Scientist Stories: Feng Zhang, Inventing CRISPR & Optogenetics

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Fong, thank you so much for being on FYI today. We're so excited to talk to you. There is so many things that we could talk to you about, so I'm excited to dig into more of them. The first one, which maybe a few less people know about because there's so much CRISPR buzz in especially what we do, but is optogenetics. So you were fundamental in developing this technology with Karl Deisseroth and Edward Boyden. Can you give us maybe a brief summary on what optogenetics is and when that sort of aha moment you had when you figured it out, and is this being used today?

Hi, Ali. Thank you for having me on the podcast today. It's a great pleasure to be here. So optogenetics is a really cool technology. It's a way to be able to dissect circuitries in the brain. The human brain or the mammalian brain is very complicated. There are many, many different types of cells that work together. They form what's called neural circuits. And so one of the big questions is, what do different components of the circuit do? Optogenetics provides a way to use light to be able to turn on or turn off specific parts of the circuit and ask questions like, what does this part do and what does that part do in controlling memory or sleep or thirst or any of these complex or fundamental neurological behaviors?

So CRISPR, now moving on a little bit, is of course one of the most interesting discoveries. It has really accelerated the possibility of potentially creating cures. For a lot of unmet diseases. And around 2011, you began working on CRISPR in eukaryotic cells, and you were actually the first to describe CRISPR-Cas9 in human cells. Can you tell me just a little bit about that experience for you, and anything maybe else you want to add about CRISPR specifically in eukaryotic cells?

Yeah, thanks for the question. So CRISPR is also a really cool microbial system. And how I stumbled upon CRISPR actually begins back with optogenetics. Because with optogenetics, one of the biggest hurdles for using the technology is to target it to different circuitries within the brain. And one way that people do that is by taking advantage of genetic programs that are unique to one type of brain cell or another type of brain cell. And so this is possible to do in mice, but as you go up to other non-standard models or to treat disease in a human, it becomes very challenging. So when I learned about genome editing, this could provide one solution to solve this optogenetic challenge because we can insert these light-sensitive proteins into the right region in the genome and then be able to control a specific set of brain cells to be able to study behavior or to be able to rectify neurological issues. And so when I learned about CRISPR, I learned that it's microbial nucleases. This means there are scissors that can be used to cut DNA. And I thought maybe I can harness these microbial scissors and use it in human cells to then be able to find the right place in the genome and then be able to edit the DNA in that location. And so that's how I got started. And it's a really cool system. The more I studied it, the more fascinating it became and the more possibilities there are.

Definitely. Yeah.

And today there's tons of possibilities and tons of companies working on creating therapeutic potential. Drugs for CRISPR, which is really exciting. And in 2013, you sort of started that journey. Jennifer Doudna, George Church, Keith Young, David Liu, and yourself, you all co-founded Editas Medicine. It was one of the first gene editing companies really to commercialize CRISPR medicines. So I'd love to hear your thoughts on the company just recently released their LCA10 data, if you had any thoughts on that, or just sort of the future trajectory for the company in general.

Yeah, as we were working on CRISPR, it was very clear that CRISPR had a lot of tremendous potential for human health. One of the most tantalizing ideas is to turn CRISPR into a therapeutic to be able to correct genetic mutations or to be able to make changes that can then correct underlying pathological processes. And so with my co-founders, we founded Editas, and they have been advancing the use of CRISPR as a therapeutic system. And with the most recent result from the LCA10 patients, I was really excited to see them, and also reading about the patient interviews where the patients reported that they were seeing improvements to their vision. I think that's really exciting. I think this shows that there's the promise, and as we further continue the development of CRISPR, not only for LCA10, but for many other diseases, I think we'll be able to further realize this potential. I think is really an important step forward.

Yeah, definitely.

And I think that article was in NPR about patient experience, which was really interesting because a lot of times we focus on the endpoints of the study, but of course the patient experience is so important. That article, I think, did a really good job highlighting it. And then obviously Cas13, so you discovered that with Eugene Koonin, which is the RNA editing enzyme. Previously we were talking about DNA editing. And Cas13 could be really exciting because it works in mammalian cells, could be useful for RNA degradation, nucleic acid deletion, etc. Maybe can you describe some of the applications where you think RNA editing may be even better than DNA editing?

So one of the key differences between RNA editing and DNA editing is that RNA editing is transient, because these RNA molecules are made from DNA, but they only persist for a defined period of time. And so one of the things that RNA editing could be advantageous for is to make changes that you don't want to have become permanent in the cell. So for example, in some cases, regeneration, where you may want to edit genes that if you change it temporarily, it can cause cells to replicate themselves or to proliferate, but you don't want to make the change permanent because it will cause the cell to continuously replicate, and that could form a tumor. And so picking some of these diseases where you want to have a transient change in activity to be able to repair something in the body, RNA editing is the more appropriate way to go.

Do you think there's ever going to be a challenge with cogs for that, just in terms of if DNA editing is a one-and-done therapeutic?

Do you think RNA editing might have a challenge in terms of the cost of goods?

I think many of these genetic medicines, they are— we're still in the early stages of turning genetic medicine into a broad platform for treating many diseases. But as the platform gets continued, it's sort of further optimized and developed, I think the cost of goods will drop significantly. Most of the genetic medicine is like writing software. Software, once you have written it, is it's actually very easy to distribute and it doesn't cost very much, but it's the process of developing it. And I think a lot of it is very similar to genetic medicine. It costs a lot to do the fundamental research and the development optimization, but once you have the drug, then the cost of producing it is not as much.

I love that analogy.

In 2016, you co-founded Arbor, which I believe was originally looking to sort of mine for the biodiversity of industrially useful enzymes. But it looks like the company is doing so much more than just that. So now working on really a variety of projects, including mining the genome for new enzymes or proteins, but also creating CRISPR-based therapeutics, including, and especially of interest, is the CNS system. So can you maybe discuss the potential for CRISPR, maybe these new proteins?

Sure. So ARPA was founded with the realization that there's enormous amount of biological data out there, and much of that data have not been really looked at or studied. And what is almost guaranteed is that within that expansive data, there is a lot of very interesting molecules. And so Arbor was founded to try to uncover some of these interesting molecules. And so Arbor has been developing a number of new enzymes that are industrially useful, especially some of the CRISPR-Cas12 or CRISPR-Cas13 type of enzymes, and they are now working on developing therapeutic applications. These different new enzymes have different properties. Some are smaller, some are very precise right out of the box, some have the ability to target different range of DNA sequences in the genome. And so I think what we're really seeing now is that there is an expanding toolbox of different proteins, and collectively they are allowing us to cover more and more different genes or different spots in the genome. And this is part of the continued evolution of the technology.

Definitely. And speaking to new enzymes, obviously Cas7 and 11, and then also when we met a few months ago, your paper on ISCB and many others, a host of different families of new proteins that could be used for genome editing instead of Cas9, I think was recently published. So firstly, obviously, congratulations on the success and progress. And then maybe secondly, has there been any further progress? And do you have confidence that these new proteins will be as or more specific and sensitive than Cas9 or Cas12a, which are sort of the proteins that are commonly used today? And as you just mentioned, one of the challenges is getting to different spots in the genome. So do you think that they'll be able to get to increased spots in the genome, less specific PAM, or TAM, I think you mentioned in your paper as a TAM.

Yeah, I think there's an ever-expanding repertoire of enzymes that could be harnessed and developed for genome editing. I think what we're seeing now is probably still the tip of the iceberg. This mechanism of using RNA to recognize DNA, even though it was first seen with some of the early CRISPR systems, Cas9 included, it's turned out to be something that is much more fundamental. In fact, with these new proteins like ISCB or TNPB, they are some of the most abundant genes or proteins on the whole planet. Within a single bacteria, you can find several dozen different copies of the same gene. And so they all use this RNA-guided mechanism to be able to recognize DNA, and they probably were then evolved and co-opted by many other systems to So this is really something that is very fundamental. I think it's really exciting to continue to develop these different enzymes. Some of them are dramatically smaller, one-third of the size compared to Cas9. These compact molecules are going to be easier to deliver for therapeutic applications. Some of them have much simpler PAM or TAM sequences, for example, with just a single letter G rather than two letters GG. That allows you to target 4 times more spots within the genome. And so these kinds of differences allow us to further make the genome editing system powerful. And I think it's really this whole combination of things that's giving researchers and drug developers more and more tools at their disposal so that they can choose the best one for their application. And we're going to see even more of these tools. I think that's really very exciting.

Yeah, yeah. And I've heard more and more people start to refer to the toolbox.

So you go into your toolbox and you choose the tool that's right for the indication that you're looking at. I don't know who came up with that, but it seems to be circulating now.

You know, at AHRQ, we love talking about cost declines.

We talked a little bit about how that might work for RNA editing, but we typically use Wright's law, but no need for any calculations or anything. But curious on your thoughts of how quickly you think costs will decline for gene editing and gene therapy. So that the access can become more democratized? And I guess the second part of that is, do you think it's actually necessary that the costs come down a significant amount? Because AARP did some work, and I've seen some work on Zolgensma on this as well, where actually if you look at it on a per-life-year basis, you know, the therapy could actually be cheaper because of you're putting a one-time cure and then you're looking at it throughout the person's someone's life. So just curious if you had any thoughts on sort of the decrease in cost, how quickly maybe that needs to happen, and maybe if it doesn't have to happen as sort of steep of a curve as we think it might.

I think the cost is definitely going to decrease as these technologies mature and more development goes into it. I think the most exciting aspect of genetic medicine or genome editing medicine is that it's very modular. So if you think about these genetic medicines, they have two components to it. There is the delivery system, so the vehicle that gets the drug into the right cell in the right part of the body, and then there is the therapeutic payload. So it could be the gene editing machinery that goes into the right cell. And so these two are modular in the sense that if you have developed a nice vehicle that can go into liver cells or a vehicle that goes into muscle cells, You can switch out different types of payloads without having to change the vehicle itself. And that means the cost is going to be lower as you develop more and more drugs leveraging the existing technologies. So the first liver disease will probably cost a lot to realize because we'll have to develop everything. But then the second liver disease can take advantage of the vehicle that's already established and optimized for liver applications. So then you just have to go in and engineer the payload. So I think these kinds of optimizations that you can take advantage of and don't have to sort of repeat is going to make the development cost significantly lower. And as we talked about earlier, the cost of good is usually a much smaller fraction of the total cost, and it's largely a development cost. I think this is going to translate into more and more affordable therapeutics.

Yeah.

Definitely.

And speaking of affordable, I guess this isn't for therapeutics, but on the diagnostic side, in 2018 you co-founded Sherlock Biosciences, which I guess came at the exact right time because it can essentially distinguish strains of viruses. And we were and still are in the midst of a global pandemic. So you developed a COVID-19 test, which you don't really need lab equipment for.

You don't really need the expertise. And it's easy to deploy, which sounds like the perfect thing that we needed for the COVID-19 pandemic.

So I'd be curious to hear your views on CRISPR diagnostics in general.

We talk a lot about CRISPR on this podcast, but we don't always focus on diagnostics, mostly therapeutics. So I think that would be really interesting. And also just having this easily accessible and cost-effective test could really help us for potential future pandemics, but and also just mundane things that we may need. I don't know if you've heard of monkeypox, but I was just reading that there were 2 cases, and I thought, oh my God, not again. So I'm just curious what your thoughts are sort of on diagnostics moving forward.

So diagnostics, or easy-to-use and widely or easily accessible diagnostics, are very important for fighting pandemics or infectious disease. And so CRISPR is a very promising platform for developing diagnostics, especially for developing point-of-care or at-home diagnostics. When people talk about diagnostics, they usually talk about two metrics: specificity and also sensitivity. Specificity means how much false positives do you have? Do you misdiagnose the infectious disease? And the sensitivity means how much false negative do you have? Do you miss any patients who actually had the virus but you weren't able to detect it? So CRISPR provides a way to have improved sort of sensitivity and also specificity. The way that it improves sensitivity is by allowing both the sample to be concentrated and then amplified using both the amplification method, usually PCR or isothermal method, and on top of that, combine that with CRISPR-based collateral activity amplification. So that gives you stronger signal for the same amount of input. And then it's also making the specificity higher because it checks for the right virus sequence twice. So the molecular amplification, whether it's PCR or isothermal amplification, checks for the virus sequence once, but then CRISPR double-checks it to make sure that what the amplification methods are reporting is actually correct because it has to pass the CRISPR detection as well. So I think those combined together makes CRISPR a nice way to be able to do diagnostics reactions. So right now it's being actively developed for use in point-of-care and at-home settings. I'm hopeful that in the near future that will be something that's available to many users.

Yeah, that would be incredible. At point-of-care, at home is something that I think we're lacking from a diagnostics perspective. So I think that would be really exciting. Also, there are other updates to the CRISPR system, some newer functionality, systems like prime editing and base editing studied now, and base editing will actually go into the clinic, hopefully this year, since Beam Therapeutics recently announced the acceptance of their IND in sickle cell disease. And of course, congratulations to you again, as you're obviously a co-founder of that company. So maybe can you describe how you think sort of base and prime editing could change potentially the amount of these variants that we may be able to treat, and why they may be good options options since they don't cause the double-stranded DNA breaks that we hear so much about lately and obviously cause some potential off-targets?

Yeah, I think they are all very exciting technologies that are continuing to expand this so-called toolbox for genome editing. So, people do genome editing through a few different approaches. Using CRISPR nucleases, it's possible to knock out genes or cut out sequences from the genome. But then if you wanted to fix single letter changes or small changes in the genome, it becomes more difficult, especially in cells that no longer replicate, like brain cells or many cells in the body. And so base editing and prime editing provides other ways to be able to make those changes in cells that don't replicate. So from that perspective, it's very powerful because you can use it to cover more disease areas to be able to develop more drugs and help more patients. It's also potentially a nice way to further increase the specificity, because nucleases make a cut in the genome. If it's only cutting where you want it to cut, then that's one thing, but sometimes it can, if you don't very carefully verify the system, it could cut elsewhere. So a lot of effort and work goes into making sure that it's very precise. With base editing, you don't make a double-stranded cut in the genome. You're just cleaving one of the two strands of DNA, but not making a full cut. And so that makes it safer because even if it nicks somewhere else in the genome, those single-strand nicks usually don't result in a mutation. And so these are some of the differences and shows the ways that the genome editing technologies are continuing to become more refined and more optimized. And I think that the bottom line is that it's going to be able to address more diseases and hopefully more people will be able to benefit from it.

And Abim, you focused on the RNA. Editing piece, and we were just talking about the benefits maybe for DNA for base editing and prime editing. So I'd be curious if you could maybe just share a little bit about RNA for base editing and how that would increase the capabilities there.

One of the most important differences between RNA editing and DNA editing is that RNA is transient. And so for regenerative applications where you want to repair the cell transiently, or you want to change the way that a cell functions transiently, editing RNA is a much better way to go than editing DNA. Because if you edit the DNA, then that's a change that doesn't reverse, and it's going to cause a sort of permanent change to the function of that cell. So for example, if you wanted to modulate the beta-catenin pathway to get a cell to transiently replicate and regenerate, then editing RNA is much better than DNA. Because if you edit DNA, then the cell will continue to replicate, and eventually it will form a tumor and could become cancerous. So depending on the target and depending on the hypothesis of how you are treating the disease, then it's nice to have the option of editing both RNA and also editing the DNA.

And according to clinicaltrials.gov and our research, this was, we did this last year, but gene therapy and gene editing trials seem to have increased about fivefold 2010, and we then estimated that there would be about 170 gene therapies that were likely to be approved and commercialized during the next decade. So obviously, this is going to be a massive increase, but based on this, do you think that gene therapy or gene editing trials could become sort of the dominant form of therapy versus maybe other types like small molecules or biologics?

I think gene editing is, or gene therapy is, still in the early stages. We have seen some early successes, but I think there's still some ways to go. But certainly, it has the potential to address many more unmet needs that face the medical community. And so I think 10 years or 15 years from now, we're going to see many, many more applications of genetic medicine. But all that really depends on continuing to make optimizations and improvements to the efficacy and also the deliverability of these genetic medicines. So one thing I should mention is that one of the biggest roadblocks for genetic medicine is getting the medicine into the right tissue in the right part of the body. So delivery technologies are very important. Right now, people have been able to target some tissues, but there are many more tissues like the brain or the kidney or the lung and all the muscle cells in the body. Those are still difficult to target. And so I think we're going to see continued advances in delivery technology, and that will help us unleash more of the promise of gene medicine.

So I think a good way to kind of get into here now then is to talk about regulatory, because that's an interesting challenge. That's definitely something that's going to have to be overcome by a lot of the gene therapy, gene editing companies. And the adoption and regulatory pathways for gene therapy and gene editing are obviously very complex. So I'm wondering if you could maybe comment on some of the hurdles you see coming down the pipe for some of these companies, you know, especially after Allogene announced recently that one of their patients had a chromosomal abnormality and the FDA put the company's entire pipeline on clinical hold. So we see that the FDA is obviously very cognizant of the risks and going to do what needs to be done. But what do you sort of see as the regulatory framework going forward for some of these companies?

I think regulatory is definitely a very complicated issue, and I think the FDA is very thoughtful. They have been very thoughtful about thinking about safety and how to evaluate the safety and efficacy and so forth. But first and foremost is really safety and making sure that things like off-target effect, things like will the molecule— will these genetic editing molecules do anything else in the body that we can't predict or we can't foresee? And so, so these are really important questions. And I think, especially with the first set of human clinical trials, we're going to learn a lot about the safety and long-term tolerability of these kinds of treatments. And I think all that data will be considered and used to kind of devise the continued regulatory framework for genetic and gene editing medicine. I think that is needed in a thoughtful and careful way. But then at the same time, I think at some point we're going to be facing the consideration of how do we think about using these things to treat diseases that affect much smaller number of individuals, especially as we start to look at genetic mutations. Some of them only affect 1 or 2 people in the world. And so how do we think about the clinical trial process? What type of safety data do we need in order to be able to move forward with that? I think those are things that are going to be tough questions that they'll be facing the regulatory bodies. And I think one thing that will help is as we get more data, we'll understand this a little bit more. But still, that is something that will probably need to be sort of very carefully thought about, and I think new creative approaches will be necessary.

Yeah, and sort of in speaking about the regulatory framework, you mentioned what does this molecule do inside the body that that maybe it shouldn't be doing. So off-target editing, and that's obviously a potential issue for gene editing that we know about. So can you comment on maybe the potential risks that this could cause, but also the difference maybe between RNA and DNA editing? RNA is transient, so maybe the risk isn't as big there.

Yeah, I think these are things that we know some things. For example, we know that with very high amount of Cas9, it can sometimes make off-targets. Off-target mutations, and especially if the guide RNA can recognize somewhere else in the genome. So as we start to discover some of these unintended effects, scientists have to engineer new versions of the system to make it more specific, more robust, etc. And I think more profiling will be necessary to understand what other effects there may be. For example, could Cas9 bind to somewhere on the DNA even though it doesn't cut it, the mere binding of the DNA could change the epigenetic state of a gene in the cell. Could there be a long-term consequence to that? I think those are open research questions that will continue to require monitoring. And then with RNA editing, it provides a different way of going after some of the same issues. It may be advantageous to use RNA editing for things that only require transient treatment, but for longer-term treatment, With RNA editing, you have to give multiple doses of the drug. Then other considerations come in. Does the RNA editing molecule become immunogenic? Is it well tolerated by the body over multiple courses of treatment? So those are things that will also have to be understood. So that's why I say we're still early days, but there are certainly a lot of exciting and promising results that is really encouraging, and I think we're going to continue to develop it And I think we'll know a lot more, and I'm hopeful that this will become something that will benefit a lot of people.

Yeah, well, I think your work will definitely benefit a lot of people, but do you think from an off-target perspective that there are tools that are better suited to find these off-target edits based on just lessons learned, maybe long read sequencing versus short read sequencing, for example?

Yeah, there are a lot of new methodologies that are being developed, and also there are even newer methodologies that are continuously getting improved to make it even more sensitive at detecting off-target mutations. So for example, one of my colleagues, Keith Jeong, has been really sort of developing newer and newer generations of specificity profiling technologies. So I think all those things are really helpful, but ultimately I think we'll have to get some information from the clinical trials. Because humans are much larger animals than mice. And so when you're treating a human, you're treating a lot more cells than you are treating in an animal model or even in a Petri dish. And so for things that have very, very low probability, when you are treating a lot of cells, then that low probability starts to become likely. And so those are things that would require more data to understand. But I think so far, the technologies for measuring off-target is becoming quite robust. And so that's what people are using when they try to assess the clinical readiness for one of the therapeutic targets.

Yeah, and maybe just two final quick questions. The first would be, I'm wondering if you have any thoughts on just sort of the general healthcare sentiment right now. It seems quite low to me. And so I think from my side of the camp, I guess, one thing might be because of drug pricing reform or a little bit of uncertainty around maybe leadership in terms of NIH or the FDA. But I was just curious if you'd heard anything or have any ideas around some sentiment around healthcare.

I think from my perspective and, and the people who I interact with, I think this is really a golden age for biology. And what is really unique now is that many of the therapeutics that are being developed are based on more fundamental understanding of biological processes rather than taking a random guess and hoping that you'll find something that works. But things where we, especially for genetic diseases where we know which mutation causes the disease, going in and fixing it is a sure way to repair it. And so the uncertainty is how well does the technology work for accomplishing that goal? How well does the delivery system work for getting to enough cells? So those are technical challenges rather than biological uncertainty. And I think that is making drug development much more engineering-like, rather than engineering in the sense that there are specific metrics and numbers that we have to hit, rather than hoping that we got our mechanism right. So that's the difference.

Right, that's really interesting. And the other question I would want to ask is maybe about, have you thought about the implications of sort of CRISPR? So the idea is that, you know, we will potentially cure some diseases and people will live longer. So I'm just curious if you've thought about how that would impact the world, maybe our potential children or our children's children, how long they might be living for and kind of implications that might have on agriculture, food supply, the planet.

I think those, those are good questions. I think one of the things driving us to work on developing new therapeutics is to help people live healthier, help people enjoy their life more rather than being sort of negatively affected by specific health conditions. It's not clear whether or not it will make people live longer, but hopefully they will be able to live well longer. And I think that is really the goal, and that means people will be happier and more productive. So that's the goal.

Yeah, and I think that's an important distinction. So maybe not longer, but the years that they do have would be more productive, happier, healthier years, and maybe even provide more of a downstream approach for healthcare as opposed to an upstream, which I think the goal we all hope to achieve. So that would be amazing.

And it's one way to reduce healthcare costs. If people are healthier longer, then hopefully the medical system will not be as costly.

Definitely. And what are you most excited about the next 5 to 10 years? Is there something that's really exciting to you? Obviously genome editing, solving new and new frontiers, which I think there were just recent papers on programmable large gene insertion, which was very exciting. But what's getting you very excited in terms of the coming decade, I guess?

I'm very excited about continuing to realize this vision of programmable medicine. I think with genetic medicine, this is really the first time when things are becoming more and more modular and more and more programmable. And really, we'll be able to engineer medicine. And I think continuing to realize this platform is very exciting.

Yeah, definitely. And maybe I keep saying last question, but you're just such a wealth of knowledge that I keep getting excited to ask more. But last question, do you have any advice maybe to young scientists who are interested, or young students? I've been getting reached out to, people are saying that there's not enough gene editing taught in schools. So just curious if you have any advice to maybe young scientists or young aspiring scientists to be.

I think this is a really great time to be doing biology and research, great time for science, and I think really just follow your passion and find something that you are excited about and then find a great mentor who you can learn from. And I think there's a lot that we're going to see the next generation creating to make the world a better place.

Well, thank you so much for your time. I know, I know we're a bit over, so I really, really appreciate it. I know I learned a lot, so I'm sure everyone else will really appreciate your time. And just thank you so much for all the contributions to science and medicine and making the world a better place through therapeutics and diagnostics. So it's really amazing.

Thank you, Adi. Very nice talking with you.

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