E70: Benjamin Oakes and the Promise of CRISPR

This month I am joined by Benjamin Oakes, scientist, entrepreneur, and co-founder of Scribe Therapeutics. He studied at UC Berkeley, working in the Doudna Lab and Savage Lab during the earliest days of CRISPR. We discuss his personal vision for the future of CRISPR, encouraging advances in the field, and the first ever drug approval for a CRISPR based therapy.

• Podcast transcript

  Mary Parker:

  I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science. I'm joined today by Benjamin Oakes, CEO of Scribe Therapeutics. He earned his PhD at UC Berkeley, where he worked with Nobel-winning researcher Jennifer Doudna on developing new CRISPR-Cas9 molecules. He has carried that engineering approach over to Scribe where he hopes to create in vivo therapies that could treat the underlying cause of a disease. He joins me to discuss his own work, as well as recent exciting advancements in CRISPR therapies. Welcome, Benjamin.

  Ben Oakes:

  Thank you, Mary. It's a pleasure to be here.

  Mary Parker:

  Yeah, it's a pleasure to have you. So can we start with your background? How did you initially become interested in this field?

  Ben Oakes:

  Yeah, I think it's a very common question and it's one that I was I think very fortunate to have a broad experience. But when I was in college, I was actually a philosophy major and a neurobiology major. So philosophy-neurobio kind of together were my own ways of trying to figure out what my own consciousness was, what was really going on in my own head. But I think actually they both ended up being really powerful, a foundation for also critically assessing not only what I wanted and what I really liked, but also where the world was going.

  When I entered college, I thought I was going to be a doctor. I thought I wanted to do an MD-PhD. I had always loved research. I had actually started out doing research back, even in high school, working at labs at Rutgers University in New Jersey where I'm from. So I always knew I wanted to do a PhD of some sort, but I also thought I wanted to combine that with medicine. However, after working at a hospital in Rural Maine for a while during college, I realized that actually medicine, at least where it was at that period in time, wasn't as much for me.

  I wanted to get into medicine to try to treat disease, not treat symptoms, treat causes, not treat the patient per se. Upon that realization in my junior year, I really had one of these moments where you have to step back and say, okay, well, if this plan isn't it, how do we reassess that? And I got really intrigued with synthetic biology and genome editing. And I was fortunate enough to have the opportunity after I graduated to go work in a lab that was engineering what was at the time really the leading edge of genome editing tools, and that was Zinc Finger Nuclease Lab.

  And that's really I think where my fascination turned into a love, because engineering zinc finger nuclease is this really involved process would be I think the best way to say it. It's a billion molecules to try to find one that binds three base pairs, and three base pairs in the human genome is not so much, right? You need a little bit more than that.

  So you do this again and again and again, and then you have one zinc finger that could bind nine or 12 nucleotides, and then you've got a couple with a whole second one that could bind the other nine or 12 nucleotides to get specificity in the human genome. And I think that really arduous process is one that has to become a labor of love or you just don't do it. And I think that's why most people at the time weren't doing genome editing because it wasn't.

  Mary Parker:

  I mean, it's a needle in a haystack, but it's almost like a golden needle in a haystack. I mean, it's such an important thing to try and look for.

  Ben Oakes:

  Yeah. I mean, hugely so. And I think that foundation of engineering, the empirical engineering where you could test a billion things, find the one or the dozen that work really laid the foundation for all of the work I ultimately ended up doing in CRISPR and still do to this day, which is this holistic molecular engineering that tries to essentially take what nature has given us and turn it into a more perfect genome editing system.

  Mary Parker:

  Do you think that studying philosophy gave you the patience to do that sort of research?

  Ben Oakes:

  Potentially? That's a good question. I never thought about the patience angle. I think studying philosophy is really undervalued. I think it gives you the ability to ask the right questions and recognize when a question should be asked or shouldn't be asked, because is it actually getting at a universal truth or not? I think it's also come to be a really important part of my education just from the perspective of building an organization and thinking critically about just because something is done in a certain way does not mean that that's the right way.

  I think that's what philosophy is constantly trying to get into you is drilling into you to ask questions and be critical and actually think for yourself. There is no right way. There's only knowing that you don't know and everyone doesn't know, so try your best, right?

  Mary Parker:

  Oh, absolutely. Especially when you're working with real cutting edge research, you have to accept that it's going to take a lot of thinking and it's a lot of time and a lot of failure before you get any meaningful answers. If you blaze a new path, that's just how it goes.

  Ben Oakes:

  No, 100%. I couldn't agree more. I think there is that sort of I think the ambiguity around whether or not you're correct in philosophy is something that's shared very much so with deep, deep research science. It's very hard to know that you're right when you're studying biology and you're trying to manipulate biology. It's very often clear that you're on the right path, but the sense that there is no absolute right or wrong and that it will take you for a very long time to really understand that is I think another interesting shared characteristic.

  Mary Parker:

  Definitely. Full disclosure, I took a posthumanism class in college as my required philosophy major. And despite getting an A in that class, I could not tell you what posthumanism is to this day. No real idea.

  Ben Oakes:

  No real idea. I like the classics a little bit more. I did some interesting radical ecology courses that looking back and now I'm like, hmm, interesting.

  Mary Parker:

  Totally. Well, speaking of research, what work is Scribe doing now?

  Ben Oakes:

  So I think Scribe is an extension even of going back all the way to that first job I had right out of college of engineering zinc fingers. Scribe is the natural extension of that. So what I did is I was engineering zinc fingers, and then Jennifer publishes her seminal work in 2012, showing the world how to use Cas9. And immediately, again, having this arduous day task of trying to engineer three base pair recognition, I realized that if you could do the whole thing with a guide RNA, my life was changed.

  And I came out to UC Berkeley to work with Jennifer, as well as another UC Berkeley professor, Dave Savage, who was more of a synthetic biology guy, in order to engineer what was at that time, really the only CRISPR molecule Cas9 into all of these really interesting and unique different types of molecules. Some that have allosteric regulation, therefore you could switch them on or off. You can control them temporally or locally.

  Some that actually have built in unlocking switches so that they could turn on in response to a stimuli, so making CRISPR genome editing systems that can sense their environment. And then when I graduated, I became one of the first IGI Entrepreneurial Fellows, which is this institute, the Innovative Genomics Institute at UC Berkeley that Jennifer founded and has been growing and is this fantastic place.

  But it's really within that time when I realized that this broader goal of engineering CRISPR systems to do really interesting and unique things could be honed even more and should be honed perhaps even more to focus on building really therapeutic characteristics into these molecules. And that ultimately is what we do at Scribe. That is our whole focus. Our goal is to take the raw material that nature gives us, which is a CRISPR molecule, that naturally has evolved to be a bacterial immune system, not a genome editing tool.

  And take that bacterial immune system, really query every possible change you can make to it, track all those changes, and then turn that bacterial immune system into a genome editing scalpel, improving things like potency, specificity, deliverability, the ability to modify the genome where you want to as well. And that is what we've been focused on at Scribe now for really the entirety of our existence.

  Mary Parker:

  So can you explain what in vivo CRISPR therapies are and how they might differ from I would guess the opposite would be in vitro?

  Ben Oakes:

  Yeah, ex vivo actually. Ex vivo.

  Mary Parker:

  Ex vivo. Yes, that makes sense. That makes more sense.

  Ben Oakes:

  It is in vitro, but ex vivo, it just ultimately ends up back in vivo. At Scribe, our focus has always been on building genome editing, modalities that could go in vivo. I think the field itself, and for example, the first approved drug now for sickle is an ex vivo therapy. Cells are taken out of the human body. You essentially remove the in vivo delivery challenge. You can modify them ex vivo, but then they have to be put back in. That process is intensive in more ways than one. It's intensive for the cells.

  It's intensive for the patient, and it has many drawbacks because of that. So when we founded Scribe with the goal of engineering better CRISPR systems, the north star, if you will, was always, well, if they're going to be better, they have to be good enough to use in vivo. They have to be more potent and safer so we can deliver less of them and get the same effect, if not a better effect, and to have much lower risks around their potential to do off-target modification.

  Mary Parker:

  Basically what you're getting at is for the newly approved CRISPR therapy for sickle cell anemia, my understanding is that they get samples of the bone marrow from the patient, modify them via crispr, but then they have to give the patient basically chemo to kill the bone marrow that exists already in their body and replace it with the modified cells that then have to grow naturally.

  So the patient has to spend, I believe, a month in the hospital since they'll be immune compromised after the chemo. But after that, they are cured. So for something as debilitating as sickle cell anemia, that's obviously a really big deal and a really great outcome. However, as you say, it's a big invasive process.

  Ben Oakes:

  Yeah.

  Mary Parker:

  So you're saying that's ex vivo. In vivo would be less invasive than that I believe is what you're saying?

  Ben Oakes:

  Yeah. The goal of an in vivo therapy 100% is to skip that entire process, because you need to myelo ablate patients to essentially make the body willing to accept engraftment of the hematopoietic stem cells that you've pulled out. If we can, instead of doing that, just target hematopoietic stem cells within your own marrow in vivo via just an infusion, you could skip that whole process.

  At Scribe, we're also focused quite a bit on treating other areas besides hematopoietic cells. That's actually a program that we're working on with our partner at Sanofi. We have a lot of programs where we've demonstrated now in vivo efficacy based on different types of delivery systems like either AAV, which stands for adeno-associated virus, which is a gene therapy vector, or LMPs.

  AAVs, we've seen really good in vivo efficacy with our highly engineered platforms now in the eye, in the muscle, both cardiac as well as skeletal, as well as in the central nervous system. And then with LMPs, we, of course, are able to target the liver quite robustly. And actually, we just recently released data demonstrating editing of hepatocytes to essentially full saturation, able to hit almost every single cell that is presumed to be a hepatocyte and therefore reduce levels of our target gene pretty dramatically.

  Mary Parker:

  That's amazing. And that also gets into my next question of can we talk about how you hope to treat broader patient populations? I think of CRISPR as a treatment for rare debilitating diseases. But could they use this therapy and apply it to other kinds of diseases? What diseases could it apply to?

  Ben Oakes:

  I think it's a really interesting, important, and highly valuable question to ask, which is where is genetic medicine the right medicine? And I think my answer is everywhere. It's not to be flippant about it, but I think that ultimately our goal should be to use and apply our knowledge of the genome to treat every disease and every aspect of human health that we can.

  The paradigm for treating diseases today is you treat a disease well after you get it. The paradigm for modifying human health should be you actually treat the potential to get a disease well before you get it. I've gone way big here rather than keeping this specifically to your question.

  Mary Parker:

  That's quite all right.

  Ben Oakes:

  But I do think it's a really important question that we should all be asking ourselves, which is where can and should genetic medicines be used? I may not be talking about the next five years, but certainly within the next 50, I do think that we should be thinking about every disease from a genetic standpoint as much as possible. We now have the ability to modify the genome, and with that comes I think a lot of responsibility to use this as well as we can.

  And ultimately at Scribe, we believe that what this means is having the largest impact on patients. So I think, Mary, one of the most interesting and important areas that we can work and which Scribe is actively working is in cardiometabolic disease and cardiovascular disease. So cancer gets all the fanfare. Cancer gets all the fanfare. Cardiovascular disease almost two for one causes more deaths than cancer.

  It is the leading cause of death globally. Period. Full stop. It's a deeply personal connection that I'm sure many of us have. In my family, I have a really significant history of cardiovascular disease. And I think because it's often viewed as more of a "lifestyle disease," it gets the short end of the stick in terms of the attention that people pay to it.

  I think also it's a disease where surgery has become the primary intervention rather than thinking about how we can use modification of our own biology to stave off something as invasive as surgery. So I think that there's a lot of reasons why this is a really interesting area to be working with genetic medicine in, just even before we get to the fact that we actually fundamentally understand a lot of the biology that underpins important risk factors in cardiovascular disease like lipid biology or dyslipidemias.

  And this makes it a really interesting area for us to start to work in. So at Scribe, we are really focused on, again, trying to build these molecules that are more potent, that are safer, that can be targeted more exquisitely, that have unique and interesting characteristics, specifically from a therapeutic purpose. For example, building tools that maybe don't edit the genome only, but can actually epigenetically silence the genome as well.

  And with that, if you can really build a technology that is significantly better, and we believe we can from an engineering perspective, the question becomes, where is that going to have the most impact? And it has the most impact the more patients you can treat. And quite frankly, in order to treat larger patient populations, those tools have to get better.

  So we really think that Scribe is uniquely focused and uniquely placed within the genome editing field to actually take that next step and move from rare genetic disease, which absolutely still needs to be addressed in every way possible, and we are doing so with actually many of our partners such as Lilly, but to also start to look at these larger and broader disorders that affect not thousands, tens of thousands or hundreds of thousands of people, but affect millions, tens of millions or hundreds of millions of people.

  Mary Parker:

  I appreciate that a lot. My mother's side of the family, the men are all quite tall, and many of them have died relatively young from heart attack. It seems to be just a factor of being too tall. Not something that's a lifestyle choice or anything like that, just a genetic quirk that makes them susceptible to that sort of thing.

  Ben Oakes:

  I mean, the more we look into it, the more we find that a lot of the biology that we have today is not suited to our current environment because it evolved 100,000 years ago or a million years ago. And many of those genes are superfluous or somewhat accessory, but they cause us to have things like high bad cholesterol or high levels of other proteins that are correlated very strongly with cardiovascular disease.

  These are genetic underpinnings that if you have, you're at a significantly higher risk of essentially suffering from these diseases. And to look at cardiovascular disease and just say, "Well, it's lifestyle. Eat less or don't eat so much red meat," sort of thing, well, it might be great advice for some people, is going to be entirely meaningless to others. And it's such a broad patient population. It's somewhat surprising that we've allowed it to go on for so long, this characterization.

  Mary Parker:

  My cousin can't really eat less to shrink himself down from 6'11, so that's not really going to work.

  Ben Oakes:

  I would say, Mary, I'm on the flip side. Most of my family is well below six foot. But still on my mom's side as well, we have had multiple deaths from cardiovascular disease in the 50s. Again, it's not lifestyle choice, right?

  Mary Parker:

  Yeah, absolutely. Yeah. Well, I mean, speaking of getting back to the more rare end of things, although still pretty large patient population, can you tell me about the newly approved CRISPR therapy for sickle cell anemia? How it works? Is its mechanism of action typical for proposed CRISPR treatments?

  Ben Oakes:

  I think actually it's a wonderful example of decades and decades of research that have gone into understanding hemoglobin and hemoglobin neuropathies coming to fruition. And I think it's also a testament to the power of genome editing, somewhat counterintuitive to how most people think of it. So I'll touch on both those points. The latter of the two, when most people think about genome editing, we often think about our ability to turn off a gene or knock out a gene.

  What's so I think exciting about the recent approvals for the genome editing therapies for sickle and thal is that what this is actually doing is using a genome editing protein to modify regulatory machinery such that we can release or pull out this "spare tire" hemoglobin that we all have. It's not actually spare tire. It's a hemoglobin molecule that we all use in utero to essentially harvest oxygen from our mothers. But over decades of study, it was realized that patients who have higher levels of this fetal hemoglobin gene expressed are much less affected by diseases like sickle cell.

  And so you take two and two together and what has essentially happened over the past two decades is understanding, okay, if we modify this regulatory mark essentially here, we can now turn on fetal hemoglobin in erythrocyte no., so we can turn on fetal hemoglobin in red blood cells. And it's a beautiful example of the... And it's not even a beautiful example. The first approved genome editing molecule is not knocking something out.

  So everyone who thinks about genome editing or genetic medicine as like, well, we're just going to get rid of a gene, is the canonical example, the one we all talk about. It's not. It's actually increasing expression of a gene that we all have to, again, not actually treat the underlying cause of sickle, you still have the sickle hemoglobin, but to modify that disease. So it is essentially a functional cure, which is, again, a real testament to the power of genetic modification and genetic medicine in a way that I think is really more exciting than most people recognize.

  Most people think, we all think about like, okay, we'll just go in and we'll fix a gene. But we've already moved beyond just going in and fixing a gene. We can now think about modifying biology so that you can live a healthier life regardless of whether or not you need gene X fixed or gene Y fixed. That's why this treatment can work for both sickle and thal. Again, I think a beautiful example of what decades of genetic study and understanding can do, coupled with technological understanding and an understanding of how to manipulate the genome in a way that's really meaningful and impactful.

  And I am very excited to see many more of these sorts of approaches that are, I think, more elegant than just turning off a gene really come to the fore in the next decade.

  Mary Parker:

  I was thinking of probably one of the most famous examples I can think of wanting to turn on a gene with I believe it's Angelman's. I think they're doing clinical trials. They have been for a while, where the patient has I believe the maternal gene is defective and not turned on, but they do have one from the paternal that is usually not active.

  So if we could just turn that one on, in theory that could potentially be a extremely beneficial treatment. Those things I think are really fascinating, turning on a gene instead of turning it off or modify in some way. That's very cool.

  Ben Oakes:

  Yeah, no. Again, it's a really interesting example of these genetic disorders where actually pulling out the spare tire, if you will, can really help. But I think this is the same way our whole biology, the entire human system has all of these different levers we can pull.

  And up until now, we've been so stuck in this one gene, one phenotype paradigm that I think really the next decade of uncovering, okay, how do we tweak, modify gene expression in ways to make us all healthier, that's what's really going to be, I think, changing healthcare and medicine more broadly.

  Mary Parker:

  Oh, absolutely. Well, speaking of, how is the industry reacting to this new approval? It must be an extremely exciting time to have the first CRISPR therapy approved.

  Ben Oakes:

  What we're seeing in the industry is a lot of enthusiasm for this therapy getting over the line, coupled with a lot of, I think, hesitancy. Because in the end, while the genome editing side of it has worked what appears to be exactly as we expect it to, it is still burdened with the necessity to take these cells out of the body, as we talked about earlier, to put these patients on really what can be, in many instances, devastating regimes of chemotherapy to make them ready to then receive the cells back.

  So we've had other types of therapies that do something similar. There's been a lentiviral therapy that actually adds back a hemoglobin gene and suffered from the same problems, which is that... And then I actually should also mention, bone marrow transplant has been around for decades now, and bone marrow transplant does the exact same thing if you can find a match donor.

  And while it's very hard to find a match donor, even for the folks who have, few of them actually choose to get the bone marrow transplant because it is a really hard procedure to go through and it carries a lot of risk with it. So I think the field in general, it's a testament to the power of genome editing. It appears to be a functional cure. I think it's going to be hugely impactful for patients, and I'm thrilled about that.

  But I think there's also a real desire to find how do we actually move this in vivo? How do we actually solve the main challenge, and the main challenge wasn't even necessarily the genome editing challenge. The main challenge was the delivery challenge and really treating patients where they are rather than requiring them to go through these massive protocols and procedures to actually be able to get this therapy.

  Mary Parker:

  Yeah, absolutely. I mean, it seems to me from this side of the table that you've had a lot of really cool experiences and breakthroughs and research opportunities in your career so far. What do you think is one of the coolest experiences of your research career?

  Ben Oakes:

  Okay, so it's not any particular experience, Mary. But the thing that I have always lived for really over the past decade is there is a feeling that you get when you have made a new molecule, a new CRISPR enzyme, a new zinc finger from scratch, and the world hypothetically... I mean, not even hypothetically, the likelihood of the world having ever seen this before is very low. I mean, did evolution see it once and discard it? Maybe. Who knows, right?

  But the feeling you get when you first see that that molecule could work, and then when you validate it on a particular outcome that you think is important is I think this continual dopamine drip, if you will, that always keeps me going, because these are things that would not exist if not for us. So we're building things that I think many other people don't get to say that. Many other things that most people build, other people would build it. It would look almost identical.

  The stuff that we're doing is entirely unique and really truly would not exist without for us. And so that I think is this experience that if you want to be a protein engineer and a molecular engineer and you focus on hard problems is one that is somewhat unmatched, in my view.

  Mary Parker:

  Yeah, absolutely. Well, thank you so much for joining me. It's been a real pleasure talking to you. I appreciate the time you could give us.

  Ben Oakes:

  Yeah, of course. It was lovely as well. Happy to be here and invite me back.

  Mary Parker:

  I will. Absolutely. And I'm also really excited to see whatever comes out of Scribe next, because I think it's going to be pretty cool.

  Ben Oakes:

  Thanks.