A CRISPR Pioneer on Gene Editing: 'We Shouldn't Screw It Up'
The first thing many people notice about Feng Zhang—nearly every article written about him acknowledges it—is his relative youth. At just 36, with glasses and a round face that make him look even younger, the biologist has already made two discoveries tipped to win Nobel Prizes.
The big one, the one that shot Zhang to scientific celebrity, is CRISPR: a gene-editing tool that could allow precise alterations to human DNA. CRISPR is already being hyped as a cure for genetic diseases, a treatment for cancer, and a potential tool for creating designer babies. (We’ll get to all that.)
It’s also the subject of a bitter patent dispute between the Broad Institute, where Zhang works, and UC Berkeley, where Jennifer Doudna made key early CRISPR discoveries, too. The patent fight has ignited a debate over who truly deserves credit for this scientific breakthrough.
I recently sat down with Zhang at CRISPRcon, a conference devoted to discussing the technology’s myriad applications and where he was a keynote speaker, to talk about the technology’s future. This interview has been lightly edited for length and clarity.
Sarah Zhang: So we have the same last name! I don’t think we’re related, though.
Feng Zhang: Yeah, it’s one of the most common ones. … It’s good for anonymity.
We’re talking at CRISPRcon, where I’m pretty sure everyone recognizes him.
Sarah Zhang: How did you first get interested in studying biology?
Feng Zhang: I actually didn’t like biology in the first place. It was like, identifying different leaves, classifying things. I was more interested in math, chemistry, and computers—taking things apart and putting things back together.
Sarah Zhang: That actually sounds a lot like what you’re doing with CRISPR. CRISPR originally comes from bacteria, which use it to cut it up DNA, and it was first discovered by scientists working on kind of obscure bacteria. You put it into human cells, and it can also cut DNA. Do you spend a lot of time reading obscure microbiology literature?
Feng Zhang: Google is pretty good, and PubMed is pretty good, so you can search for different things. The way I look for things is that I have some hypothesis or an idea. And then you search things related to that hypothesis. And then just read broadly around that area to see if anything touches on the subject.
Sarah Zhang: You worked in a gene-therapy lab in high school, and gene therapy has had this interesting arc. [Gene therapy inserts normal versions of a gene into someone who has missing or defective ones; gene-editing with CRISPR can be theoretically used to insert, delete, or modify existing genes.] Gene therapy was so hyped in the early ’90s. Then it went through a dark period, and now finally we’re seeing gene therapies getting approved by the FDA. Have you followed that arc? Has it given you perspective on CRISPR’s future?
Feng Zhang: Absolutely. I first heard about gene therapy in that Saturday class on molecular biology. This was back in 1994, 1995 maybe, and the potential of gene therapy was really apparent. If we can fix disease at the genetic level, then we can treat many things.
So then when I was in high school, it happened to be that in Des Moines there was a gene-therapy lab, and they were taking volunteers, so I began working there as a sophomore. I was exposed to all types of approaches in gene therapy.
A major challenge with gene therapy is delivery. How do we get the therapeutic gene into different tissues? In the lab at the time, there were people working on all sorts of viral vectors: Moloney murine leukemia virus or herpes simplex virus or adeno-associated virus or adenovirus. These are all different ways people were exploring to get medicines into patients. And it was very exciting that researchers were making progress in making it possible.
And then in 1999, that’s when the news from the University of Pennsylvania came out.
Sarah Zhang: You mean the death of Jesse Gelsinger in a clinical trial. He died after the virus used to insert his gene therapy caused a massive immune response.
Feng Zhang: That was a very sobering moment for everybody in the field. So some of the things, back in the day, we didn’t fully understand the delivery systems enough. We didn’t know the biology of these viruses sufficiently. A lot of that applies to gene editing, too.
Sarah Zhang: What are the challenges you see to using CRISPR to treat human diseases?
Feng Zhang: The types of delivery systems we have are still really limited. For many of those diseases, we just don’t have the right delivery systems. Right now, we can get access to the blood cells, the eye, maybe the ear. But if we want to do something that’s body-wide, we don’t really have good ways to do that yet.
Viruses are nature’s way of delivering things into cells. That’s one approach, so we work on that, and explore other diverse viruses that people have not harnessed for delivery. We also look at things like exosomes, which are vesicles that cells release to be able to transmit information between cells.
Sarah Zhang: Also nature’s way.
Feng Zhang: Also nature’s way. And we also have collaborations to look at lipid nanoparticles, liposomes. I think we’ll have to take a broad approach to comprehensively figure it out. It’s very likely that different tissues will require different approaches.
Sarah Zhang: Which organs are the hardest to get CRISPR into?
Feng Zhang: I would really like to be able to get something into the brain. But beggars can’t be choosers. You kind of explore the basic biology to figure out where does nature want us to go.
Sarah Zhang: Speaking of the brain, your lab has gotten a lot of attention for CRISPR, but the other half of your research is on the brain, specifically psychiatric disorders.
Feng Zhang: I’ve been interested in the brain since I was in college. It’s what makes us who we are, and unfortunately, we know the least about that. I also had a really good friend in college who was affected by a psychiatric disease. From that experience, I realized psychiatric diseases are very much real illnesses. They are things we don’t really understand, and it’s not just that the person is having a really bad day. If I can understand it more, maybe I can develop ways to help.
Sarah Zhang: Psychiatric disorders are maybe the area where the gap between our understanding of the biological mechanism and the effect is the largest out of anything in biology.
Feng Zhang: Yeah, exactly. Part of it is the complexity of the brain. So many different cells. So many different cell types. And part of it is the brain is hard to study. It’s encased in our skull, and it’s a big dense piece of tissue. It’s hard to peer into this tissue to understand how things are working. Also, molecules and signals are so microscopic, they just make studying the brain challenging. So that underscores for me that we need new technologies and tools that help dissect different cells and different molecules, how do they all work together as a system in the brain.
Sarah Zhang: How are you using CRISPR to study the brain?
Feng Zhang: Through DNA sequencing, scientists have identified many genetic variations, and some of those variations are linked to increased risks for brain diseases. So we build mouse models using CRISPR to try to understand how do they work. What is the mechanism through which they affect the function of the brain?
Sarah Zhang: Do you get a lot of emails from potential patients who want to know how CRISPR can help them?
Feng Zhang: Yeah, I get emails from them pretty much every day. And the patients are—they really are trying to understand what this technology is. They’re trying to see if there’s any way to advance the development so that therapies can reach their loved ones sooner. And that’s a really energizing and inspiring message to be receiving. Every day I’m reminded how there is a possibility of developing something that can help people, and just work faster so we can get there sooner.
Sarah Zhang: Is it also hard, though? Because, as you were saying, there are still all these challenges, and you probably have to tell some people that’s not possible anytime soon.
Feng Zhang: I think it’s good to be reminded that we are in this very fortunate position to be able to make a positive change, and we shouldn’t screw it up.
Sarah Zhang: Who deserves credit for CRISPR?
Feng Zhang: I think many people deserve credit. CRISPR is something that has been worked on for more than a couple decades, so there were a lot of people involved at different phases. Some were important in the early discovery. Then other people took up the baton and continue to understand the basic biology. That’s kind of the beauty of scientific discovery. We build on giants that come before us. That’s just how everything, history or civilization is built—one brick at a time.
Sarah Zhang: Some of your fellow scientists have taken it upon themselves to talk about the potential risks of using CRISPR—like Kevin Esvelt on gene drives and Jennifer Doudna on CRISPR in humans. Do you feel you’re in a position of moral authority because you helped bring this technology into the world?
Feng Zhang: Well, I think we all have a responsibility: scientists, media, policymakers, bioethicists have an obligation to participate in the discussion. I think as scientists we can help convey what is the technology, help explain what it is, and to understand what the technology’s potentials are.
One thing I’m really excited to focus on is how do we turn CRISPR into a real therapeutic tool, so that we can treat disease. We’re still a ways from that. Designer babies and so forth, I think those even farther out. We don’t even understand biology enough to even contemplate what those things would be. We can’t even treat a single mutation that causes sickle-cell disease right now.
Published at Thu, 07 Jun 2018 18:51:00 +0000