The Most Transformational Biologist of Our Era?

; Feng Zhang, PhD

Disclosures

March 31, 2017

From the Mainland to the Heartland

Eric J. Topol, MD: Hello. This is Eric Topol, editor-in-chief of Medscape. I am delighted to welcome Feng Zhang, who is with us today to discuss his extraordinary work in CRISPR (clustered regularly interspaced short palindromic repeats). He is at the Broad Institute and is a professor of neuroscience at the McGovern Institute for Brain Research. Feng, welcome.

Feng Zhang, PhD: Thank you, Dr Topol. It is a pleasure to be here.

Dr Topol: I understand that Feng means "head of the spear." Is that the Chinese translation?

Dr Zhang: It means sharp.

Dr Topol: You have been called the most transformational biologist of our era. That's pretty good for somebody as young as you, only in your mid-30s.

Dr Zhang: I am just trying to do something useful and that I hope will make our lives better.

Dr Topol: You have already done much in a short time. You came to the United States when you were only age 11, with your mother. Is that right?

Dr Zhang: Yes. I was born and raised in China. When I was 11, I came to the United States with my family. We moved to Des Moines, Iowa. It has been a phenomenal experience. People have been so warm and welcoming. The public school system in Des Moines was fantastic. Teachers really cared about students' education. They looked out for opportunities, and they brought them to us so that we could develop our own interests. I cannot imagine a better place to have grown up and received an education than Des Moines, Iowa.

Dr Topol: The heartland of America. How did you wind up in Des Moines?

Dr Zhang: It's an interesting story. My mother was a visiting scholar at the University of Dubuque. She had an opportunity to visit one of the schools in Dubuque. Education there was very different from the way they teach in China. There is a lot less focus on rote memorization, and students get to use their hands and try to develop things. She thought: Wouldn't it be great if I could bring my son over here too? She decided to stay in the United States and work, and then she brought me over.

An Early Interest in Gene Therapy

Dr Topol: I understand that your mother would drop you off and wait for you in the car while you were doing experiments in a gene therapy lab. Is that right?

Dr Zhang: Yes. Methodist Hospital in Des Moines had a gene therapy lab and an internship program. My high school teacher Ed Pilkington said to me when I was a sophomore, "I know you are interested in molecular biology. There is this great opportunity. Would you like to sign up and volunteer there?"

That is where I met my first mentor, Dr John Levy. He was a molecular biologist; and he is smart, intelligent, and a fantastic teacher. He would sit down with me every afternoon, take out a sheet of 8.5 X 11 paper, and just scribble all sorts of fascinating biology knowledge on there. Every day I would go after school at 2:00 PM and stay until 7:00 or 8:00. In science, time can be unpredictable. My poor mother would sit in the parking lot and wait for me to finish the experiments.

Dr Topol: When you were in high school, you won the Intel prize—you got third place. You were even interested in curing HIV at such a young age. Is that right?

Dr Zhang: That was the project I worked on in the gene therapy lab. The lab was working on viral vectors for delivering genes to treat cancer. One of the vectors they used was retrovirus. I worked with John to figure out how the HIV virus put different components together. We used the retrovirus as a model, and that formed the basis for the project. It was a lot of fun and a fantastic learning opportunity.

Dr Topol: Then you went off to Harvard, and you got a combined degree—your baccalaureate degree in chemistry and physics. Then you headed to Stanford, where you got a PhD in chemistry. And there's a side of you that people may not be aware of. At Stanford, you worked in optogenetics, in Karl Deisseroth's labs. Tell us about that.

Dr Zhang: After Iowa, I went to Harvard for undergrad. There, I continued to work with viruses. I did research with Don Wiley, who is a structural biologist, and also Xiaowei Zhuang looking at virus infection. During that time, one of my good friends developed an episode of psychiatric disease. Prior to that, I did not have any appreciation for that. I thought, like many other people, that psychiatric disease is just a person not being strong enough. You just have to have stronger willpower, and you will get over it.

Through that process, I realized that psychiatric disease is very much a physical illness, just like cancer or diabetes. It is something that affects the brain. I wanted to learn more about the brain. When I went to Stanford, I had the opportunity to meet with Karl Deisseroth, who is both a bioengineer neuroscientist and also a practicing psychiatrist. I had a great conversation in which he told me about his vision of developing new technologies to make the study of the brain more accessible. I was really inspired by that vision, so I joined Karl when he was just starting his lab and started working on optogenetics.

Dr Topol: Now, a lot of people in the medical community are not up to speed on either CRISPR or optogenetics. Do you want to just tell us a little bit about what that means?

Dr Zhang: Optogenetics is a way to stimulate brain cells using light. Brain cells have many different types, and different cells form different circuits that control our movements or the way that we think. To understand brain disease, we need to figure out where the different circuitry is in the brain. Optogenetics allows us to use light to stimulate specific groups of cells to be able to systematically map out how the brain is wired and how things work.

Dr Topol: It is an exceptional research tool to understand the brain and perhaps well beyond that, in the future.

A Chance Remark Opens Doors to CRISPR

Dr Topol: Going back to CRISPR, you then went back to Boston and MIT, and you set up shop there. That is when you started to delve into the CRISPR story; is that right?

Dr Zhang: Right. One of the remaining challenges with optogenetics was how to put this gene into specific locations in the genome so that we can control specific types of brain cells. That turned me to genome editing. I started by looking at zinc finger nucleases. I started to work with zinc finger nucleases, but it turned out to be pretty challenging. Then, because it was so challenging, I was looking for alternatives. I first worked on another system called TALENs (transcription activator-like effector nucleases), and more information was becoming available about how TALENs bind to DNA. After developing the TALENs system, I started my lab. This was in the beginning of 2011. As I was teaching students to build TALENs, I realized that this was still a pretty difficult thing to do. I thought maybe there were alternatives.

Then I went to a seminar at the Broad in the beginning of 2011. One of the professors, Michael Gilmore, was talking about his study of Enterococcus bacteria. Just as a side point, he mentioned that enterococci also have CRISPRs, and they are an interesting set of nucleases that people are just starting to understand. I had no idea, but I was interested in nucleases.

Dr Topol: That is what led you down the path.

Dr Zhang: Yes. I was interested in nucleases. I did not know what CRISPR was. I went to look it up. Around that time, a paper from Sylvain Moineau in Canada was published describing how it was RNA-guided endonuclease. That got me really excited, and I started to work on the system.

A Target on Grievous Genetic Diseases

Dr Topol: You have done such extraordinary work, which we do not have time to review, both with respect to the multiple CRISPR systems and the details—the breaks on CRISPR, the RNA potential editing—all sorts of things that can be done. Then you decided to found Editas Medicine. Tell us a little bit about that.

Dr Zhang: Editas Medicine is a gene-editing company that I cofounded with George Church, Jennifer Doudna, Keith Joung, and David Liu. The mission of Editas is to develop the CRISPR genome-editing system for clinical applications. More than 5000 genetic diseases are caused by specific mutations in our cells. We thought it would be great if we could build a platform that systematically developed this to treat the many diseases for which we know the cause but have no way of treating. That is the basis of Editas.

Dr Topol: Will Editas get into clinical trials soon?

Dr Zhang: The plan is that Editas is developing CRISPR-Cas9 and CRISPR-Cpf1 so that we can go into clinics and try to treat grievous genetic diseases.

Dr Topol: Are any particular diseases at the front of the line for this type of clinical trial?

Dr Zhang: One of the things that they have publically described is trying to go after eye degeneration. There is a disease called Leber congenital amaurosis, and that is one of the things that they are working on. They are working on other diseases as well.

Dr Topol: It may well start in the next year or so; is that right?

Dr Zhang: They are working very hard on it.

Dr Topol: That is exciting. A lot of people in the medical community have heard a little bit about CRISPR. You certainly have been a pioneer in this field. The promise to deal with all of these rare diseases for which there is no therapy whatsoever is exceptional.

The other thing that spawned controversy about CRISPR is the whole idea of doing genome editing of the embryo, sperm, or egg. Can you comment on that concern? Just last month there was a big National Academy of Science ethical review. There seems to be a global consensus. Where do we stand with that?

Dr Zhang: There has been an ethical debate around the application of genetic manipulation to embryos. Embryos are what we call "germline." If you make a modification, it will get passed down to all subsequent generations. There is a remarkable amount of consensus that the technology is not mature enough right now to use it responsibly in treating diseases at the embryonic stage.

Also, there are a lot of ethical concerns about where to draw the line. You can start with very grievous diseases, but what do you define as disease? The line can get quite blurry. The good thing is that there are a lot of very smart people—experts in ethics and science—all coming together to think about these issues.

Dr Topol: It is somewhat reminiscent to me, because I am an old codger, of when we were starting with recombinant bioengineering. That was when I got involved with tissue plasminogen activator and other things. We are talking now about something that is so much more dramatic in its potential as a therapeutic agent.

We applaud you for what you have done to transform this field, along with so many others around the world. You really have been a pioneer. We look forward to seeing your work translated into something that will be therapeutic for people; especially the people who are often neglected—those with rare, Mendelian diseases. Congratulations on what you have already achieved. Just think what is in store.

Dr Zhang: Thank you very much.

Dr Topol: It is great to have you with us. Thanks so much for listening to our Medscape One-on-One.

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