professor at Gladstone Institute of Cardiovascular Disease, and Department of Pharmaceutical Chemistry, University of California San Francisco. Today, we sat down with Dr. Ding to hear his thoughts on CRISPR and the research findings.

Your original interest is in stem cell research, what attracted you to CRISPR technology?

Ding: Genome editing is an essential tool for conducting stem cell research, such as generating reporter cell lines, making isogenic iPSC lines for disease modeling, and performing genetic manipulation in stem cells to understand basic biology. In addition, stem cell is a great vehicle for many gene therapy approaches. It is quite natural to get into using CRISPR, which is much more convenient and powerful than previous genome editing techniques. Lastly, we are simply curious whether CRISPR mediated process could be modulated by small molecules, which is a central theme of what we do in research.

Can you elaborate a bit more on your recent findings in the context of the power of CRISPR?

Ding: Despite CRISPR technology is convenient and powerful, it is still at its infancy. Uncovering new ways to modulate its efficiency and precision, and better understanding its underlying mechanisms would be highly useful. Our recent work only scratched surface of it, and focused mostly on the precise editing of genome sequences through homology-directed repair (HDR), which is very inefficient. Through high throughput phenotypic screening of small molecules, we identified a couple of molecules that can significantly enhance the HDR-based high fidelity genome editing. Interestingly, we also identified inhibitors of HDR, which can enhance frame shift insertion and deletion mutations (for making sequence-specific gene knockout) mediated by non-homologous end joining (NHEJ).

How do you see these new insight may be translated to drug discovery and clinic?

Ding: Having more efficient CRISPR editing capability will certainly make it more useful for in vitro applications (such as making disease-specific cell lines for drug discovery). In addition, more precise control over CRISPR editing activity (e.g., turning it on and off) would potentially allow more safely deployment of CRISPR for therapeutic applications.

Any insight regarding the opportunities to combine CRISPR and stem cell technologies to tackle major diseases?

Ding: You are right that it is currently pursued by many researchers to combine CRISPR and stem cell technologies to tackle many untractable diseases. We are quite fortunate to be in the field and contribute our expertise.