Interview with Feng Zhang, PMWC 2019 Honoree- Neurobiologist Who Led the Development of Optogenetics and CRISPR

Dr. Zhang’s lab at MIT is focused on using synthetic biology to develop technologies for genome and epigenome engineering to study neurobiology. Zhang played a central role in the development of both CRISPR technology and optogenetics, a biological technique that uses light to control cells in living tissue, usually neurons. Zhang’s group optimized the Cas9 system in human cells starting in 2011. They then compared their RNA expression approach with a design based on the Doudna / Charpentier chimeric RNA for use in human cells and established features of the guide necessary for Cas9 to function effectively in mammalian cells. Read his full bio.

Interview with Feng Zhang, PMWC 2019 Honoree- Neurobiologist Who Led the Development of Optogenetics and CRISPR

Q: What research are you or your lab focusing on and why, and what problem(s) are you trying to solve?

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.

Q: What excites you about your work?

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.

Q: Your lab was the first to successfully adapt CRISPR-Cas9 for genome editing in eukaryotic cells. Can you tell us how this came about?

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.

Q: How will genome-editing affect health care and what are some of the key advancements that will positively impact the field? By when can we expect more routing applications in the clinic, agriculture, and other?

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.

Q: Recently the CRISPR technology has been challenged as a flurry of articles casted doubt on the overall safety as it can introduce imprecise, off-target modifications in the genome which can be a problem. a. What are your thoughts on this? b. How severe is the issue and can it be overcome?

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.

Q: What are the short-term challenges that your scientific field is facing?

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.