A: Our overall driving goal is to improve human health, and we do this largely through the development of new tools to study basic biology and the discovery of novel therapeutic approaches to treating human diseases.

A: There is a strong element of discovery to what we are doing – from finding novel microbial proteins that have never been studied before to figuring out an elegant solution to a technical problem at the bench – these moments where we know we are really on to something that will make a difference are the most exciting for me.

A: I had been working on tools for genome engineering as a Junior Fellow at Harvard, and when I first started my independent group at the Broad Institute, I went to a seminar talk and heard about microbial adaptive immune systems known as CRISPR. The tools I had been working with were powerful but difficult to use, and I had been thinking a lot about how to make them easier to work with. CRISPR systems naturally solved the main challenge – the enzyme that targets DNA is guided to a specific sequence by a short, complementary RNA (by contrast, the enzymes I was working with recognized DNA sequences through amino acid residues, which meant the whole protein had to be re-engineered for each new target). I was immediately intrigued and started to read all I could about CRISPR systems, and trying to figure out how these systems could be harnessed for use in mammalian cells. Within days, I had started to work on it at the bench, and tried to be as systematic as possible in tackling the challenges of moving this bacterial system into mammalian cells.

A: I think genome editing has already started to affect health care by accelerating the pace at which basic research in mammalian systems can be done. For example, it is possible to make a new mouse model of disease in a few months or less, whereas it used to take a year or more. Moreover, we can now easily create patient-specific mutations to better understand the molecular consequences of these changes. Another application of CRISPR systems is molecular diagnostics, and some of these platforms are already being deployed in the field to help monitor infectious disease outbreaks. Outside of health care, genome editing is being applied to a number of problems in agriculture, where it can significantly speed up the breeding process, a major bottleneck for improving crops.

A: There are still many open questions about the safety and efficacy of CRISPR-based therapeutics, and as a field, we are working to address these. For example, we and others have engineered more specific variants of Cas nucleases that exhibit very little off-target effects. Others are exploring the potential immunogenicity of CRISPR components, which will be very important to address before this technology can be used therapeutically. Clinical trials using CRISPR-based therapeutics in limited contexts are beginning this year, and as we see data from these studies, we will get a much clearer picture of what the outstanding challenges are.

A: We need additional approaches for delivering CRISPR-based therapeutics (and other cellular and genetic therapies). We are currently quite limited in our ability to target specific organs and tissue types, and until we solve this, we will not be able to realize the potential of genome editing.