Rodolphe Barrangou Interview Transcript

Bruce McCabe: Rodolphe Barrangou, you are a professor here at North Carolina State University and you are, to me, one of the gods of CRISPR. You were involved very early in the whole process of proving out the science. And particularly, you proved the linkage between the immunity effect and bacteria two phages. So your experimental work actually closed the loop on proving that was what CRISPR was for. So you are I guess the last so 10 or 20 people in the chain here of making the thing real, a tool that's changing humanity. I think that's fair to say.

Prof. Rodolphe Barrangou: It's for you to decide and others to apply. [laughter] I was, yeah. I was privileged to be involved in some early work indeed, proving the hypothesis that CRISPR's an immune system. And my team, DuPont, my colleagues at DuPont showed that indeed CRISPR is an adaptive immune system, which has the ability to capture a piece of DNA from invasive viruses and then provide sequence specific resistance. And then also fortuitously almost, we implicated the Cas genes in that process, both in space or acquisition and in the expression of the immunity. So immunization and immunity. And I had the great fortuitous chance with my own bare hands, so to speak, to knockout some of those genes, including a gene now called Cas9. [laughter] And I actually proved that Cas9 was necessary and involved for the ability of CRISPR to provide sequence specific targeting. And then of course we did that, that work a long, long time ago, 15 years ago, which is prehistoric ages in the timelines of CRISPR, back in the mid-2000s. And by extension ever since, I've had the great privilege to observe firsthand, the evolution of the field, the scientific developments, more importantly the technological developments. And now towards the end of 2022, looking at the future, the deployment of many of those technologies for various applications and products in many different industries spanning not just therapeutics and medicine, but also bio-technology and agriculture.

BM: And that's what makes you a really good person to talk to about the future because you have that spread. I think you've co-founded five different CRISPR-based companies spanning therapeutics to food and agriculture and everything in the middle. And now your current focus is very much on food technologies. Would that be fair to say? But you've got an interest in all of these camps.

RB: That is fair to say. So of course, I have many scientific and business interest in all kinds of applications of CRISPR-based technologies for genome editing of all kinds of organisms across the tree of life. Maybe first and foremost in originally human gene therapies and human therapeutics, saving lives is quite noble and achievable today as however crazy as it may sound or however crazy as it sounded at the time.

BM: Yeah.

RB: But I think moving forward, given my foci, given my interest, given my training and given the relative lack of focus on the ag side and the relative impact that deploying those technologies in the realm of food and agriculture is the most enthralling, the most exciting and arguably in some ways, the most impactful and useful for humankind towards a sustainable agriculture system that feeds our species off of limited land, limited water, limited resources, and then even maybe more importantly longer term, sustainable forestry at a time of climate change and decarbonization and carbon capture needs, not just for now but for future generations.

BM: And I really want to drill into that because one thing I've learned from spending time with you today, probably the biggest thing I've learned is just how little investment we're making relatively on the agricultural side compared to what we're doing on the therapeutic side, and just how much more important that is as an opportunity space for this planet.

RB: But this is what I we call the CRISPR conundrum. It's very defensible for people, scientists, investors, entrepreneurs, regulators, to focus on human therapeutics because there's a lot of money at stake.

BM: Yes.

RB: And it's fairly obvious how feasible and achievable this is in a relatively short time frame. So deploying disruptive, powerful, democratized CRISPR genome editing technologies to alleviate human disease. Treat human disease, maybe even prevent sometimes human diseases, is a great pursuit and a very lucrative pursuit, a very defensible pursuit, very strategic pursuit. And that's why the large majority of my fellow CRISPR scientists, 95% plus of them, is focusing on medicine and therapeutics. However, in some ways equally important, arguably in some ways more important, is the opportunities that we have to build sustainable agriculture to feed a lot more people than people afflicted by human genetic diseases. Impact quantitatively more lives than those afflicted by, human genetic disease.

BM: Several orders of magnitudes more of...

RB: Several orders of magnitude. Again, we can speculate or ponder some of the quantitative numbers at hand here. In many ways if we were to invest unabated right now, which is a hypothesis, and deploy CRISPR-based therapies and medicines in the next seven or eight years, let's say between now and 2030, somewhere probably around, 100,000 patients could be dosed. If a few things go right. And regulators and bio manufacturers find that agreeable and feasible. So north of 10,000, less than a million. Maybe 100,000 lives would be impacted, potentially saved or enhanced using CRISPR enhanced gene therapies. And again, we've probably dosed a couple dozen patients until now. So it's orders of magnitude more than we have until now. But I think if you compare that number, very significant important number to hypothetically the number of consumers who could benefit from unabated deployment of CRISPR at the farm level. Again, the World Economic Forum has come up with a number of 100 million farms. So maybe 10%-15% of our agricultural pursuits commercially planting genome edited seeds by 2030. Maybe the number of people who would benefit from that is north of 100 million, probably south of 1 billion, somewhere in that order of magnitude.

BM: Well north.

RB: But either way, orders of magnitude more than the number of patients who could benefit from CRISPR-based therapy. So I think it's important to note that. It's important to recognize that. And it's not just the business opportunity, but maybe a moral obligation that we have to some extent.

BM: Yeah.

RB: Within the CRISPR community and the crop and livestock breeding community to deploy those technologies for more sustainable agriculture.

BM: So, this is about the future. This conversation, let's start there. What's the dream? So maybe we'll take 50 years out and it's very hypothetical, but if we did this really well, if we... And we'll get into the barriers and issues, but if we really did this as well as you would like it done in using CRISPR for this planet, and if we look at the food system, what could it look like? What could we accomplish? What would that future look like?

RB: So sustainable ag?

BM: Especially that, but I think, yeah, the big contributions would be ... I would imagine sustainable ag and in yields and tolerance in plants and all those things. But we're talking on a vast scale. So give me a sense of what that future could be, because it's about... That's painting a picture of the opportunity space.

RB: So every single crop, commercial crop... No, row crops, but every single crop used in food and ag, food and feed across the planet being that's planted, being genome edited by 2050. I think that's a hopeful future. And that will enable us to across the board, be more sustainable in the sense of better yields, more efficient use of limited water resources, more efficient use of limited soil and land resources. Localized customization. Personal medicines, personal agriculture. For local cultural idiosyncrasies and preferences, local climates, local conditions, local environmental constraints. And not just enhancing canonical act traits like yield or even to some extent, flavor and texture and all the attributes that make food delectable but also nutritious. The protein composition, the lipid composition, the nutritional composition thereof, again, enhanced and customized to local preferences and biases and needs. But also more importantly, in some ways right now, breeding those organisms across the tree of life to prevent disease, all kinds of pests, be they insects, fungi, bacteria, viruses. All the ag plagues that have literally plagued humankind since we've deployed to some extent, agricultural practices on this planet. And then equally importantly, breeding all those species across the tree of life for the changing environmental conditions that we're facing right now. So that's heat stress, drought stress, and even in some cases frost tolerance and water usage or over abundance in some cases as extreme weather patterns keep being disseminated. So it's in some ways genome edited spread precision ag driven, machine learning informed cultural idiosyncrasies accounting for precision ag.

BM: And if we look at this... Throwing some numbers at a dart board here, but if we look at yield, we're currently editing photosynthesis in various plants and learning about that. We're learning about how to edit plants so they're more efficient at distributing the nutrients so they're more resilient to changing conditions. So, is it possible that we could have the global food production per hectare, that efficiency, if you like, the dividend in terms of say, calories per hectare? I don't know if that's the best measure, but is it a 30% opportunity increase? Is it a... What sort of sense can you give me of that?

RB: Yeah, I think if we look at past success that we've had in breeding, in agriculture, we look at way north of 20%. I think I'd be disappointed if we only reach 20% enhancement. So people would be like, "We've been very good until now. And maintaining the momentum is challenging," and I'm not necessarily a believer in this. So I would be disappointed if we have less than 20%. And I think 50% is an upper hand ambitious goal. So we're not gonna double or triple or quadruple or... Within the order of magnitude here. But being able with current limited constraints and eroding value of the soil and challenging conditions that we're operating under, if under the same current land and condition we can increase outputs by 30%-40%, this will be a good outcome.

BM: It's a big number.

RB: And it's more than the population is gonna grow.

BM: Exactly. That's an opportunity to refocus.

RB: I don't know if we need a lot more than that per se. I think the need is not quite there yet. And of course, predictions and forecast for the world population, their precision and their accuracy is unclear, I think at this point in time. But the world is changing at a faster pace than we think, and in ways that we don't always consider or anticipate. So I think north of 20%, maybe close to 40% is gonna be feeding our needs and suiting our needs.

BM: Yeah.

RB: But critically, I think it's not doing that just for existing crops that are being bred for big ag, I think it's being able to do that for any crop of interest that we have. So, it's the diversification of the food supply chain. It's the diversification and enhancement of the biodiversity of the plants that are being planted. And that has huge value outside of just "the yield" for a select handful, maybe two handfuls in some cases, of species that are scalable for human farming at this point in time. And I think this is where technologies like genome editing and molecular breeding will enable us to bring back diversities that are not, at least, right now, combined genotypes that are difficult to cross-breed right now and provide the biodiversity that is needed to match the biogeographical diversity in which we wanna plant them. And that's more genotype within species, and that's more species in total as well.

BM: Do you see the preponderance of opportunity? Because we'll get into what's actually happening, but just this future opportunity. The vast preponderance in crops rather than livestock? Because there's this whole shift away from meat, and to me, there's probably a lot more resistance to gene editing in livestock and how far we should go or could go, and the opportunity space seems larger and also easier in terms of acceptance in agriculture when it comes to farming practices.

RB: Yeah. I think perception is reality in that sense. So people relate with livestock in ways...

BM: They do.

RB: They don't really relate with plants. Because it's just the way that we are and where we stand on the tree of life. They're more relatable and they're much closer to us in many ways, biologically and functionally. And so, the ethical concerns that people have when it comes to animal breeding and livestock editing are somewhat different to a certain extent than crop breeding and plant editing, understandably so. However, I do think that when people think about food, it's a continuum. And where does seafood stand? How about fish and crustaceans and insects. And if you're willing to eat insects, where does an edited insect stand on that spectrum? [laughter] Or edited fish, or edited seafood and shrimp, right?

BM: Yeah.

RB: As opposed to chicken or cattle, right?

BM: Cattle, pigs, exactly.

RB: So I think there's a little bit more of an elastic spectrum and that it is a continuum to some extent. And that once you're willing to consider putting genetically altered or edited food in your mouth, maybe you start with a plant, right? But it doesn't mean you're gonna stop there. And how about bacteria and fungi? And what if it's an ingredient that is derived? So where does milk stand that comes from an edited cow? You're not eating the cow per se, you're eating a derived product. So, if you have edited soy milk or soy juice versus edited bovine milk, it's not bovine juice as a matter of fact, I think that there's some gray area there. And once that possibility is considered, once the barrier is crossed, I think some of the a priori reservations that people have will change, and the edited foods as a food group will be generally acceptable.

BM: One thing I like about the vegetable side of this equation though, is that there are sustainability footprint advantages. The more you enhance that side, you actually get a double benefit, if you like, in terms of carbon and all the rest of it. Whereas with livestock, the footprint can be negative. You can enhance them, grow more of them, but it's not... It's still got a downside.

RB: Operationally, absolutely. In terms of sustainability, absolutely. But I think the advantage is there, it's a more humane farming of livestock, right? It's like as opposed to removing the horns, you breed them without horns, that seems agreeable. Or if we're faced with culling of a flock because of a viral disease a bacterial disease, and you can lose very large numbers of relatable animals...

BM: Yeah, swine flu.

RB: Because they're... Swine flu is a great example. Bird flu, right? Those are challenges that are very real for people. And if we can say, "Well, we can solve that problem by breeding them with genome editing, so they're resistant and recalcitrant to those diseases," there's an ethical operational benefit. And I'm not convinced that people are willing to give up 100% of their meat supply. I believe in the flexitarian approach of, "Well, I'm gonna eat less meat, and I'm gonna integrate alternative protein landscape more so in my diet." But maybe some people are not willing to give up bacon or a good steak, or combinations therein thereof. I'm certainly in that category. I'm very much willing to eat all kinds of alternative protein products, all kinds, I'm very flexible. But I'm not quite ready to give it all up because the product is not quite there yet fully. The satisfaction I get from their consumption is not a perfect match, it's an imperfect proxy. And I still enjoy [laughter] a good steak.

BM: Yeah. So do I.

RB: With a side of bacon and sausage and the like, and...

BM: And one thing I've learned from you today is that taste comes first. The experience of eating always comes first in our choices, we're not giving that up. The idea of some sort of dystopian mush as the future food is just a non-starter because they have to be flavorful and have the textures and all those good things.

RB: There's a reason between food and nutrition. They overlap to some extent, as we all know. But the enjoyment of the culinary experience and the social benefits of sharing a meal supersede the nutritional benefits in many cases of a health promoting diet.

BM: Priceless. Yeah.

RB: Right. And that cultural part, that Sunday family dinner, a recipe from your grandmother. I mean my grandmother didn't have impossible foods, [laughter] I don't think there's any of her recipes that have that. Or synthetic meat roast. It's not quite in the vernacular as of yet. So I think there's some cultural rationales for that and perquisites and benefits thereof that transcend some of the purported benefits, actual benefits of alternatives that are on the rise.

BM: So that's the dream. That's the best case if you like. Working backwards now to the journey to that dream, what are the big things we've got to solve? We've talked a lot about attitudes, we touched on that at the beginning. What are the big milestones that we've got to look for and the big things to tackle from a science perspective and an engineering perspective?

RB: Yeah, so there's the science and technology behind it, that's one piece that team science is ready and team engineers is ready to kind of work through. And there's some obvious milestones we can highlight here and discuss. And there's a scalability of it. Being able to do it or do it in the lab. Which is, do you need that scale to feed, overall large amount of food is different. And then there's acceptance and an acceptance by regulators, acceptance by the pundits, acceptance by the consumers. So to me, those are the three categories of hurdles that we have to face. And tragically but excitedly at the same time, I think the science is the easy part. Informed by the sophisticated CRISPR genome editing toolbox that we can adapt from human medicines and therapies into foods, crops, and trees and bacteria and seafood and livestock and the like. That toolbox is very good.

BM: And we've democratized that toolbox heavily.

RB: It's accessible, it's affordable, it's agreeable, it's practical, it's deployable, it's scalable, it's efficient, it's precise. So as long as you can afford some of the IP licensing rights that come with it, the science in and of itself is straightforward. Not trivial but achievable. And doing the editing is not a learning factor anymore, is being able to do so in elite, commercially relevant breeding types. That's can be a challenge sometimes with the delivery of DNAs, it's not always easy and straightforward.

BM: So acceptance is the big obstacle?

RB: And then once you're able to do it, then knowing what to edit genetically again, I think we're walking through that in the era of affordable and scalable genetic sequencing and platforms and AI and machine learning. So being able to do the editing and figuring out what to edit those technical challenges can be surmountable, short term, midterm, and long term. I think the scalability of it operationally, has some constraints. Like doing that in different countries is easier than others because of the workforce, the labs, the material, the availability of the context in the workforce that you need is not quite equally distributed yet. But we are training all those people, and it doesn't have to be de-localized necessarily. You can centralize in areas of interest. You can have core or not for profit centers. Allow that locally in different continents, different countries. But scaling that up is challenging, right?

BM: Yeah.

RB: So think of how long it took for us to build farming industries in some sophisticated first world environments, and then scaling that up and deploying that in other countries that don't quite have the same operational excellence. That don't quite have the same facilities and equipment and resources and the water supply and soil quality and all the inputs that need to be there to get the outputs. I think there's some challenges there, but we know how to solve those problems. There's just geopolitical constraints that we can work through, we'll have to work through. But I think the impetus, the drive and the relevance and the obviousness of the path is clear enough that it's feasible and achievable. So that brings us to the constraints that are regulator driven and consumer acceptance driven. And those challenges to me, as a scientist, I think are a lot harder to solve as a CRISPR Journal editor in chief, seemed a lot more insurmountable and difficult and complicated than the science and agreeability of science and technology, especially for disruptive technology at that and disruptive innovation.

Circa 2022, 2023 with anti-vaxxers and misinformation and disinformation and scientific skepticism, that seems a lot more challenging problem to solve than being able to do the editing itself. And convincing people or explaining to people why the risk is managed, why people who are deploying this are responsible and trustworthy and doing it for the right reasons. The way I articulate that is to solve grand problems and grand challenges, we need to have grand science and grand technologies. We understand that in many pursuits in science.

BM: And it seems to be the biggest misunderstanding in your field, is the perception around the scale of the risk and the manageability of that risk that people perceive it as something that might go outta control or spiral out of control, whereas the risk for GM foods is as I understand it from our conversation so far today, is quite easily managed and quite cheaply managed. We can get on top of and test out the risks very quickly.

RB: Yeah. In terms of time and resources and data sets that we need to generate to quantify the risk, manage the risk, measure the risk and then essentially de-risk the proposition. This is pretty straightforward. It's been done for much more complicated technologies than genome editing in terms of true GM. 

And there are guidelines and there are frameworks and there are methods and there are approaches, and there are data sets and data packages that regulators know and scientists know how to fill in and achieve and provide data and provide answers or results or quantifiable outputs. And that exists today already. So that path is somewhat straightforward. It doesn't take forever. It doesn't take insurmountable amount of resources of time or energy or science or money or combinations thereof. So that's a question of time and commitment, we can solve that problem. The acceptance by the public is a different beast.

BM: Yeah.

RB: And we've done a relatively poor job at explaining to people why we're doing this, what the benefits are. And on the other hand, other people have done a very good job of, fear mongering is a strong word, but triggering. Some people's imagination, wild imagination. Fear-based nudging so to speak, with an agenda to say, "Hey could this happen? Could this be possible? Could this crazy science fiction scenario sound like a potential outcome?" Or as long as you say that's not impossible, you've done your job. Yeah. And using the scientific method to disprove that is a very tedious pursuit.

BM: Yeah. Yeah. Well, it's something I come across all the time. Almost every technology has a duality. It can be applied, if evil intent is there, in a different way. And unfortunately, the human brain seems to leap to it very quickly. And as you say, there are people with agendas who will inflate the fears very, very easily. But in this case, are there any other misunderstandings out there that in terms of the messaging that you... [laughter]

RB: Yeah.

BM: … that frustrate you?

RB: I think there are two. So I think it's the idea that that technology is good or bad, right? Science is good or bad. It's neither good nor bad. It's agnostic. It's how it's being used and it's not really the how's being used, that's the question. It's never really the why it's being used as the question. It's what's driving the people using it. And that's where the imagery of the crazy scientists playing god in the lab, going after things that are indefensible crazy scenarios that are great for movie making, but that are science fiction, more fiction than science, that's what captures people's minds. And the lack of trust in what drives the scientists is the wildcard. Whereas most the scientists that I know are dedicating their whole lives, tens of years of their careers of challenging, difficult, sometimes insurmountable mountains are being moved to solve other people's problems.

BM: Yes

RB: And those people are being doubted with their motivations. Those people are being fantasized about with regards to their pursuits and their playing god in the lab type behavior that the large majority of the scientists that I know, this is not how they operate. This is not who they are. This is not what they do. This is not what they're in it for. And if you wanna be nefarious, there's many better careers than being a scientist [laughter].

BM: Absolutely.

RB: And many easier paths to achieving mischief than being a scientist, trying to tinker with people's imaginations and worst fears. So that's the part where how scientists are portrayed or perceived in the media or in science fiction is a concern.

BM: Yeah.

RB: And how to solve that is difficult at a time where sensationalism and dramatization...

BM: And misinformation.

RB: ... is premium, premium coverage.

BM: Just rewinding, you said the science is the easy part, relatively speaking now. Well, the straightforward part. A comment you made earlier today, when I listened to you talking in that panel, you talked about the size of the genome in trees and how much bigger it is than the human genome. And I'm just wondering how much we don't understand yet. So, how much headroom is there in terms of research to better understand?

RB: So I make the joke on regular basis. Now what we're trying to do with using and employing CRISPR to breed healthier trees is about a million times more difficult than curing human genetic disease. And that sounds outrageous.

BM: It does, it sounds absolutely outrageous.

RB: Let me clarify that. Because it's actually an underestimate of the level of the magnitude of the challenge that we have. [laughter] And let me quantify that for you. How much bigger are some of the tree genomes compared to the human genome? Ten times. Not three gigs [gigabytes] but thirty gig. So we have a10 times bigger genome. How much less do we know about the tree genome than the human genome or otherwise stated as, how much more do we know about the human genome and human genetic disease and the tree genome and tree genetic disease? At least 1000 times. Easily. But let's just say one hundred.

BM: Yeah.

RB: How are the resources that we have right now? How about the protocols? How about the literature? How about the tools? How about the toys? How about the people that we have to do tree editing compared to human gene editing? Give me 100, maybe 1000, probably 10,000 to be honest with you. And then last but not least, how long does it take to actually do it? How long does it take to grow and edit a tree? Transform a tree to edit it, grow and regenerate the tree to edit it at least 10 times?

BM: A lot longer. [laughter]

RB: A lot longer. Let me give you at least 10 times. Right? So you start multiplying those numbers by each other The size of the genome, the amount of our knowledge, the availability of the tool …

BM: And how long it takes to grow trees.

RB: … the availability of the people, and the amount of times that it takes to do it, let alone deploy it at scale. One million is putting it nicely as an underestimate.

BM: Yeah.

RB: I'm not gonna say it's a billion times harder. Because then I sound like crazy even more so than I do right now. But I would argue it's at least a million times harder. Now, are we up for it? Absolutely. Can we do it? Absolutely. Should it be done? Unquestionably. But is it an easy pitch to tell people, "Hey, do something that's a million times harder than curing your a human genetic disease and come back in 10 or 20 years and tell me if you succeed." Sounds like a very concerning pursuit.

BM: Yeah.

RB: Whether you're fundraising...

BM: There's no quick money in that.

RB: …Making a career move, deciding where should you spend your time in the next 10 years. So let me ask you the question. What should I work on tomorrow? Should I work on curing human disease? Should I work on feeding the world? Or should I work on bringing a more stable flow for it. If I had to pick one, which one should it be? Or if there's a hundred of me, how do we split them up? Because right now the number is like, forget about a hundres. It's more like 10,000 of us, right? In that 10,000 number, it's actually 50,000 of us, but in the 10,000 number, take 10,000 scientists. That's probably 9,500 plus that are working on human medicine.

BM: Yeah. That's crazy. In terms of the future outcome of this planet.

RB: And maybe a couple hundred are working on feeding the world and maybe there's one crazy or wise enough, patient or desperate enough to work on breeding trees. So is that a... Is that what it should be? Or should we redistribute that?

BM: Yeah.

RB: And we're not even talking about other things we could be doing like de-extinction or, advancing other tools that will enable that. If you had a finite amount of people you can deploy to do that, what's the ideal mix? What's your portfolio of science, so to speak?

BM: And it's not what we're doing today.

RB: Well, but in some ways that's what we're doing today. That's what the NIH is doing today. Whether it's how much the funding, where they go is with the NSF is doing today. It's what governments do today. That's what investors do today. So if you're an investor, you can be like, "Let's invest in a new startup company using CRISPR to cure human disease." And I know what the path to IND is. I know where the path to the NASDAQ is. I know where the path to the clinic is, versus, wait, if I'm gonna do trees, can I even do that in my mind before 2050? I'm not sure.

BM: The other message here is we need all the CRISPR scientists we can get, we need all the students we can get. We need 10x, 100x 1000x times the population of researchers.

RB: That's the conundrum.

BM: Yeah. Because there's that much opportunity in this space. And we've just begun the journey, right?

RB: There's 8 million scientists give or take in the world today. 8 million trained people with graduate degrees that do that for a living. So how do we split their time? What's our scientist portfolio? Where should they be? What should they work on? How should they prioritize what they do across all the areas of science and technology? That's a very deep question. And I would argue that right now what we're doing in the food and ag world is not enough. And when we look at the opportunities and the gaps that we have today, we should have a little bit more, maybe even a lot more sense of urgency on remedying this and doing something about it. What that is, when that happens, time will tell. But, my opinion on that should be pretty clear.

BM: So our last questions to close this out, let's just get back to, today, this week. What are you working on this week? What would the... Apart from hosting crazy futurists at your lab, what more important things have you been doing?

RB: Apart from working on all the above? One thing that's gonna help change maybe the next 10 years of the CRISPR craze and the CRISPR phase, it's working on technologies that allow us to do editing at a larger scale. And it's not editing one letter or one G, it's rewriting DNA. So it's novel technologies that allow us to not just edit, small-level editing. But to multiplex, rewrite de novo chunks of DNA, so we can scale that up and literally rewrite the future of all organisms of interest for us across the tree of life.

BM: Explain that a little bit more. When you say rewriting, give us a... Can you draw a picture ...

RB: For example, there's a rare species of CRISPR-Cas systems that is molecularly tethered to transposons. Now, what transposons do in nature is move genetic material around, sometimes very large pieces of DNA, like 100,000 letters. And they hop around right between different molecules of DNA. So we can use CRISPR to help geolocate a transposon and generate integration of up to 100,000 letters of DNA that we can now write with synthetic biology and write in a location in the genome, 100,000 letters at a time. So we've done that one letter and 10 letters, then 100 letters, then 1000 letters, and then we've done 10,000 letters, and we're working on going from 10,000 to a 100,000. That's the extent to which we're doing it. And then when we try to take things out. We've already shown we can take things out 100,000 letters at a time. So now we're talking about editing genomes with CRISPR-based, transposon-based technologies. CRISPR-directed transposon-based manipulations to write 100,000 letters at a time with the genome.

BM: Give me an example, a phenotype example of what such a big rewrite could mean in an actual organism.

RB: A whole new pathway. A whole new pathway. Or replacing a whole allele in a large chunk of DNA that represent 10,000 letters. So in the book of life, instead of changing one letter in one word, in one sentence, we can change the whole chapter and the whole volume in one book in the encyclopedia. And this means that we're one order magnitude away from doing a whole chunk of a chromosome along the whole chromosome. So instead of changing one piece of one gene in one chromosome, we can be like, "Let's just do a whole chromosome, let's do a whole arm of a chromosome," maybe at that. And that fundamentally changes the number of genes and the functions that go with them, and by extension, the phenotypes that go with them that we can change. A whole pathway, a whole capability, a whole nutritional, fallible molecule, new proteins. We can remove allergenic proteins, people who have allergies with nuts [chuckle] in trees of interest, or we can enhance protein content in things that need to be more proteinaceous. Personalized food at the scale of personalized medicine.

BM: Fabulous. So last question, just a human one. I love asking this question because innovation and science is fundamentally a human process, and it takes courage, it takes resilience. Can you tell me something about someone who's inspired you in this journey you've taken?

RB: Yeah. My friend Jack, Jack Wang, who's a forester, a true forester and tree reader, has compelled me to realize that being patient is part of the process, right? As an innovator, as a disruptor, I always thought impatience was a driver of disruptive innovation. Impatience with an impetus where you're like, you can't wait for other people to catch up to do things. But in some cases, as a forester himself, to really change the world and have a big impact is gonna take time and effort, whether it's the wisdom of the forest in him. I don't know how to articulate that, but to realize that patience is a virtue, even in disruptive innovation, otherwise inspirational to me. And then do you have the courage to commit to doing things that will take a long time when you're impatient? Like, I'm impatient. But do I have the courage to curb my impatience and have the wisdom to be patient enough to tackle things that will take decades to solve? That's inspirational. But that's not for everyone. And I still struggle with that, but I try to channel my inner Jack Wang to do that.

BM: That's a great way to end it, Professor Rodolphe Barrangou, thank you for being so generous with your time today. It's been an absolute privilege, seeing the lab, then spending time with you. Thank you.

RB: Thanks for having me.