Circular RNA with Orna Therapeutics' Tom Barnes, Ph.D. and Advancing RNA's Anna Rose Welch

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com , hit the listen and watch tab and choose Business of Biotech in the dropdown . Welcome back to the Business of Biotech .

I'm Matt Pillar , and it's a special day here in the studio because we're going to be talking in circles , circular RNA , that is , with Orna Therapeutics CEO , Dr Thomas Barnes , and if you're watching , you can see that as such , I've brought along with me my dear friend and colleague , Anna Rose Welch , who is editorial and community director for our relatively new

Advancing RNA Community at Life Science Connect . Welcome , Anna Rose .

For its part ORNA , that is is developing circular RNA therapeutics delivered via lipid nanoparticles to treat indications including B-cell lymphomas and DMD , in addition to some discovery stage , vaccine and other therapeutic programs . Dr Barnes , who's been at the helm there since 2020 , previously co-founded or led a number of biotechs , including Intelia and 11 Therapeutics .

It also serves as an executive partner at the investment firm MPM BioImpact . Dr Barnes , welcome , thank you , pleasure to be here . It's our pleasure to have you , and I want to start out by getting to know you a little bit before we kind of dig into the company and where you guys are going with your therapeutics .

Your academic experience in genomics stands for itself . You've got a Cambridge PhD , a Harvard postdoc , a McGill fellowship . Rewind the clock quite a bit and tell us why . I guess when and why you decided to take that academic experience into industry .

It's a three-year program and the fourth year is optional , which you spend in the lab if you want to do that extra thing . So I was very interested in doing that , but in coming out of that I was pretty sure I didn't want to be an academic .

That point in time represented the end of all the forward momentum from high school and you're going to university and it's all on a track . And then it's like now what ? Yes , so I could go do a PhD at that point , but I wasn't sure that that's what I wanted to do . That was the direction I wanted to go in academia .

So I actually took a year off doing a variety of odd jobs In fact , ranging from working in a department store to being a taxi driver , and in the end there was a biotech company that was starting in Sydney , australia , just like they have in America .

This was a long time ago , so it was in the early days , so this is in the 80s , early 80s , and so I thought , well , that could be interesting , let's try that . So I got a job there and very shortly after joining that I was like , oh yes , this , I understand this , I get , I love this .

I don't like academia and what is the this that I was liking the this is the teamwork , the fact that everybody across the whole company is pulling together at the same direction and that the pace at which things move are not limited by your own clumsy fingers , but that ultimately , it's everybody's hands working together that pulls things forward at an incredible pace

. So it's much more stimulating and there's a much stronger sense of camaraderie across the whole organization , whereas in academic labs you have these fiefdoms you know my lab , you get your stuff off my freezer shelf kind of mentality , and so that sort of team sport aspect of science was instantly appealing . So I was there actually for four years .

That's what the world was doing back then . So at one point I thought all right , maybe I want to do more than this . You know what would that be ? I considered various . I'm doing this sort of career thing here . I don't have to be going on quite so much about it , but I think let's maybe Please do .

I've used that piece of advice many times , and so I realized that the answer to the puzzle then was go get a PhD , because I can still do everything I was contemplating on doing . That was one of the things I was going to say I should go get that , because it's also a terminal degree , there's nothing more after that .

So then I launched off to do my PhD and then a postdoc at Harvard , but the plan was to go back to biotech .

Originally , when I left , I was going to back to sydney , but then I kind of got stuck , ultimately in the boston area , which is well , now there's something up and coming , but it's now certainly the epicenter of biotech in the world , and so , um , basically I got stuck like a fly to fly paper yeah , yeah , so we'll talk about some of the stops along the way

, I think throughout the conversation , uh , but but I'm going to hit the fast forward button real quick here for a minute , because you know you've had exposure to a lot of different modalities , a lot of different areas of biotech .

You know , editing was very new , it was very cool and so it still is . It still is he , uh , was it was ? I would say it was so cool , it was white hot um back then . Um .

So yeah , I had the opportunity to join a cso , which I did , but interestingly , everyone in that space was thinking about doing cell therapy ex vivo manipulated cells , because that was technologically tractable or doing some sort of viral delivery editing and so you had CRISPR therapeutics . That picked the first one and Editas was an exemplar of the second one .

Now , we certainly had at Intellia we had an alliance with Novartis on the cell therapy , but we also were trying something a bit kooky , which is to try and do RNA delivery through a lipid nanoparticle where the editor was encoded in a messenger RNA . The guide RNA was also in the mix and they would all get sorted out once they got into a cell .

One would get expressed . The protein would find the short RNA . The two of them would trundle off to the nucleus . Get expressed , the protein would find the short RNA . The two of them would trundle off to the nucleus , cut some DNA and do some damage literally . And so that seemed science fiction-y . But we thought we'd give it a shot .

And again now I'll press fast forward . We got it to work some years later and I think ultimately when the first clinical results came out in the summer of 21, . Obviously it was international front page news editing in vivo for the first time , and we were the ones who showed that such a thing is possible .

Now of course everybody thinks , well , of course you want to do editing that way . All the other ways are so fiddly . But before we started it was science fiction . So I wasn't drawn to RNA so much as I fell into it .

What is it about you that that that uh makes you want to , yeah , drawn to , like how it takes a special person to embrace something that is , so you know , more dramatic than nascent right , and make a career of it . I mean , you could , yeah .

Well , I guess I guess my point is you could have done a bang-up job in antibodies , for instance , but no , you chose to go do some cutting-edge gene editing and get into the RNA space . What is it about your makeup that makes you embrace that ?

So that's one reason why I'm risk tolerant to that . But the other thing is I'm very curious . I'm interested in a lot of things , and so I do . I think it's a bit of my makeup too . Maybe I'm a sort of a science hipster . I kind of go off the mainstream and I like going counter-culturally , cross-current or something I don't know .

By the way , anna Rose , it's really nice to have you here , because when I can't think of a word , anna Rose is a I'll be your thesaurus . She's a trained poet , so she's very wordy yeah .

Now , of course , these days , venture typically goes and scours science directly from universities and so on and builds the company to their own sort of preconception . But all of it was really in that old mold .

So our story goes back to 2016 or 2017 , dan Anderson of MIT is listening to a talk on naturally occurring circle RNA in China and goes , huh , I wonder if that could be an interesting variant on a theme . Of course , moderna already existed at that time .

11 was coming through and it had already been known for attempting at least the RNA-based editing , and Dan had a long history in LNPs and RNA in any case , and so he gave the task to a graduate student , alex Wesselhoft , who completely blew it out of the water PhD finished in three and a half years , green thumbs at the bench and solved the fundamental problem ,

which is how can you make circles efficiently at scale and large enough to be useful and figure out how to make them useful by getting them to express things . So he did all that and so that was the basis of IP that was filed . And then they thought , well , there should be some value here , and so a company was formed .

It wasn't called , or called at the time , and um , and they basically encountered npm .

Capital is now npm biopact and uh , this is in the 2019 , so the first funding came in in mid 2019 , but part of that funding was a , a conception that what this company should do with its circles is to see if it could figure out a way of doing an in vivo thing , but not editing at this time , because the RNA is going to be transient .

But can we get the RNA into immune cells ? And if we could , could we disrupt or displace CAR-Ts and cell therapy completely , because it would be so much more convenient . So , in other words , there's a very high science concept that predates me , and it was really an idea that came from NPM .

And so money came in and they started building the team immediately , with Alex on board , and I started talking to NPM . I had left Intelia earlier in 2019 . I was scouting about things to do and I started talking to them in October or so and we kind of sealed the deal in 2019 .

I was scouting about things to do and I started talking to them in October or so and we kind of sealed the deal in December , so I started early 2020 .

There's something that I noticed early on is that up until that time certainly in the papers that Alex and Dan had published and in the early materials it was called Cirque RNA , because C-I-R-C lowercase , because that's what it's called , that's the standard abbreviation . But I realized almost immediately that people get confused .

They look up Cirque RNA and there's thousands of papers , there's a lot of papers on circRNA , but none of that is relevant to what we're doing , because ours is completely synthetic . We're not extracting circRNA cells . We're making it in vitro , designed to exactly encode exactly what we want , and it's made in a different way than it's made in vivo .

It just in the end looks like a circle . So we need a branding for what this is , and I remember being at a bar one Friday as one is .

And I thought , well , I don't know , o-r-n-a . I thought , oh , that's cute , because then we could call it also O-R-N-A , where the O just means circular . It doesn't stand for an O word , it just means circular , and so that was just born in a flash there , and so we was just born in a flash there , and so we changed .

But for our listeners' benefit , maybe just more color on where O-RNA fits in the landscape , the landscape that we've seen linear RNA for quite some time .

There's a number of theories , but to my instinct , I don't think any of the theories have really nailed what they're there for . It doesn't quite feel right . But the one thing that people know is that naturally occurring circular RNAs hang out in cells a lot longer than the linear RNA counterparts .

Particularly , even , especially , if it's derived from the same gene , the circular piece is more long-lived than the linear piece , so circles live longer than lines . Um , and so that was really what dan said . Well , okay , if you could do a whole technology based on circles , you'd have , you'd be better . Well , you know , longer half-life is better and that's so .

We've gone on to show that that's true and I think it's been shown now in multiple people's hands . Um , but what we discovered along the way is that circular RNA . I call it the gift that keeps on giving , because it continued to show these unexpected advantages of mRNA and the way .

I would summarize it again , coming back maybe to the business and less on the science is that if , if the world could make circular RNA the way we make circular RNA for products , nobody would make linear RNA products anymore , because circles have advantage upon advantage over lines and no disadvantages . There's no trade-off .

There's basically fewer better , more bits and pieces to get a circle to work than there is for a line . It's funny because of course the mRNA is our RNA . It's how our structures are encoded . So naturally we try and mimic that in the product and no one knows what circles do . But as a biotechnology , as a product , the correct answer is circles .

It's not the way we do it , but the correct version of a product should be a circle , because it's more stable , it's easier to make , it's far cheaper to make , it's made at high yield , you can make them much larger , you can express them much higher , they hang out in cells much longer and they package much more efficiently in the lipid nanoparticle at the end

of the day . So they're just better in every way .

The thing is , though , that there's , as far as I'm aware , there's only one way of making circles efficiently , and that's the way that Alex discovered in . Dan's lab and we have an exclusive license to that .

So now , having said that , there's more than one way to make a circle and you can make it inefficiently if you wish and if you in the end had a , you know , one gram of circle made this way and one gram made that way , it's still a gram of circle . At that point , then it's what is in code . What are the other differences in the molecule ?

But you know , in terms of ease and efficiency , I would say ours is made in one step . To be clear , there's no capping , there's no tailing . There's a single enzyme , which is the polymerase . There's no capping enzyme or tailing enzyme . So there's no mods .

We don't need mods because circles purify more readily from the contaminants in the in vitro transcription reaction , for which you need the mods . So if you don't have the mods as contaminants , then you don't need the mods at all . And mods are much more expensive than regular nucleotides .

So our cost to make a gram of finished stuff is like one-tenth to one-fifteenth of mRNA .

So I've been watching it . Really I've been watching it with a lot of anticipation to see where it goes , because I have been watching sort of the numbers of pipeline products right start to creep up in the circular RNA space . It's getting some more respect and some more attention .

And I really liked what you were saying earlier too , because you were talking about it , sort of the iterative innovation that the entire space is sort of going through , and how you approach failure and the challenge of working in a potential area that still has yet to really find its future .

I think the RNA space as a whole , particularly on the encoding side , right , your mRNAs , your self-amplifying , your circular still have a long ways to go , right , I think , in terms of efficiency of development and their biological impacts , right .

So I'm really curious to kind of pick your brain on how heading up in a circular RNA company is challenging today , right , especially since we are still trying to figure out I always kind of call it the mRNA identity proposition right Within the advanced therapy space within the biologic sector .

How do you , you know , how are you navigating some of the risks of working with a very novel technology today , and how does that impact your leadership strategy of a company that's kind of been paving the pathway for this modality ?

Everyone kind of thinks these things go to the liver as a default . So not only were we trying to develop circles as a novel payload and promulgate the idea that they don't need mods , which is iconoclastic In fact , you know , a Nobel Prize has been given on the need for mods and there we are saying , well , you don't actually need them if you use circles .

I'm not saying it wasn't a great idea . You know I myself have received linear RNA vaccines , but it's an interesting point . Technology evolves , but we're trying to do this thing with delivery as well . We were doing two things . So you know , my feeling was , yeah , this is not going to work . I love the honesty , but you know so , how do you do that ?

Basically , it's exciting what you're trying to do . The vision is there , yeah , and some people are always drawn . Basically , it's exciting what you're trying to do . The vision is there , yeah , and some people are always drawn to that , to that exciting possibility . They're risk tolerant , I guess , like I am . That's always true in the early stages of a startup .

I mean , npm was a very good , a very solid name in terms of the venture banking , so there was good funds available . But you know , you also have to have a backup plan . Okay , what do I do if this doesn't work out ? And so we had all that .

But in the end we actually got it to work and so that was an amazing day that we could deliver to immune cells and they would take up the circles . The circles would express , they would produce a CAR protein on the surface of T's and NKs and macrophages , and then those cells would go and attack other cells in the animal , just like a car T does .

So that was pretty , pretty amazing and you know , we showed that . So we , you know our innovations were not only academically that we showed how to make . I'll be this is a broader way . Of course , this is Dan's lab , but you know Orna and its origin story , you know , showed how to make circles . That was possible . We showed how to express from circles .

We showed that it was possible to find an immunotropic lipid . We showed the value proposition behind doing that and what you would do to get that to work . So we have blazed a whole series of trails as we've pushed into this and you know , one of the challenges obviously when you start out is also that it's very hard to be noticed .

And Squid Company is being started all the time and when I was at Intelia it was a luxury because you'll notice editing . You know everyone would notice every single thing you would do People lining up around the block to join the company . It's like you could pick and choose whoever you want to come .

It was that intense and RNA was still very you know , it was very hot at the time .

As you know , the pandemic had started and there was something with the vaccines , but you still , you know you try and be noticed and one of the things that was surprising I still don't really understand to this day is that the idea that the RNA could be circular seemed to capture the imagination of reporters or people who like to write about it .

It wasn't like oh , we've got a different cap structure or we do mods a different way , or something like that . No , the RNA is circular .

It just seemed intriguing enough that we got noticed early enough , and because we were sort of the first one out there and because it's right there in the name , we kind of became I don't want to say synonymous , but we certainly became like the name in the space . So it was a little bit of luck .

It was with a friend of mine , brian Finrow , at Lumen Biosciences , and we talked about that concept of being first on the scene with a new technology or a new approach and how it creates awareness . Potentially inherently right , it's something new , but it can also create tension . It can create challenges .

Have a good , strong partner there , but I guess take us behind the scenes a little bit around . When you're revealing something new to the community not just the scientific community , but the investment community what goes into ensuring that you're winning the funding you're going to need to move forward and hit milestones ?

The premise here was that cell therapy is fantastic from an efficacy perspective , but it's so cumbersome , so difficult , so challenging for patients that have to be managed so intensively , that there's the cost of the therapy and then there's the adjunct costs of just administering and managing the patient during the administration of the therapy and the risk associated with

that . And so the idea was well , if you could just do the manufacturing inside the patient not at the bedside , actually , just in the patient that would make everything go away , and that's self-evidently true . The idea that if only you could , then that would be great . That's an easy sell , because that's obviously true .

The question is well , how the heck do you do that ?

At least our attempt , which in some ways didn't have to work , but it was a shot on goal , and there are , but there was no name for what we're trying to do Now the field is called in vivo CAR or in vivo CAR-T , so there are some groups that are trying to do it through adapted viruses , where the viruses will deliver , will do the job of delivering .

Now , of course , they tend to then integrate into the genome . Some viruses don't , but , like lentivirus , vectors will integrate and ours is um , transient , but it's redosable , which a lentivirus is not . So , um , uh , when you um get to that point of showing that it works , the value proposition is self-evident .

Okay , it's like , if only you could do this like teleportation , yeah , that could be useful . Okay , can you do it ? It's like you do a little demo . I don't have to explain what you would do with teleportation . You can take your mind , can take it from there .

So I just have to show you look , particle , animal boom , cells gone , tumor gone , people go , I like um tumor .

We're making great progress in solid tumors and so on and so forth . So I'm curious about your perspective of how the CAR-T community might , I guess , receive Orna's news that Orna thinks it can kind of leapfrog Carti . And specifically , how would Dr Carl June feel about the prospect .

So I would say embracing the potential . And obviously , in some ways it's a competitive technology to CAR-T and it's much more pharmaceutical in a way . Whereas CAR-T is a living drug , it will expand . You can't really control it , whereas this you can control the dose .

It has a a half-life , it has a maximum concentration which then fades over time and that's a function of the dose that you give . So there's much more like a traditional pharmaceutical in that way , and so many .

So there's car t companies that of course want to defend their turf and their franchises , but there's also many things about um this that would be appealing to a pharma player that isn't in cell therapy , because those who might have found cell therapy a bit fiddly would probably find LNPs , whilst more fiddly than a small molecule , a lot less fiddly than a cell

therapy .

Right , the prospect of a durable , you know , potential cure . Right , it's not everything approved has been curative , but that one and done does have some appeal to it . I'm curious to you but the fact that I think too , investors can be aware of if RNA is a chronically dosed therapy that fits , similar to a biologic .

Right , that sort of that risk proposition is understood . Right , it's well known . But I'm curious , do you find that navigating the funding today has changed at all ?

Right , I mean , as more players come into the space , with RNA as the space , we're not mature by any sense of the word , right , but as we have moved beyond the pandemic realm , you know , are you finding that you know there is investors are interested in different types of information or data ?

Or , you know , has getting funds become more challenging in any way ?

You start with a venture , uh appeal , and then later on you're appealing to different kind of later stage investors and ultimately pre-public investors and ultimately public investors , and these investors are all looking for different things , different proof points .

They typically you can probably distinguish them based on their own risk tolerance profile , where they feel their sweet spot is and where they like to get in . In terms of our story , our story resonates . In the case of Orna it resonates pretty well .

What we're trying to do is relatively differentiated , so it's not just the name that people remember , but they do tend to recall that we're doing what we call now pan car , because our , our lipids don't just deliver to t cells .

So if you have a lentivirus it's going to find the t cells because it's a t cell tropic virus , whereas our particles are , um , pan lineage , they go to t's , nks and macrophages and so , uh , to the point that uh , people feel cell therapy have only scratched the surface . Yes , you have some people doing CAR-T's .

You have some people doing CAR-NK's Our whole company is doing CAR-MAX CAR-M's . Well , we do all three with one injection . We create all three with one injection . So that's why we call it pan-CAR rather than and we call it in vivo-CAR rather than in vivo-CAR-T , because we're reaching all the effective lineages in the immune system .

So you know , people like that and the potential that we could do something in solids is there without having to change anything of what we do , because we're in the macrophage already . We just have to think about what the target is . What does the car target ? But there are companies out there already trying to blaze a trail in car max space .

We're content right now to be looking at relatively tried and true targets . This is one of the , I think , rules of bringing new technology forward is you don't want to stack your risk , you don't want to try new biology and new technology . So our technology is new .

So we are using a fairly vanilla target Helps us compare and contrast , but it also helps everybody understand what you have in that way .

Um , you know , it's it's drug development . Yeah , it's , it's a . It's a low probability business , from where you start to the chances that you'll get an approval . Um , right , you have to start so many threads so that one of them is going to make it all the way through .

But you know , you try and shorten your rods by getting the right kind of proof points in animals in vitro ahead of time . You shorten your rods by using a known biology . But yeah , there's many things that can go .

Well , there's a lot of good companies competing for talent , so everything that happens is done by the people in the company . So you have to be good at I mean as a group , as a company , as attracting talent , and when people are here , it's got to be an environment where they like to stay . They can always leave .

You know , the best retention tool that you have is have people not want to leave , not , you know um , golden handcuffs or other sort of perks . Just create an environment where people feel um , seen , heard , appreciated , where they feel they um , you know , they participate , they understand what's going on .

Something I've always striven for is transparency , as much as I can , so that everybody has a common sense of what we're doing , where we are , what's going on . I mean , obviously there are limits , but as much as I can , and I think that tends to help people buy into the mission .

One of the things that people often say after they've interviewed here is that everybody said exactly the same thing in terms of what we're doing , what the mission is . There's no duality or multiplicity of views , because we all have the same , we have a common view . So I think that's . People talk about culture as being important .

I think it often comes across sounding very platitudinous , but I think culture is very important in terms of retaining people , because when you're in a good one , you know it , and then you know things do go awry or sideways from time to time , and that is that is when the true value of culture emerges , because that's if , if , if , like .

Well , I'm here because you know the pay is good and we're on a ride . I'm'm waiting for my stock to vest . Then it goes south . It's like , oh , my stock isn't worth anything . Well , everybody's out the door .

I mean , if it's a place that people don't want to be at , but if it's a place that people do want to be at , they say well , you know what , I'm going to stay , I'm going to see this through .

But yes , it would be different if we were doing a new kind of small molecule , a new kind of chemistry , or it's an old kind of chemistry but a new kind of target that we've chosen here to take biological risk because , hey , we found new targets . That's what we're going after , that's the what we're going after .

That's the hypothesis we're going to test when we get to the clinic . That is , I think it's just unless you're good at telling the story or there's something really compelling that tends to inspire a little bit less readily than you know . Gee , whiz technology , yeah .

You know biopharma companies and you've got specifically partnerships with Merck and Renegade Therapeutics , maybe others . So share a little bit about those partnerships and what sort of your strategy , as the leader at Orna , has been in establishing those partnerships .

Investors like to invest in platform because it means if the first thing doesn't work , you've got a second thing . The alternative to a platform is a single asset play , but it turns out that's not a binary thing . Platforms , or at least an approach , which give two or three products okay , that's most things .

It's less common to have a platform that could really do a vast number . Editing was one , certainly , because a lot of the liver targets were all picked over , but in the early days it was all there . It was all there to be done , and it's almost like this embarrassment of riches , of the number of things you can do .

And the same is true for RNA , for our approach . I mean , we have fewer people than Moderna , but we are doing fundamentally the same thing as Moderna . We are putting a long coding RNA into a particle and administering an IV . That's what they're doing . Our RNA has a different shape and we have other advantages .

We think that we can do it , and their delivery is different than our delivery , and that's a fundamental thing . The topology of the payload matters . Lines versus circles , I argue circles are better , but they're not necessarily the killer app . Back here , I think the real killer app is the delivery . We were the first to show immunotropic lipids .

Now everyone's looking for them and trying to replicate what we've shown . But until we showed it it was possible , no one was really doing that . So , in terms of partnerships , then you look across all the things you could do and there's like oh , there's so many things that you can do and and you can't do it all .

I think the mistake a lot of companies do is say mine , mine , mine , we're going to do it all . Um , but uh , you know , I've one of the things I like to say . I like to challenge people is how many products does it take to make a successful biotech company ? It's just one . So you know , how many of these things do you really need ?

So it kind of defies the partner strategy . We pick the area we declared we're going for in vivo car . That's what we're going to do and we will . This doesn't mean the partner is off the table , but the kind of partnership we're looking for is going to be very different , more selective , narrower , and everything else that we can do . We'll partner that .

We'll partner that out , we're opening to partnering that out , and so that is the basis of the Merck relationship , which is primarily focused on infectious disease . So we weren't going to do anything in that space , particularly we were a little bit late to the party . But even before the pandemic we were founded not to do vaccines .

We were founded to pursue in vivo care . That's what we're doing Now . The relationship with Merck goes a little bit beyond infectious disease as well . I think they have had relationships with other linear RNA companies and so they have an interest in this space . So it goes a little bit beyond that .

In the case of Renegade , renegade was a company that also came from the same stable . It's another NPM company . It was founded about two years after us and it was going to address the delivery question . So it's going to be delivery focused , not payload focused .

It was going to be relatively payload agnostic and so you know , we thought , well , okay , we could always use some cool new delivery . So that was the with Renegade , as they were building things out . Now , of course , one of the places they started to see is , could they get a better vaccine lipid ?

And so , you know , the relationship with Merck came along at a time when we already had some early hits out of that , and so the Merck deal is actually a three-way deal between Warner , merck and Renegade . But , yeah , we continue to work with Renegade on other things .

So there is another deal with a Chinese company called Simnova , which is a member of the Simsea family , and that was an opportunity to , from our perspective , firstly doing excellent work there , discovering novel binders , novel CAR proteins with their clinically validating cells , so it was a way to potentially get access to that , but also to get access to accelerated

clinical evaluation through a particular setup that they have in China called investigator-initiated trials . It's something that most Chinese companies do and something that we could do with them in our collaboration , so that was appealing to us as well . I like to think we were already thinking globally , but actually there was a practical angle to that .

So there are various financial incentives of going down there as well .

You know , I often am talking about the RNA toolbox , the identity proposition that the different modalities can play within the broader biologic space , even just within the mRNA sector as a whole .

Right , you know , moving from , I think the space in general is moving towards some of these next gen modalities more regularly , away from the linear mRNA for a number of different reasons .

But I'm curious to hear you know how you foresee circular RNA really fitting into , or perhaps dominating , you know , do you see it fitting into more as one tool right in the toolbox , applicable , you know , kind of , only in very specific use cases ? Or do you see it being used in partnership with a lot of different mRNA therapies and biologics ?

Or do you just kind of see it dominating the space , right ? Does it become the one to throw in a Lord of the Rings joke , the one ring to rule them all ? I mean , you're welcome to steal that as well , by the way , but we might get in trouble with the Tolkien .

It's just so easy and they don't have a constraint that way . So there's going to definitely be ongoing research with circles , on what you can do with circles . The main limitation , though , the thing that will limit its reach , is how many different delivery solutions you can .

If all you have is liver delivery , it doesn't really matter , at the end of the day , whether it's a circle or a line . You might get slightly different performance . It doesn't really matter , at the end of the day , whether it's a circle or a line . You might get slightly different performance .

But what is really going to push things forward is the delivery question , and at that point , if you were forced to suffer with a mere linear RNA but you had a very , very cool new delivery , you can make fine products with that , and nothing's prevented in that way . Mind you , if you had the circle , it would just be easier and better .

So I think people are going to continue studying natural circles . That still is a bit of a mystery what they're doing there . I think people are going to do some technical innovations .

An area where we've been focused technically on the circle side is how you get expression , because there is no cap , there's no end to the RNA , so you have to mark the start of the protein with a different sequence element . Now single-stranded RNA viruses use a trick to do that and that's where we're drawing our inspiration from .

But we've been doing I think we've been leading in that that space . We've been the first to really explore that in more of an omics way , and so we're um , we're really trying to define the universe of possible ways of expressing , at least as already um instantiated in nature .

Obviously you could go to random sequences , but amongst those that are out there and there's a lot that are are out there . So it is a little bit daunting and we use , you know , we use omics approaches , we use machine learning to get after all that .

So I think , notwithstanding the IP barriers , I think there will continue to be a lot of interest in circles and there'll be a lot of people trying to you , you know , work the way around those patents in some way other . Maybe they'll just be straight up very clever ideas that are very different to the ones that we have .

That get you there , and once you have the circle , um , you know you will enjoy all those advantages . Now , of course , you still have to express , and so that's why we think the expression system might be another line of defense . I know you're trying to think about opening doors , and here I am talking about closing doors .

So there's going to be continuing approaches with RNA , not , I think , less about circles versus lines , but creativity will emerge in other ways . So you know tRNA or you know we see RNA editing as something that's out there now , or there'll be other kinds of RNA splicing things that are going on , I mean . So there'll be RNA this and RNA that , for sure .

You know , just get ready for the ride is maybe what I tell myself , but I'm not really sure my younger self would have even understood , you know . Oh , it will be like this . Yeah , I think you have to sort of live through it to really sort of sense .

It's a very central role , I think , at the CEO level , particularly in the early days you've got , you basically have to do a lot of different things because the team is not fully fledged . But then , as it grows , then what you're trying to do shifts and evolves and changes . And there's raising money Is the story good enough ?

Polishing your craft in terms of pitching and getting people interested in what you're doing , getting the message across succinctly or in an exciting way , you know . And there's your board as well , making sure everything is very smooth and aligned there .

I've been in any number of board meetings before as a participant , but not , as you know , ceo , which is a far more central function in that . So that was maybe the newest thing to me , because I'd done early stage startups before where they didn't have the title of CEO . I was basically doing everything anyway . So the early phases of Honor were very familiar .

Yes , I don't know that there's , there's advice , um , just to say that , uh , you know , it's , it's , it's a lot , it's a big role .

So just one follow-up to that and then we'll let you get on with your day . You said get ready for the ride . Looking back , what aspects of the ride .

And , um , you know , uh , there was you . You know there was the big boom time in 21 and then it all sort of went south and sort of the investment dried up .

So that was , you know , that's really out of your control , as you're presented with a scenario and you have to solve for what you're trying to solve for and then , if the conditions change , you have to resolve for that . So that's less . You know that's , and that's not you .

I mean , that's your team at that point , that's everybody , from your board to your executive team , to yourself , and then everybody in the company is trying to create value through what they do . I mean the path to salvation is value creation . I didn't mean for that to rhyme , but it did .

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