FUTURE OF EPIGENETIC MEDICINE - WITH BEN OAKES

UNLEASHING NEW therapies WITH EPIGENETIC EDITING

Imagine a future where, based on a diagnostic in your teens, your doctor gives you a customized infusion with a top-up every 5 to 10 years that “dials down” your genetic risk factors for all kinds of diseases WITHOUT making permanent changes to your DNA.

Welcome to the world of epigenetic editing, a frontier that will unlock a new universe of gene therapies that are both potent and reversible.

My guest today on FutureBites is Dr Ben Oakes, Co-founder, President and CEO of Scribe Therapeutics, a company that’s focused on designing and applying CRISPR-derived tools that not only edit genes directly and permanently, but also control and fine tune the conditions that decide whether a gene is turned on or off. 

How does epigenetic editing work? What are the advantages and disadvantages? What are the current and future disease targets? If we think about the long-term future of medicine and healthcare, what might be possible? I asked Ben these questions and more. In a fascinating exploration, he discusses the journey towards effective interventions, and why multipurpose genetic editing tools will eventually revolutionize the future of medicine.
 
And it’s NOT far away. While complexity challenges are high, this is an active and vibrant field with many players and many pathways forward. The science is moving fast. We’ve come a long way with DNA editing in 12 years and I expect FDA-approved epigenetic therapies will transform the lives of tens of thousands, if not hundreds of thousands, in another 10-15 years (2034-2039). Ultimately, therapies that target multiple risk factors for cardiovascular disease offer an opportunity to reshape the healthspans of billions.

You’ve been hearing a lot lately about gene therapies based on editing DNA. Now hear about the ‘next-level’ in gene therapies. The future of medicine is truly an amazing place!

meetING BEN OAKES

As well as being co-founder, President, and Chief Executive Officer at Scribe, Ben has contributed to over 25 publications and patent applications on synthetic biology, molecular engineering, CRISPR and zinc finger-based genetic modification. He was named to Endpoints 20 Under 40 in biopharma and Business Insider 30 Under 40 transforming healthcare. Previously, Ben was an Innovative Genomics Institute Entrepreneurial Fellow, received a Ph.D. in molecular and cellular biology from the University of California, Berkeley, and worked in the lab of Nobel laureate and CRISPR co-inventor Jennifer Doudna.

I thoroughly enjoyed our conversation. As well as being a dedicated scientist, Ben is passionate advocate for his field. He was full of personality and generous in his responses to my many questions, and he helped me think bigger (much bigger!) about the future opportunities in epigenetic therapies and the future of medicine more broadly. The real deal. He was embarrassed when I labelled him a “luminary,” but that’s what he is, and we need more like him!

Listen to Ben by clicking below, or by subscribing to “FutureBites with Dr Bruce McCabe” on Spotify or Apple or wherever you get your podcasts.

Scroll down to read my personal thoughts and takeaways. At the end of this blogpost you’ll also find a full transcript.

Thank you, Ben Oakes. What a privilege.

MY PERSONAL TAKEAWAYS

ADVANTAGES COMPARED TO GENE EDITING

The Johns Hopkins Department of Genetic Medicine offers this summary of what’s going on ‘under the hood’ when we talk about alterations to gene expression:

“Although every cell has a complete set of genes, only some genes are used, or “expressed.” Genes can be switched on or off, causing one cell to be a brain cell and another to be a bone cell. In cells, the DNA is wound around histones, and together, the DNA and histones are called chromatin. Chemical groups on the DNA and histones are called chromatin marks. Chromatin marks switch genes on and off. Some chromatin marks switch genes off by tightening the DNA around histones; other chromatin marks switch genes on by loosening it. These changes are epigenetic as opposed to genetic because the DNA code is not changed. Epigenetic changes can cause medical conditions by changing how genes are used and whether they are turned on or off correctly.”

When diseases alter epigenetic expression in the body, epigenetic editing offers a way to make corrections.

Epigenetic editing offers the following advantages over gene editing. Non-permanence and reversibility (hence lower risk), fine-tunability and nuance, and powerful ‘multiplexing’ capabilities (the ability to target multiple genes at once).

FINE TUNING AS WELL AS “ON-OFF”

Until now I’d always thought of epigenetic therapies in terms of switching gene expression “on” or “off,” but Ben made it clear that, while early applications are likely to be “on-off” because it is simpler, there are in fact more nuanced options available to control gene expression, more akin to a volume dial or a graphic equalizer on a sound deck. As he explained to me, gene expression in the body “is not binary. It can be, but it doesn't have to be. So you can get expression of a gene anywhere from one to a hundred, and in cell type A it's one, cell type two it's a hundred, cell type three, it's seventy-five.”

So it makes perfect sense to aim for future epigenetic therapies that are also more nuanced “in which we are thinking about tuning multiple genes to various levels to have a great effect on diseases that may be more complex.”

The future, then, is about tunability as well as switching.

SAFER PATHWAYS, faster pace

Non-permanence and reversibility attributes mean epigenetic editing can sometimes offer a safer pathway for trialling gene therapies (e.g. when patient need is high but there remains some doubt over progressing with permanent DNA edits) and for experiments that improve our understanding of the biology of the epigenome. I expect epigenetic editing will, therefore, accelerate the overall pace of all genetic medicine.

CARDIOVASCULAR DISEASE IS A BIG TARGET

Cardiovascular disease is a big target. Ben reinforced loud and clear the messages I received from my visit with Kiran Musanuru at University of Pennsylvania when discussing gene editing to reduce LDL cholesterol production, with the new insight for me that many cardiovascular disease risk factors beyond LDL production might be addressed simultaneously in single interventions via multi-target epigenetic fine-tuning.

I also learned that cardiovascular disease is far more consistent target than cancer, which has hundreds of variations and thousands of different driver mutations, and so in principle offers a much simpler target. When we look at how far and how quickly we’ve come with cancer therapies, I’m doubly excited by the prospect of learning the results of Ben’s trials in the next 5 years!

Cardiovascular disease is the number one killer in the world. When we combine the science pathways, I feel even more certain we will achieve the goal Kiran shared with me last year: we will shift the bell curve of cardiovascular risk for humanity.

EXTENDING THE TOOLSET

Epigenetic editing will NOT supersede gene editing; it is an additional toolset enabling a range of new therapies, some of which will target what was previously untargetable (eg by applying the new attributes of multiplexing and fine-tunability to complex diseases), and some of which might offer an improved pathway over existing gene editing approaches (eg because of the attributes of non-permanence and reversibility). To be doubly clear, for many diseases, permanence is the preferred outcome. It’s all about extending the toolset!

fine-tunability ALSO means MORE COMPLEXITY 

We spoke several times about complexity compared to gene editing, including when I referenced the Human Cell Atlas project. Ben reinforced my thinking that our understanding of gene regulation in nature (ie which gene expressions connect to what outcomes) must increase exponentially before we can take full advantage of all the fine-tuning and multiplexing opportunities on offer, and that this task is exponentially more complex (just think of all those dials from one to a hundred!). Ben called it a ‘beautiful problem,’ which indeed it is, and one which will keep him in work for many years!

A corollary is, an exponentially greater amount of data will be needed to fuel this medical frontier to its full potential. And it’s coming. The Human Cell Atlas is a great illustration of the “next-level” data-set exponentials that will transform the future of medicine. Scientists sequenced the first human genome in 2003. The Human Pangenome Reference Consortium aims to this year (2024) increase our reference dataset to 350 human genome sequences to better represent human diversity. The UK Biobank project Ben mentioned has sequenced half a million people and matched them to their medical records. The Human Cell Atlas is progressively sequencing bigger and bigger datasets across the approximately 37 trillion cells that make up the human body. Why? Because if we can understand all the mechanisms determining how genes are expressed and cells differentiate (into heart cells, lung cells, etc) based on spatial location, then we can also better understand epigenetic pathways to diseases (like lung cells becoming asthmatic) which will open up new pathways to treating those diseases.  

1 … 350 … half a million … 37 trillion. Now THAT’S exponential!

THERAPIES IN 10-15 YEARS 

While our biological knowledge hurdles for enabling nuanced and multiplexed therapies are high, clinical impacts for epigenetic editing are NOT far away. First, there are a ton of well understood gene pathways we can target already. Second, there are plenty of targets for simple, on-off type interventions. Third, this is an active and vibrant field with many players and a LOT of pathways forward, and the science is moving briskly. As Ben pointed out, look how far we’ve already come, and how quickly, with gene editing!

He’s right. CRISPR-Cas9 was enabled as a gene editing tool in 2012 – 12 years ago at time of writing – and FDA-approved therapies enabled by these tools, such as CAR T-Cell, Sickle Cell, etc, have already impacted many tens of thousands of lives.

I predict widescale patient impacts from FDA-approved epigenetic editing therapies in a similar timeframe (2036-2039). Indeed, this may be conservative. I will revise as I research and find more data points.  

REWRITING THE FUTURE OF HEALTHCARE

The long term opportunity is monumental.

When Ben (together with other scientists such as Kiran Musunuru, who is pursuing the gene-edit route) hit their targets for cardiovascular disease, the lives transformed won’t number in the tens of thousands, or even tens of millions, they will number in the billions.  

In fact, the aim is nothing short of a shifting the entirety of healthcare further towards the “preventative” end of the spectrum. I’ll let Ben paint the picture: “There might be a world in which, every five to 10 years, you go into your doctor, you get your booster for your epigenetic. We're going to make your genome healthier … we're going to transition from a treatment paradigm to a prevention paradigm … Everyone lives healthier lives. I think that's the vision we have to aim for.”

I’ve presented on this many times, and I cannot emphasize enough, all transitions towards disease prevention and extending average ‘healthspans’ also represent pathways to revolutionizing the economics of healthcare.

Of course, Ben was careful to point out that this is a decades-long journey, but there is a pathway. As he put it, “there's line of sight to it, at least within Scribe. We have line of sight to how we would do this already.”

THE PRINCIPLES MUST ALSO APPLY TO AGRICULTURE

All the principles and opportunities Ben discussed must, in my opinion, also apply to revolutionizing the future of agriculture. Epigenetic editing must (1) open up countless new nuanced editing possibilities in crops and livestock and (2) offer pathways forward that are inherently lower-risk and more acceptable to citizens than current gene edits, thereby allowing scientists to be more adventurous in exploring new crop variations, in turn offering a way to accelerate the overall take-up of gene-modified agriculture. It strikes me that a particularly big opportunity might lie in lower-risk categories of gene-targeted herbicides and pesticides. I don’t know. The implications for the future of agriculture deserve a follow up, perhaps with another visit to the wonderful Rodolphe Barrangou at North Carolina State University (as always, the more I find out, the more I realise I don’t know :-)

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INTERVIEW TRANSCRIPT

Please note, my transcripts are AI-generated and lightly edited for clarity and will contain minor errors. The true record of the interview is always the audio version.

BRUCE MCCABE: Hello and welcome to another episode of FutureBites, where we explore pathways to a better future. And we're in the healthcare realm today, and our special guest is Dr Ben Oakes. Welcome, Ben.

BEN OAKES: Thanks, Bruce, I really appreciate it.

BRUCE MCCABE: I'm excited to talk to you because we're going to talk about a real frontier today, in epigenetics and epigenetic editing specifically, and I thought I'd just briefly highlight that you are quite a luminary in this field. Forbes magazine did quite a splash on you last year, so you're obviously a mover and shaker in this. But you also worked in the Doudna lab. There's quite a history and, of course, Jennifer Doudna and Emmanuel Charpentier were the Nobel laureates for this stuff. So I've been, you know. I can't wait to hear a little bit about your story and to learn more from you today.

BEN OAKES: I appreciate it, Bruce. I don't know that I would say luminary, but I've been trying to engineer these tools for a while. Let's just say that, yeah.

BRUCE MCCABE: And you're currently co-founder, president and CEO at Scribe Therapeutics right? And Scribe is heavily focused on this area.

BEN OAKES: Yeah, that's correct, right. So again, my background is really as a technologist, a molecular engineer, building better versions of genome editing technologies, and we founded Scribe to try to take really CRISPR genome editing tools from what they evolved to be the bacterial immune systems that they started out as, and turn them into more exquisite genetic medicines, medicines with a focus on greater potency, specificity, and with that came a focus on not only building genome editing but building epigenetic editing technologies.

BRUCE MCCABE: So, like the rest of the world is just catching up a little bit on what genetic editing is, and then they're kind of just getting little bites of the potential that we explore so much in this podcast, of just how much is going on in gene editing. So what was the convoluted pathway for you to get to this, the ultimate frontier really in complexity, it seems to me? Anyway, how did you arrive at epigenetic editing?

BEN OAKES: My story all starts out with the realization, I think, that medicine was not really focused on treating the underlying cause of disease and, quite frankly, medicine was really more about stabilizing patients and, you know, modifying things we could, which very often happens to be symptoms.

And that led me, well over a decade ago, to try to figure out why that was, and I realized at that point in time that it was because we didn't have really the tools and technologies that would allow us to modify the underlying, underlying causes of disease, which very often were genetic or at least heavily influenced by the genome. And that resulted in me working on the first generation of genome editing tools, or some of the first generations of genome editing tools, including things like zinc finger nucleases and TALENS.

Before the invention of CRISPR, and then when Jennifer really demonstrated to the world how to use an RNA to specify DNA, I, like, immediately saw the potential, came out to work with her in 2013 and spent the next, really, five years engineering better, or more interesting, a whole bunch of really unique genome editing technologies. We then founded Scribe with the stated mission of trying to engineer genetic genome editing technologies to be safe and effective enough to be utilized in broad patient populations.

And doing that at Scribe for a while, we realized, quite frankly, that our ability to build better versions of genome editing tools was not limited just to genome editing. We could build really any genetic modification technology to accomplish similar goals or actually even entirely unique goals, by not modifying just the genome but but by also building the tool set to modify the epigenome, which, uh, I'm sure, as everyone is familiar with, is is how essentially all of our genes are expressed, right. It's the reason why we have … Maybe we should get into that ...

BRUCE MCCABE: I don't think we should assume that everybody's familiar with it! I do a lot of medical audiences, and even when we get into CRISPR, you've got to sort of sit there and work back to, ‘hey, it’s cut and paste, let's go racing along the DNA and looking for sequences,’ and so, yeah, if we can break it down in layman's terms, that would be wonderful.

BEN OAKES: We can try [laughs] You'll have to jump in if we're doing all right or not.

The way I think about epigenetics at its most basic level is that our neurons, our brain cells and our hepatocytes, our liver cells, or our skin cells, or your cells in our eye, they all have the same genome but they look incredibly different, they're accomplishing different things, and so it is the level on top of the actual genomic code that actually allows each of these cells to express different genes in different amounts, and that's what essentially allows them to accomplish these, this really beautiful myriad of things that becomes the human body, right.

BRUCE MCCABE: Yes.

BEN OAKES: So epigenetics can really, you can think of as the, the tuning switch for every gene, turning it on, turning it off and everywhere in between, um, and that's really interesting and unique, because the body, our body, every organism's body, um, already is using epigenetic signaling to modify gene expression. You know, throughout itself, throughout, you know, from head to toe, every single cell looks slightly different. And so if we are able to tap into that, that it kind of opens up this whole other level of creating medicines that can really treat the fundamental underlying causes of disease, but in a way that doesn't require permanent modification of the genome and actually may be reversible, right? So we can start to imagine creating drugs that have a lot of the advantages of genetic medicines, in the sense of one and done, getting at the underlying cause, but also could be tuned on and turned off which is really a unique future.

BRUCE MCCABE: Yeah, it's so exciting. It's so exciting. So when I have a mental picture of this, it's chemicals that bind on somehow to the structures around the DNA which then decide what gets expressed and what doesn't, and they could come from lifestyle. But that's how I. I mean again, correct me too. I'm trying to really dumb it down for myself, just that mental picture. But we can influence what maybe binds on, or we can remove what's there or reposition what's there. So these are the chemicals that then decide which genes get expressed or don't get expressed. So we can change those chemicals right, the placement of them, the composition of them. What's the best way to think about that?

BEN OAKES: So it's really both placement and composition. And the way to think about what we're doing is, we're utilizing CRISPR again, which, to your point, is this programmable DNA binding technology. We can use an RNA guide, roughly 20 base pairs of specificity, to find a location in the human genome. And then what we've built at Scribe and what others have built as well, is that if you use that CRISPR tool to recruit what's known as epigenetic modifiers, things that essentially can place new epigenetic marks or remove epigenetic marks are there. It allows you to essentially modify a particular locus, very often a gene, and turn that gene on or turn it off.

BRUCE MCCABE: And earlier you said, “and everything in-between,” so it's not a binary process necessarily. This is new for me.

BEN OAKES: Now this is where we get really nuanced, and binary is obviously the easiest, or may seem like the easiest, but sometimes you can't accomplish even binary. There's a lot of really interesting things that can be done here, where in a cell very often genes are and I'm kind of you know, Bruce, referring more to how your own body does it, it's not binary. It can be, but it doesn't have to be. So you can get expression of a gene anywhere from one to a hundred, and in cell type A it's one, cell type two it's a hundred, cell type three, it's seventy-five.

BRUCE MCCABE: Ah.

BEN OAKES:Right, and that is, I think, really interesting because, again, that may be, that may differentiate between a skin cell and neuron and a liver cell. And the the thing that we can now tap into is more of the binary change onto off. That's, I think, the most straightforward. But we've also seen, and others have seen, that you can get, I'd say, more of these quantitative changes where you can get, you know, on to partially off, or almost all the way off, or maybe just a little bit off. I think pharmacologically, like thinking about how we intervene, It's a lot easier to think on to off right now, but the future will come, I predict, in which we are thinking about tuning multiple genes to various levels, to have a great effect on diseases that may be more complex.

BRUCE MCCABE: Do we already have the tools to implement that sort of gradual or variable change? Or are those tools not there yet?

BEN OAKES: Those tools are not quite there yet, and I think the complexity of epigenetics and the understanding of epigenetic regulation is not quite there yet, right? So even if we think that we have a technology that could accomplish that at one site, which we may, which we believe we do, you all of a sudden go to site two in the genome and it's completely different because of the complexity of biological regulation. So it's, it's somewhat a beautiful problem in that it is a, we are assured of job security in it [laughter]. But it’s a worthy problem nonetheless.

BRUCE MCCABE: Yeah, you have a lifetime of work ahead [laughter]. I love it, I love it. And that word complexity, let’s just explore that a little bit, because to me one of the key challenges that everyone doing gene editing is understanding what all genes do, right? And that's a huge, monumental problem, just the understanding before we can apply editing.

BEN OAKES: Yes.

BRUCE MCCABE: So here we're talking about a chemical slider, like a volume control, potentially deciding, you know, the expression of genes. But this is another layer, a meta layer if you like, of information, of data, that we need to understand before we can apply tools. Is it another order of magnitude in complexity to the, to the, to the gene?

BEN OAKES: I would think it absolutely is, but we don't have to treat it like one yet.

BRUCE MCCABE: Okay.

BEN OAKES: And that's the interesting thing. And this is what allows us to utilize some of the epigenetic silencing and epigenetic modification technologies that we've built, is that there are fairly simple interventions that we understand, if we do to the genome, will result in a really positive outcome for health, and those interventions can be made with editing. We can also go and just recapitulate, making that same intervention with an epigenetic modifier as a first step of getting there. And then I think what's really interesting is, because epigenetic modifiers have these, you know, some specific advantages, including the ability to potentially be multiplexed. you can imagine starting with modification A, that you could do with an editor or an epi-modifier, and either one would be potentially sufficient for the task, but if you want to make modification B, you need an epi-modifier because what you want to actually do is, like, modification A plus modification B.

BRUCE MCCABE: So in a sense we already have, from the genetic work, we already have a list of targets where this is an alternative approach to the same targets, but with new advantages potentially, right?

BEN OAKES: Yeah, and Bruce, that's exactly right. I would add that there are targets where you may not, you may well understand the genetics, but you may not want a permanent edit, and this is where you know again, even full ‘tuning down’ using an epigenetic modifier could be useful.

BRUCE MCCABE: So let's get into those advantages. So permanence has come a couple of times. So here people worry, scientists worry, medicos worry, patients worry, if you're having gene editing, “what if there's something we haven't taken into account? We're removing it, but maybe there's an unintended consequence or maybe there's off-target cutting that occurs in the DNA strand and we do something we shouldn't.” So there's some element of risk in these therapies, as there are with all therapies. So, as I understand it, one of the big potential advantages here is that because we're not cutting, because we're not making permanent changes to DNA, because we're modifying the expression or how it's expressed, we can reverse that more easily. Is that the key advantage?

BEN OAKES: I think that is an important advantage. You know, at Scribe we also build genome editing tools, so I don't want to take them out of market. [laughter]. I also don't want to say, there's other ways to solve some of those challenges, Bruce, and maybe another time we talk about some of what we've done in genome editing, but for the off-target, from the off-target perspective, we have built genome editing technologies that not only appear to be highly potent in non-human primates, but we can't find off-target editing, and that's only accomplishable if you engineer these tools right. So I think there's some real solutions to some of the perceived editing problems.

I think what's interesting is that with epigenetics is that there are targets that are, you know, maybe have less clear biology. Right, you were talking about, okay, you know, there's some really well, both biologically understood and pharmacologically validated targets, and like 3% of the population's walking around without that gene. So you don't need it. I don't need it. No one really needs it. And we just basically lost the genetic lottery and someone else won it. And that person's never gonna have a heart attack. So, like, congratulations, right?

I think many of those genes exist, you know, from a simplistic understanding that we can really get rid of. But then there's a whole another class that are more rare in terms of really understanding the genetics of, basically, a full gene knockout. Seeing that in the patient population is much more rare and therefore you can't have as much certainty around that target as you would, you know, the first target we're talking about. That's where, all of a sudden, epigenetics becomes really interesting, because you may still want to provide a very durable effect on that target. I mean, I don't know about you, Bruce, but for me, like I don't want to take a drug every day, I've had enough of that shit, right?

BRUCE MCCABE Absolutely [laughter].

BEN OAKES: I don't want to have to take a drug every week or every year, or you know, ultimately I'd like to fix the problem at its source, right? That's my whole goal from the beginning. At the same time, you know, if we're limited just to what we have a really good genetic understanding of, we'll be limited in our number of targets. If we can start to apply epigenetics, we can start to explore, you know, things that are, for example, arising from some of the deep sequencing that we're seeing out of the UK biobank, where they've just, for the first time, sequenced, you know, half a million people and matched them to their medical records and we're starting to learn really interesting things. But the variants are rare, right. So we don't have the scientific confidence that we do for some of the more common genetic variants and therefore we need to go in and pharmacologically perturb those targets and understand how that works. Epigenetics is a beautiful way to do that, because you have this ability to reactivate that gene if, in you know, from as laid out, you saw that you wanted to, right.

BRUCE MCCABE: Yeah, it makes sense.

BEN OAKES: It's like an interesting question too of the stability of the environment you're in. Okay, yeah, and that's where you know if the stability of the environment you're in is, you know if the world is going to look exactly the same 25 years from now as it does today, then you know we can safely modify, permanently, edit many different genes that we know. But if the world looks different, you know, who knows what that means. 25 years is actually a long time, given that CRISPR was invented 10 years ago and we already have a drug. There's potential reasons that you might want to be able to have that ability to turn off the therapy.

BRUCE MCCABE: Yeah, understood. So let's use an example, put some meat on the bones a little bit more, especially for people that aren't as familiar with the technology side. On this podcast recently we've interviewed Kiran Musunuru at UPenn and they're doing this wonderful stuff with cholesterol. Uh, so how do we edit the liver to produce less of that LDL cholesterol. And, and that's what they're doing now, that's a permanent change. Now would this be an example? Maybe we could have a cholesterol therapy, in this case, just to sort of flesh it out, but what they're doing is editing all the cells in the liver to produce less LDL cholesterol. That at least attacks the genetic component of the risk of heart attack and that, for a lot of people, can be a really big deal. The risk of cardiovascular disease drops, yeah, so that's really cool. So if we did it this way, could we give people a drug that has the same effect, because we now know the pathways, we know the genes we're targeting, but we're doing it with the epigenome and not actually by editing the DNA? Would it be a potential case? I don't know what would be the advantages. Is that something we could do?

BEN OAKES: And so I think this is so. You know, Bruce, we are actually doing very similar things, like this is what we're thinking about doing in terms of you know, how do we in many instances really dramatically reduce the risk of cardiovascular disease or cardiometabolic disease? When you think about doing what you know, when you think about doing some of those genes, and this is kind of exactly what I was talking about from the genome editing perspective. Some make sense as a permanent edit. Like again, you have three to 5% population walking around with at least one copy of that. It appears pretty safe. But there are other genes and other targets where it's maybe less clear, or you don't want to go all the way to the bottom, right, and you don't want to knock out the gene entirely, and that's where these epigenetic therapies become really interesting. And that's where these epigenetic therapies become really interesting.

LDL cholesterol is incredibly important. If everyone can get that under control it will dramatically reduce the incidence of heart attacks. For anyone listening, LDL cholesterol, we know how to intervene here. If you're not where your doctor thinks you should be, and even if you are where your doctor thinks you should be, you might want to get it lowe. I'm like an evangelical for that, because I think it really is an important intervention. But the thing that's interesting is that it's not the only risk factor, right? By no means is LDL the only risk factor for cardiovascular disease. And there are others, right, you know there's a lot of talk about LPA recently being another really interesting cholesterol associated target. And then you have things like blood pressure and you have things like obesity and insulin resistance that are all really huge risk factors. And a single drug that hits your LDL-C you would not imagine to be nearly as effective as a drug that hit LDL-C and other lipids as well as obesity or blood pressure.

And this is where it really is the future, right? How do we create single interventions that dramatically reduce, you know, many of the risk factors for cardiovascular disease. Versus just one. That's not something that you likely would want to do with a genome editor, at least not all at once. Interested in doing it in sequence, but if you could do it with an epigenetic modifier, I think the level of safety becomes … number one, of the reversibility, number two of the ability to multiplex really safely, becomes really important from the epigenetic modifier standpoint.

BRUCE MCCABE: Can we just get into this word ‘multiplex’ a little bit? Can you flesh that out for me?

BEN OAKES: Yeah, so the way to think about this is essentially the ability to target multiple genes at once. And so again, you know, target a gene that modifies your LDL-C and target a gene that modifies your blood pressure. Right, and that's how I would think about multiplex. There's more complexity here, which is you can imagine actually multiplexing the same target to get again maybe different levels of expression, but the complexity there kind of starts to spiral …

BRUCE MCCABE: But you've basically got, it sounds like there's a lot more fidelity to this. So this toolkit okay, not today, but theoretically pushing forward, because we're tinkering with the volume controls, the ‘sliders’ if you like. We have a lot more fine tunability. Is that fair, with our targeting of our efficacy, our effects?

BEN OAKES: I think we will. Again, Bruce, not today, but we know that it's possible. And I think exactly how we achieve that is still, as I said earlier, a really important open question in the field. But we and many others are working on this diligently, and so I think it is something that we will achieve.

BRUCE MCCABE: Okay. So let's get into the timeline a little bit, and some early targets, because I think people want to kind of contextualize this. Is this a, “we're going to see stuff in the clinic in 10 years or 20 years?” But let's not start there. Let's just say, “Where are we now? What are the early targets that we're going after?” and maybe we can flesh that out and kind of look forward from there.

BEN OAKES: Yeah, and so again not to continue to repeat myself here, Bruce, but from Scribe's perspective, we are actively working on all of these cardiovascular disease targets. I think it is, you know, one of the things that I'm sure you know you guys talked about in your last podcast, is that cardiovascular disease kind of gets the short end of the stick right now. Everyone's focused, and has been for the past couple of decades on cancer and we've reduced cancer deaths pretty substantially. It's quite amazing If you look at the stats.

BRUCE MCCABE: I'm utterly amazed at all the different pathways of research now that are fanning out in different directions for different approaches. It's just amazing what's going on in cancer.

BEN OAKES: Yeah, which kind of leaves this really interesting opening right? Cardiovascular disease, leading cause of death globally, outstrips cancer almost two to one, and it is, at the same time, actually a much less stratified disease. And when I say that I mean, there's many fewer different modifications that you would envision having to make to actually meaningfully move the needle on something like ASCVD. Yeah, meaningfully moving the needle on ASCVD. Again, if you could focus on dyslipidemias, things like LDLC, blood pressure and, you know, obesity, slash insulin resistance, you would have a dramatic impact. You know, when you compare that to something like cancer, of which there's hundreds of different types, thousands of different driver mutations, and all of a sudden you start to realize that intervening there – at least this is our thesis at Scribe – with genetic medicine could have some of the largest and most profound impacts possible.

BRUCE MCCABE: Absolutely.

BEN OAKES: When we think about bringing genetic medicines forward, whether they're genome editing or epigenetic editing, it is all focused on that particular area and I don't think it's 10 years. I think there are folks who are already in the clinic with genome editing-based approaches for this and we will likely be in the clinic within you know the next five as well. Um, hopefully with significant amounts of data.

BRUCE MCCABE: Okay, so in the next five years we should see trials. We'll be hearing about trials, uh, where we've got epigenomic editing and cholesterol. That's. That's kind of where we're hoping to be. That’s Scribe. That's exciting.

BEN OAKES: It is exciting, I think it's, and I think it will go well beyond that as well. But of course I would say stay tuned.

BRUCE MCCABE: Yeah, of course, only share what you're comfortable sharing, because I want to share all of this with everybody. There's no secrets if you say it on this podcast [laugher]. Do I hear an undertone there, when we talk about cancer, that this is actually potentially a simpler thing to target than cancer? You know, where you look at all of the nuances and all the different variants of cancer. But here with, for example, cholesterol, whilst it's, it requires a multiplex approach and there's multiple factors, our targeting perhaps is even simpler than cancer? You know we've got a bigger problem, but with an easier solution?

BEN OAKES: It's a bigger problem and it's certainly how I think about it, with the one difference being, you know, when you think about treating cancer, obviously we think about if and when possible, really creating like complete responses, whereas when we think about treating cardiovascular disease, we think about modifying risk, and so the solutions I truly believe, you know, a smaller number of really intentional solutions can have a very large impact in cardiovascular disease, whereas with cancer it it's a, you know, it's many more different types of interventions. It is, I think, a really interesting opportunity to work in a space where, you know, we can really potentially move the needle with a fewer number of therapies.

BRUCE MCCABE: Yeah, it's a very cool space and if we get into the cardiovascular side, I think the expression over at UPenn they used was “moving the bell curve, the risk bell curve for humanity.” That's the opportunity. It's a pretty big opportunity. You're talking about public health here.

BEN OAKES: Yep, it is, I mean, and it's pretty dramatic and, again, I think, really exciting and also the ideal space to really have these long-term durable genetic medicines, whether it's genome editing or epigenetic editing.

BRUCE MCCABE: Yes.

BEN OAKES: Because compliance is one of the largest issues in the space.

BRUCE MCCABE: So, just down to practicalities, and the way you envision something like that rolling out, the cost, the frequency of you know, a drug. Obviously we're not going to be able to put numbers on it, but do we think that this is a cheaper way to get to market than than, um say, the gene editing, straight gene editing? Or is it a similar toolkit and they have similar processes and therefore similar costs?

BEN OAKES: Very similar toolkit. Very similar in terms of genome editing for epigenetic editing. The real differences are actually at the molecular level. Just what these tools look like. They're all delivered via some sort of in vivo delivery system, very often mRNA, base tees or lipid nanoparticles …

BRUCE MCCABE: And a transfusion? Or ultimately a pill? What are we looking at? Oh sorry, infusions.

BEN OAKES: We’re looking at, most likely infusions.

BRUCE MCCABE: Infusions.

BEN OAKES: Unlike well, the first genome editing therapies which actually do require, basically, hematopoietic stem cells to be brought out of the body, folks to be myeloabladed and for them to be essentially put back in. Everything that we're doing here at Scribe, including all our genome editing and epigenetic editing, is going to happen within the body. So it does require, it's an infusion, but to your question about ‘how many times and duration,’ we expect it to be a very durable approach.

BRUCE MCCABE: Like multi-year or decades, multi-decade, that kind of thing?

BEN OAKES: We don't know yet. This is the interesting thing. There's large animal, there's non-human primate data that suggests that these things will last four years. Yeah, um, you know it's out past a year, but it is always a question about what happens when you translate into a human of course.

BRUCE MCCABE: Of course. But if we're imagining the future, we probably should imagine that it's multiple therapies over a life, it's not one and done, because there's some time table or time limit to the durability. I think you used the word durability.

BEN OAKES: With epigenetic editing, I think the safe assumption right now is that you would get in the order of years, but potentially not permanent. Yeah. But we also, you know there's data now that support redosing with genetic medicines, even with genome editing, and I think that redosing all of a sudden creates this really interesting paradigm under which there might be a world in which every medicine you want to get starts to transition to thinking about how do we deliver or make this possible with an epigenetic approach. Yeah, maybe not every one, but like a lot of them, you could imagine and it could be, you know, every five to 10 years. You go into your doctor, you get your, your booster for your epigenetic. We're going to make your genome healthier and therefore you're all you know. You're going to be healthier and we're going to transition from a treatment paradigm to a prevention paradigm. Oh my God, everyone lives, healthier lives. I think that's the, that's the really exciting future that could be possible because of these, you know, really durable one-time therapies.

BRUCE MCCABE: That's huge. Just the thought of that, that's really expansive. So maybe from multiple conditions packaged up in a one-time shot, sorry, a regular shot every few years that “hey, these are your conditions, we'll just make sure we stabilize all those and in multiple places in the epigenome,” that's amazing.

BEN OAKES: I think that's the vision we have to aim for. You know, Bruce, I don't want to over-promise here. This has been happening for decades, right? But there's a world, I mean there's line of sight to it, at least within Scribe. We have line of sight to how we would do this already, and I think that's really exciting. Of course, there's so much risk to overcome in the clinic and downstream, from just the perspective of “how well do these things translate and what are the doses you need to achieve in humans to achieve that,” but they're all technical engineering problems and for us at Scribe. That's our bread and butter, that's what we run in, is “how do we improve things technically?” So I have no question that, given time, we will solve us, and I should say us and others will solve many of these challenges.

BRUCE MCCABE: When you were talking earlier, in my head I was thinking also it's almost as if, because we're dealing with the expression of all this stuff, and because there's these advantages and there's more fidelity, it's like maybe one day, almost all gene editing you say, ‘well, why don't we just do everything with the epigenome rather than doing the gene?’ But I think you answered that earlier. There are some things that you wouldn't want to do that with, because you want a one and done and you want to, you know, so …

BEN OAKES: And there are things absolutely Bruce, which you can achieve with genome editing that you can't achieve with epigenetic editing.

BRUCE MCCABE: Give us an example.

BEN OAKES: A good example like that would be just a particular genetic outcome. If you want to delete something from the genome, maybe it's a toxic allele, maybe it is a transcription factor binding site that is responsible for coding somewhere else. Those sorts of deletions. Maybe you want to essentially do something called exon skipping, which is jumping from essentially how genes are regulated, very complex, but it's something that's very useful and actually we have therapies already, for epigenetics is not going to allow you to do that. Okay, because that's just not how it they work really right now, at least in our current understanding. Maybe it will, who knows? Right now that would be a much better approach via a genome editing approach. Likewise something like a base editor which can change one nucleotide to another if we want to install a SNP, a single nucleotide polymorphism, because that gene, it was broken with a SNP. An epigenetic approach is not going to help you there per se. Although you might imagine other ways in which you could utilize epigenetic approaches to kind of modulate that disease in a different way. Yeah, okay.

BRUCE MCCABE: The other thing you touched on, the in vivo aspects of it, and to me that's one of the most exciting transitions in medicine, as we're moving all these things inside the body and using the body cells as the manufacturer, I guess, of different things we need. The costs plummet. I was talking to Bruce Levine about CAR T-cell therapy and their biggest problem is manufacturing the CAR T-cells. That's the cost there, because it's outside the body. You get it all inside the body and these things become affordable therapies, ultimately.

BEN OAKES: I think that's exactly right, and that's why one of the reasons why, at Scribe, we've always focused on actually building therapies for in vivo application. Just the complexity of everything you have to do ex vivo. While it's an important stepping stone yeah, absolutely, in the space.

BRUCE MCCABE: Yeah, so any other targets that are obvious in the medium term or that pop out where you say, beyond cholesterol, “these are things we should keep in mind, that epigenetics might make a big difference?”

BEN OAKES: Well, again, I think there are a ton. But the ones that I I think, again, the ones I'm most focused on are certainly in cardiometabolic disease. So even beyond cholesterol things, um, you know, all of the other risk factors I think are really important. There are other organizations out there which are actually using epigenetic modifiers to kind of approach rare disease in some interesting ways. Yeah, because there are some diseases that are actually underpinned by epigenetic misregulation. Okay, which is interesting. So there's a disease called FSHD it's a muscular dystrophy and there's an organization out there that's trying to build epigenetic modifiers to treat this disease, because that disease is actually underpinned, of course, via a genetic mutation, but that actually causes some epigenetic instability in a gene, causing it to be expressed when it shouldn't be. So it's a really interesting example of, again, where the problem is. This gene should be epigenetically silenced. It's no longer epigenetically silenced. We're going to go and epigenetically silence it. It's a really interesting example of another therapy that I know folks are actively trying to bring forward.

BRUCE MCCABE: Really interesting. So now let me take you outside of your domain. I want to connect this, and you can shoot me down if it doesn't make sense, but I just want to connect it with some of the other things that I'm seeing elsewhere. So let's just put medicine aside … Is the application also enormous in agriculture? I mean, when you talk to people like Rodolphe Barrangou, he was the guy who isolated what CRISPR did in nature and his life's work now is, how do we edit plants to make them more tolerant of salt and all that sort of stuff and how do we do a much better job in agriculture with CRISPR. But my head goes there now, after my conversation with you. Maybe there are simpler ways of modifying crops through the epigenome? I don't know, is that mad?

BEN OAKES: It's not mad at all. And again, like I am not the right guy to, talk.

BRUCE MCCABE: No, you're not the right guy, but you're a better guy than me!

BEN OAKES: What I can say is I have had some of these discussions with folks um over the years, because I'm actually somewhat of a plant enthusiast myself, okay, I like flowers, you know, I like gardens, and I'm super nerdy and really into this stuff. Plants was really interesting because the epigenetic landscape of a plant actually also dictates traits, just as much as they do in humans, right, and they pass on their, you know, they pass on their epigenetic inheritance in a very similar way, and so you absolutely could imagine using, while not the exact same tools, the same principles, to kind of create, without modifying the plant genome, right, so not a genetically modified organism at all, and we can have that debate if you want to go there, but without any genetic modification, really interesting modifications to plant traits, and I think that kind of goes for for all organisms, because epigenetic control is so important for basically all multicellular organisms, any organism where you have more than one cell, that is, you know, therefore needing to turn certain things off.

BRUCE MCCABE: I've got more homework to do then, to go and investigate! So, here's another field connecting you to the work of, say, the David Sinclair Lab, and George Church at Harvard. So, they've got this ‘information theory of aging’ where they feel like … I'm getting you smiling, but here we go … they're saying well, we can potentially clean up the epigenome with the errors that accumulate to reverse cellular aging, and that relates to some of the work that Shinya Yamanaka did, and all this stuff, but basically cellular age reversal, they're saying, is an epigenetic thing. Now what's your take on that? Just as a triangulation point for me.

BEN OAKES: No, it's a really interesting set of questions. And there's again this is kind of what I was saying earlier There's job security in epigenetics.

BRUCE MCCABE: [laughter] There is! You’ve got 50 years of hard work. 50 years.

BEN OAKES: It's really intriguing and complicated and beautiful in so many unique ways. Again, this is where I'm not the right guy. You know I'm not the epigenetics of aging guy, but there is a lot of very compelling work being done in that field, both in aging and reprogramming or partial reprogramming of your epigenetic state. What I would say is that other folks, I hope, are going to continue to figure that out, and us at Scribe we're going to continue to make the tools that are potent and safe enough to actually accomplish it. So that's really our mission and I look forward to hopefully being able to work with the teams that are kind of identifying exactly how things need to be reset.

BRUCE MCCABE: Fantastic. Okay, and one other project which is really interesting because it's something I've been trying to learn more about recently, the Human Cell Atlas. As I understand it, this project is to try and make a Google Maps of how all our cells interrelate, in terms of how they switch on or switch off characteristics depending on where they are located in the human body, and it seems to me, just looking at it as a couple things that pop out, it seems to be a very, very important project, because it should give you a whole lot of data to work with. Is that fair as an assessment? And it also seems like a project that's going to go for 40 years because we've got to do a lot of sequencing for 37 trillion cells to really understand all the dependencies!.

BEN OAKES: I agree, I think it's incredibly important and this kind of gets to the complexity of the challenges. That is, of course, as we were talking about, every one of these cells, you know, looks somewhat different based on what it's it's supposed to be accomplishing. And that's within a single body, right, that's within a single human. And we're not even talking about somatic mutations or, you know, epigenetic modifications that happen, you know, over the course of development, because something goes awry or right, and any of these things, and at the same time, with that sort of data, you know, at us at Scribe, would be able to do our mission much more effectively, which is build the technologies, okay, these are the marks that need to be laid down here at this point in time. Now, I know what the tool is that I need to build, to enable that sort of outcome, whereas right now, I mean, there's some really interesting databases that, of course, have been built, but they're just much smaller, with much less depth and, like you know, honestly, very often in cell lines and culture, which all cell lines culture, cancer cells, it starts to be a much more important project to look at that with primary human cells, and then ultimately even translate that into primary human cells that come from different genetic backgrounds.

BRUCE MCCABE: Okay. Wonderful. That's amazing. Are there any other messages that you wish people knew more about with epigenetics, especially people in the healthcare system? You know just ordinary physicians, nurses, administrators, other things you wish they knew more about? Or knew more about Scribe?

BEN OAKES: It's a good question. I'd say there's actually a couple. So, if you'll let me ....

BRUCE MCCABE: Absolutely.

BEN OAKES: The first is that when we think about CRISPR, we think about genetic medicine in general [but] genome editing is different than base editing, which is different than techniques like prime editing, which is different than things like epigenetics. Right now, they all get put together and it's like genetic medicine. We're doing things – every single one of them, from a guy like me who's a technologist, right, who's hyper focused on how these molecules actually behave, how they work structurally, biochemically, from an on-target, off-target perspective, from a potency perspective – every one of those is different, has its own benefits and its own potential drawbacks and risks. We can really start to assess and think about disease from this completely different paradigm that allows us to really modify it before it happens. Or, you know, maybe allow us all to win the genetic lottery, right, all to get the best you know, genetics, from a health standpoint. We need to really assess each of those tools based on its own merits.

And so that's number one, right? Someone says, “CRISPR,” say “What type?” because it's not all the same.

Number two, I would say that we are, you know, and I think Scribe is really one of the first organizations that's bringing this forward, but we are now making some of these genetic medicines, even from the genome editing perspective, that are safe, like dramatically safer than they were in the past and that they were when they were originally discovered, cause we're engineering them from their original context, which is, as this, like bacterial immune system that we've just co-opted yeah, really, to be a therapeutic scalpel. You think about it as, we've taken the raw material that nature has given us, we've melted it down and we've turned it into a scalpel. You know, you don't want to go to the surgeon and then take out a piece of raw iron ore to try to perform surgery, but that is, you know, for lack of a better metaphor, what we've been doing up till now. Scribe is really taking these tools and sharpening them to the point where we think, fundamentally, everyone should be thinking about how we can get genetic medicine into patients' hands.

And then, I think, on top of that, you bring in this concept of epigenetics and how we can really move towards a paradigm where we should be thinking about not just how we can drug people, but how we can fix each other, right, how we can fundamentally allow people to live the life they want to live from a health perspective, without being burdened by our, what I like to say, their genetic destiny. And I think that's the transformation, from disease treatments to disease prevention. It’s one that is going to take a long time. I think we all, I think we all understand that. But I think it's a really important mission for everyone in the healthcare community to kind of be trying to pioneer, because right now, you know if you treat disease, you know if you treat a heart attack or or, um, really anything after it happens, there's only so much you can do, but we building the tools that will hopefully allow us to really think about staving it off.

BRUCE MCCABE: Preventative. Proactive. Yeah.

BEN OAKES: But we have to start to—you know, up until now we haven't had drugs that allow us to do that in the same way, and it really will require a real mindset shift from a medical professional, from a research professional, from a patient. It's not, “Oh, I'm 20 years old, or I'm 30 years old, I don't need to worry about anything.” It's like “No, if you don't get certain things under control now, by the time you're 60, you know your, your risk for X, Y or Z is going to be quintupled and there's nothing you can do about it because it's all about lifetime exposure to certain things.

BRUCE MCCABE: Ben, you look to me like an optimist. I feel so optimistic when I talk about this stuff.

BEN OAKES: We are quite optimistic, but I would say very realistic as well, and that really comes down to our engineering approaches and trying to build the tools we actually need.

BRUCE MCCABE:

Well, this truly to me one of those absolute frontiers of medicine, and it's a really really expansive frontier. It could change so much. So very exciting to learn more about it and to travel a little bit along those pathways with you.

BEN OAKES: Yeah, likewise, I look forward to continuing to catch up.

BRUCE MCCABE: I look forward to watching developments in the next five years. I'll be watching very closely and with the timelines I have in my head, you can usually add about 10 years from those sorts of things to clinic, so it's not completely out there, we're going to be seeing therapies arrive in the clinic in that sort of timeframe, right? That's the sort of thing we can expect, 10 to 15 years from now? And we can look forward to that.

BEN OAKES: Exactly

BRUCE MCCABE: Yeah, that's brilliant.

BRUCE MCCABE: Thank you so much for joining us, Dr Ben Oakes. It's been very exciting for me. I really appreciate you making the time.

BEN OAKES: Likewise Bruce. I appreciate the conversation and the invitation, so thank you.