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An Interview with Feng Zhang, Phd

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An Interview with Feng Zhang, Phd INTERVIEW Jurassic Park, Gene Therapy, and Neuroscience: An Interview with Feng Zhang, PhD Interview by James M. Wilson, MD, PhD* Editor, Human Gene Therapy Clinical Development Feng Zhang, PhD Core Member, Broad Institute of MIT and Harvard Investigator, McGovern Institute for Brain Research, MIT James and Patricia Poitras Professor in Neuroscience, MIT Associate Professor, Departments of Brain and Cognitive Sciences and Biological Engineering, MIT New York Stem Cell Foundation-Robertson Investigator Editor’s note: Feng Zhang is a pioneer in the brave new world of genome editing. This interview captures his passion for science and provides insight into his very young but incredibly ac- complished career. Feng, thank you for agreeing to share your thoughts that was really a phenomenal experience. There about your career and your science with us today. were many teachers there who were really engaged How did you initially become interested in science, in developing students’ various interests—and for and what drove you to become a scientist? me that was science. My first exposure to science and biology was I have always been interested in science. I grew a Saturday enrichment class that I took when I was up in the early 1980s in China, during a period an eighth-grade student in middle school. I had ta- when there was an enormous emphasis on science ken biology classes before that, but I did not find and technology, and both of my parents have an those to be very interesting or exciting, because they engineering background. Together, those factors were mostly about dissecting paraformaldehyde- reinforced my interest in science. fixed frogs or memorizing the names of trees. I Plus, growing up as a kid, I always enjoyed learned more about what modern molecular bi- taking things apart and trying to see how they were ology is from that Saturday enrichment class. built. It was that tinkering curiosity and support- They also showed us Jurassic Park, and that got ive parents who encouraged me to pursue science me really excited. I learned that biology is not just that sustained my interest. about rote memorization. At that time, we were When did you come to the United States, and what exploring the genetic code and how DNA, RNA, was your first experience conducting research here? and proteins all relate to each other. Biology was reaching a stage where it could be possible to en- I moved to Des Moines, Iowa, when I was 11. I gineer biological systems that could benefit people enrolled in the public school in Des Moines, and in the world. *Correspondence: Dr. James M. Wilson, Editor, Human Gene Therapy Clinical Development. E-mail: [email protected] 4 HUMAN GENE THERAPY CLINICAL DEVELOPMENT, VOLUME 28 NUMBER 1 DOI: 10.1089/humc.2017.29022.int j ª 2017 by Mary Ann Liebert, Inc. INTERVIEW 5 My enrichment class teacher, Edward Pilk- In this case, there are two problems involved. ington, remembered my strong fascination with First, there are many different kinds of cell types in molecular biology, and he came to me when I was a the brain, and each one is different from the other sophomore student in high school and said, ‘‘I have because the combination of genes that are ex- a really interesting opportunity for you.’’ pressed are different. There is a local hospital in Des Moines called To study these different cell types, it would be the Methodist Hospital, and they happened to have very helpful to be able to manipulate specific kinds of a gene therapy lab. They were running gene ther- cells. One way to solve that problem is to take ad- apy clinical trials and he said, ‘‘It is possible that vantage of transcriptional promotor elements that you could get an internship position at the Gene regulate gene expression in specific cell types. That Therapy Institute.’’ is what first got me interested in genome editing. When I learned about that opportunity, I got If we could manipulate these specific promoter really excited and applied to become an intern. elements by introducing either reporter genes or After I turned 16, I was eligible to volunteer at regulatory proteins into the promoter regions, then the lab, and there I met my first mentor in ex- we could start to probe, monitor, and manipulate perimental biology. John Levy, a staff scientist at specific groups of cells. the Institute, was incredibly knowledgeable and There have been enormous advancements in patient. He would sit down with me almost every the genetic analyses of neurological diseases, and afternoon and take out a sheet of paper and start the second, but equally relevant, challenge is the to draw all sorts of fascinating molecular biology question of how to study all of the different genetic processes, which is how he taught me molecular mutations that result in these diseases. Genome biology. editing, or the ability to manipulate DNA in animal With John, I worked on a couple of different cells, would really help us accelerate our ability to projects. One of them was looking at how green study genetic mutations. fluorescent proteins (GFPs) can be mutated so that It was those two things that got me really in- they absorb different wavelengths of light, and terested in trying to see whether or not we could another one was using GFPs to track retroviral more easily manipulate the genome. proteins to see how they assemble in cells to give rise to new retroviruses. When did you enter the world of CRISPR? In that process, I learned how to design experi- ments, clone constructs, work with cells, and do I started to work on CRISPR when I first opened lots of very cool molecular biology experiments. It is my lab at the Broad Institute and the Massachu- that experience, I think, that had a really profound setts Institute of Technology (MIT) in the begin- impact on me deciding to continue to study biology ning of 2011, after hearing a talk by Mike Gilmore and then later to pursue a career in research. on Enterococcus. Leading up to that, I had devel- oped an interest in genome editing right after You then continued your training, which eventually graduate school in 2009. One of the predominant brought you to the field of genome editing and its genome editing technologies available at that time potential applications. When did you first begin was zinc finger nucleases. As I was getting started thinking about genome editing, and what prompted with that, I realized that it was a very challenging, you to start actual research in this field? cumbersome system to work with. Also, the know- how for making these zinc finger proteins was re- After that really great experience in high school, ally complicated and not easily accessible. I went off to college and continued to do research. It From there, I thought that maybe I could try was during that period of time in college when I to develop something easier, and that led me to started to become really interested in the brain. wonder if there were other solutions from nature That led me to graduate school and to working on that we could harness to manipulate DNA. developing new technologies, called optogenetics, The first thing that I learned about was the TALE that could be used to understand how the brain (transcription activator-like) proteins that gave works and to study what goes wrong in neurologi- rise to the TALEN nuclease platform. I worked on cal diseases. TALENs for about a year, between 2009 and 2010. In As I was wrapping up my graduate work, there mid-2010, I had an opportunity to start my own lab at were a few challenges that I wanted to continue to MITandtheBroadInstitute.BythetimeIstarted work on—one of them was about how to better my lab, I was getting ready to use TALENs to ma- study neurological diseases. nipulate the genome and study neurological diseases. 6 INTERVIEW I was working with students and teaching them systems, like zinc fingers, TALENs, or CRISPR, how to build TALENs, which was very cumbersome, and the new systems, like CRISPR-based nuclease so I thought that maybe there were easier ways. systems, all work through the same mechanism— In early 2011, I went to one of the scientific ad- you reprogram a nuclease to target a specific loca- visory board meetings at the Broad Institute. One tion in the genome, the enzyme goes there and of the scientists there, Mike Gilmore, was pre- makes a cut in the DNA, and endogenous DNA senting his work on Enterococcus bacteria. During repair machine arrays are stimulated to either his talk, he casually mentioned that these En- knockout the gene through an erroneous DNA re- terococcus bacteria happened to also have CRISPR pair process called non-homologous end joining systems in them. (NHEJ) or to replace a piece of the DNA sequence CRISPRs are these interesting bacterial im- through homology-directed repair (HDR). mune systems that encode nucleases. When I heard NHEJ works quite well, whether the cell is a the word nuclease, I got really excited, because at replicating cell or a somatic cell. that time I was thinking about nucleases—zinc The HDR process is a lot less efficient. It pri- finger nucleases and TALENs—and so I wanted to marily works in cells that actively replicate. It is learn more about these CRISPR systems. very difficult to be able to use HDR to make precise When I started reading about CRISPR, there changes in the genome for any cells that do not was a paper published by Sylvain Moineau at replicate.
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