RNA Sandbox with Johns Hopkins RNA Innovation Center's Jeff Coller, Ph.D. and Michelle Kim, Ph.D.

While the development of RNA therapeutics is arguably the brightest spot on the biotech horizon , you might also argue that the public and private research infrastructure required to support the advance of RNA as a therapeutic modality has some catching up to do . I'm Matt Piller .

His colleague , Dr Michelle Kim , is Managing Director of the new Johns Hopkins RNA Innovation Center , the ambitious initiative the duo are spearheading A Hopkins molecular biology and biochem PhD herself . Dr Kim brings more than a decade of research experience , earned at Howard Hughes Medical Institute , Circulomics and PacBio , to the party .

Jeff and Michelle , welcome to the show , Thank you . Thanks for having us . Thanks for joining us .

I first started working on mRNA-based therapeutics back in that time and the space of mRNA therapeutics was something that most people just weren't paying much attention to , and I had gone to some of these meetings that were very small at the time only a couple dozen people and had met some of the big players in that field , in particular , a guy named Mike Houston

who was a CSO of a very small company out of Seattle called PhaseRx , and I was talking with them and Mike and I had some ideas about , you know , how to improve mRNA-based therapeutics . You know this was more than 10 , 15 years ago now and I started working with FadesRx and sadly , they basically went under .

But during the pandemic , mike gave me a call and he was now a CSO of Trilink Biotechnologies , which , as we all know , you know , bloomed into this huge organization during the pandemic because they were supplying CleanCap for Comirnaty , or Pfizer's version of the vaccine , and what was clear in some of the conversations that Mike and I had was there's a lot of

interest in the RNA therapeutic space , but there's only a few dozen labs on the planet that are even working on mRNA , mrna translation , mrna stability , and so how are you going to develop a new therapeutic modality , which has really become a pillar of medicine now , and innovate that , if the academic support network just doesn't exist ?

And you know , one of the rate limiting steps , of course , with getting academics interested in this is feasibility and accessibility to materials at a reduced cost and at a cost , you know point , where they can do rapid experiments and try to innovate around the iterative experiments that they would do .

And Mike and I started talking about this and he put me together with one of the founders of Meriby , which is the parent company of TriLink , a guy named Carl Hall , and Carl and I had a conversation around this where we thought wouldn't it be great if we could get into academics' hands , at a very reduced cost , rna based molecules that they could then , you

know , rapidly screen through , rapidly innovate their technology around and then do experimentations and and and continue to to uh , uh , evolve from that , that standpoint and , um , that's essentially what we did is we created this partnership with Trilink in order to make mRNAs at a clinical grade level and sorry , at a preclinical grade level so that our investigators

could work on it and really there's sort of two hopes here . One is that , since we're working with Trilink and we're using their SOPs , that any molecule that gets developed in a laboratory would be easily moved to a GMP type production facility . Be difficult to move that beyond the preclinical stage .

But the other side of it again is this idea that if we have mRNAs that are at a reduced cost , it allows the investigators to play with it and allows us to try different structures , try different modifications , try different arrangements of open reading frames , whatever it is , in order to improve upon whatever disease it is that they're after going after .

Because one of the clear ramifications of what's happened in the last five years is that mRNA-based approaches work brilliantly for vaccines .

But to get them to that next step , that promise of cancer neoantigen therapy or gene replacement , of monogenetic disorders , we really have to innovate in ways to go beyond the biology that is naturally limiting to the mRNA expression space . So in a nutshell , that's really where we're trying to go and why we formed the center .

We're trying to go and why we formed the center .

The other aspect of that is , which I think is a very key piece of the RNA Innovation Center is that we are situated right next to individuals that are world expert in LNP delivery , because it doesn't matter how much you innovate in the mRNA space , if you can't get it to the right cells , well then you're just not going to be able to do anything .

So by having our investigators in the INBT , the Institute for Nanobiotic Technology , it really allows us to play these two technologies off of each other and then go after hard to solve problems .

I reached out to Jeff because I saw that he is active in the startup space , and we got to talking and he said you know , actually I have this other thing that's going on and you might be interested in that . So when was that . I guess that was in the beginning of 24 , maybe around January , that I reached out to you .

So I was very excited because I was trained in grad school as an RNA biologist and going into my postdoc I took RNA into a translational research space and then when I went to the startup , I took a step away . So I always wanted to come back . So this just seemed like an amazing segue to go back to the place I wanted to be .

So , yeah , very serendipitous .

But as you formed up , Jeff , how would you sort of crystallize the mission of the center now ?

It's to take on challenging problems and work with investigators who have expertise in whether it's cancer , biology or some sort of monogenic disorder , to work with them to try and solve a problem .

So having experts in RNA biology , experts in manufacturing and then experts in delivery and , of course , experts associated with whatever education , to put those pieces together in a way that is beneficial and can go through experimental reiteration , so that we can learn from each other and then gather that information and then hopefully make inroads into this technology .

And I really think this sort of model is the only place this is going to really occur , because by the time something gets spun out at the biotech level , they're already set on their way , right . They have whatever product it is that they're thinking aboutch level . They're already set on their way , right .

They have whatever product it is that they're thinking about , their indication they're going down there , there's not much time to go through experimental iterations . And in the academic setting , in the pure academic setting , there's not necessarily the roadmap in how to commercialize and go after therapeutic development .

It's really this you know , it's always been known as this valley of death between academics and industry and I think what our center does is sort of fill that void in a unique fashion .

So our mission is really that to put into the hands of our investigators the power to be able to try different therapeutic applications and test them and then hopefully spin those out , either to market them to other partners or to make their own companies associated with Johns Hopkins .

So , and a long-term aspirational vision that we have is to make our own , to start from ground zero some sort of therapeutic and take it all the way to a clinical trial at Johns Hopkins and have this sort of wholly owned program that we've developed and hopefully that would take advantage of some of the novel science that we intend to explore .

I mean , hopkins has a very rich history of taking research from basic science to a therapeutic , and so we would like to be a part of that narrative and we're hoping to bridge the place where people are at the point of discovery which , as Jeff said , is more challenging to do if you're in your biotech or pharma setting so we can meet people where they're

exploring things , exploring ideas , and help them get to the point where they're ready to try something larger in a clinical trial .

But as you know , as Michelle said , all are welcome .

And I've seen sort of how my life has changed since 2019 and the explosion of interest into the research we do , into old things that we had done in the past , and there's just it's a floodgate has opened since 2019 , 2020 of people wanting to get into this , this game , because when it comes to sort of therapeutic development , as you guys know , you've been

doing this for a long time . This podcast , you know , therapeutic development is really very particular . Right , you have an indication , somebody discovers a small molecule or you know interesting gene therapy , whether that's base editors or CRISPR or something . But in the mRNA space , it's so easy to really think about things that you might want to try .

Easy to really think about things that you might want to try , whether that's creating antigens or whether that's gene therapies as an mRNA or base editors or CRISPR as an mRNA . It's just really easy for people to imagine things they'd want to do , and so that does open this floodgate of like well , hey , I could try my favorite thing now .

All I need to do is have some tools on how to do it , and that's the piece . Right now that a lot of investigators are missing , but they're eager to get involved . You know , even before we officially launched this , you know the rumor mill in Hopkins was brewing and we were getting so much interest of people just coming up and asking could we do this ?

And my lab in fact started making RNAs for people just in the bench , because there was too many people asking us to do this . So you know , when I say that we start out small , we have to , because I just think we will get flooded with a lot of requests .

And you and Michelle and Jeff and you and I , we met just a couple of weeks ago right at the Alliance for mRNA Medicine's first Ascend conference , right , and so we were kind of privy to a lot of the ongoing challenges that the space is having . But I'm curious , you know , how would you answer the why now question ?

Why do you think that the center is so extremely necessary today , given what's going on in the mRNA space and what are some of the biggest innovations that really you think need to be made in the space that you think the center will really help pave the way towards ? So maybe we can start with Michelle and jump to Jeff .

Like we are starting with the Hopkins community because , as Jeff said , there are a lot of researchers here who are interested in working in mRNA or with RNA generally , but they don't necessarily have exposure or molecular biology skillset in their labs . So we want to bridge that divide .

I think it's a time where a lot of people can start thinking about this new modality . It might spark some different , novel approaches to treating things that previously were not treatable . So I'm so sorry , I just lost track of your question .

We can offer them guidance , we can offer them resources and we can offer them a pathway to taking their ideas from discovery stage to the point where they might be ready to go to a larger scale study .

I mean , the manufacturing is one aspect , but then the biology is another aspect . And how many other things are out there that we haven't tried yet ? Right ? I mean , they work really well for vaccines , but mRNA as a drug is . It is a good drug because it's cleared by the body .

It's cleared by the body very rapidly and that's perfect in some applications like a vaccine . It's not great if you're trying to do something like a gene replacement or protein replacement therapy , and then you know we're learning other things as we move along .

I mean , the pandemic fueled a need to get these vaccines out right away , and so both BioNTech , pfizer and Moderna linked you know , decided to use , you know , m1 pseudouridine as their modification .

Well , that might not have been the best choice now in retrospect , because we're getting data coming out in the publication sphere that you know those modifications will allow us for the vaccines to be useful .

There could be , you know , unintended read-through events that you know we might not want , and there's over 150 unique nucleotide modifications that we know of . Have we explored that entire space ? Could we get to a point where we could improve the expression profile of an mRNA and reduce its immunogenicity better than what we already have ?

And there's real examples where we might need that . So , for example you know it's not a case , it's not , it's not . What we've heard from our colleagues in the government is that the influenza outbreak is not a when I'm sorry if it's a when that there will be eventually a large scale influenza outbreak and we're going to need viable vaccines for that .

And in those cases you often have to mix multiple mRNAs together , but you get to a point where you have too much mRNA per dose , and so that creates an immunogenic response .

And so can we explore technologies , modifications or alterations in mRNA structure that can reduce the overall amount of mRNA needed to get the same amount of protein product and that allows for us to go into these more complex therapeutic options . And so I think , why now ? I mean that was your question why now ? It's because we don't have this .

Technology is powerful , we need it . We're going to need it for rapid responses to pandemics . We're going to need it for other you know , rare diseases that we might want to go after , or just simply reducing the costs of already existing therapeutics because it's cheap relative to other therapeutics .

But the why now is because we don't have the decades of knowledge on how to improve upon the efficacy in vivo , but also the manufacturing , and you could even see from the event you were talking about , the Alliance for Amarni Medicine's event there's so much interest in just the manufacturing alone and how we can reduce the cost and make things better and safer ,

so it really is an important moment .

Right is to help us sort of answer the questions that maybe biotechs today are not quite capable of answering yet , or because of different risk tolerance . Right and regulatory tolerance there can be some limitations there commercially that aren't necessarily faced with academic research , yeah that begs the question .

You know . You hinted at the translational um capabilities , the , the relationship with trial link being sort of foundational to to your point , being able to take some of these ideas eventually into the clinic . Um , what , what does that infrastructure look like at the at the center right now ? And what , what do you aspire for that ?

Uh , I guess , yeah , infrastructure functionality to look like in terms of a business support mechanism versus just a ? You know some , some lab space and some you know sure highly decorated scientists who can help you yeah

Um , so what that means is that if the researcher again I think I've said this before , but the researcher can take it from the preclinical state to the , to the clinical market , without having to do too much new optimization .

So I think that's an important piece , because things can break between preclinical studies and clinical studies and you don't want that to happen .

But I think , from sort of , the support and business structure is it's really this reiterative approach where you know if you can give an investigator an mRNA at cost , essentially for materials , and then they're testing it and they see whatever it is that they want to see , they might come back to us and then say , hey , we need a little bit more , we need

either we're getting too much off-target effects or the immune reactions are too high , toxins too high , something . So we can try and play with that to get to a point where they're happy with the outcomes that they're getting .

That then might allow them to move on to either new co-startup or licensing it to a pre-existing biotech and with a product essentially that has been very well vetted in the academic clinical setting , hospital setting here at Hopkins . So I think that provides a lot of value , because you don't often see that and it's certainly I mean again .

This goes back to this valley of death issue . There's a lot of great ideas that start in laboratories like mine that just wither on the vine either because they can't leap that valley or when they do traverse that valley they die of starvation because there's just not enough energy to keep them going to get it into the market space .

So I think we can help provide some of that by offering input and looking at their data , helping to evaluate and then really seeing what more levers can we pull to get them to the place that they really need to be .

So instead of getting one type of mRNA molecule , they can get 10 , right , and they would all vary in different ways that we think might be beneficial to its expression or stability , and then they can see which one is the best in their assays . So it's a much more powerful approach when they're working with us .

So if we have investigators that are doing neoantigen therapy in the pancreas , we take that information back with us and we learn something about what worked there and what didn't work , and then the next person who comes up and wants to start a program somewhere else .

We learn from that and over time we're gaining expertise about when you know , when do you need to have ultra pure RNA , when do you tolerate a little bit less purity , when you know would it be great to have this particular type of RNA modification or this you know particular UTR or whatever it might be , or LNP formulation .

By gaining that information , keeping it in our records and then advising you know , we're educating ourselves , we're educating our own community to help , and so it's creating value to the center itself .

So the employees of the center are employed by Johns Hopkins through that money . But it's it's as with any academic center . It's never a money-making business . It's basically break-even . That's it , and so we charge . We charge for our services , enough to keep , you know , the everything balanced , um , and ?

But we are an academic unit , so we also can apply for grants and take donations . If you want to send us a check , go ahead .

Hopefully in time becomes self-reinforcing and sustains the , the uh , the operations .

And when a new code is started , then there are , you know , the license has to be negotiated with Johns Hopkins . That's a very standard operational procedure for any university and how they spin out companies and that's that's really . It is that if we develop things at Johns Hopkins , then if the investigator wants to patent that , then they're welcome to do that .

Then it's all done through the terms of Johns Hopkins University .

We , we don't really want to start making GMP mRNA at Hopkins . It's a whole different ballgame , different ballgame , yeah . And and since we are using their , their , their protocols , the we would be sending business to them and so that's what what they get out of it more than anything . So a lot of the de-risking is done .

What they probably see is that most of the de-risking is done with us through the academic center and then they get the good stuff that they can make . But in terms of IP , there's no tether .

So , yes , the idea is , because of this relationship , the transition to larger scale production should be seamless relationship , the transition to a larger scale , production should be seamless .

I'm curious to kind of get a trajectory here of some of the innovations that your lab has been involved with right on the scientific side for RNA Leading up to this point . First of all , you know where have you been particularly active in mRNA and next-gen RNA .

You know prior to the launch of the center and then also how you see that supporting some of the work right that you're going to be doing moving forward with the center .

And that's sort of our knee-jerk reflex is to make sure that we design it the way we think it should be designed , which is not necessarily as intuitive as you might think , Because we know a lot more about all the various little features that control stability .

And it's not as simple as just like going to some web protocol and hitting like optimize my RNA and poof , there it is . Yeah , there's a lot more that goes into it . The other side of it is I'm really fascinated by the RNA modification space , because that is an area we just simply have . Like I said , we're in N of 1 here , where it's M1 .

Pseudo U is what everybody throws in for the most part . I mean , there are a few others , but there's so many other RNA modifications out there yet to be explored that could really be used for particular applications . And then , lastly , the one that you know Matt was laughing and I said I was been working on this since 1993 .

It's true , and back then we were . You know when somebody would say , cause we used to program cells with mRNA . Back then we would inject mRNAs into oocytes and stuff and reprogram cells and people would play with this idea could you use it as a therapy ? Well , no , because it was delivery , Delivery , delivery . Delivery Delivery is always the problem .

How do you get the transcript to the cell that you care about ? And back then nobody was really even thinking about the LNP space as start exploring that space together , Because it is true that we're not going to innovate unless we can do that .

So that's another place where we've had some success , you know , on this sort of individual basis of you know , here's an RNA , here's an application . Let's talk to our colleagues Do they have an LNP that might work ? And all of this will have to be sort of combined as things change .

For example , if you start changing modifications on an mRNA , that's going to change its chemical property and so how that gets packaged into the LNP is going to be different .

So I mean , are there innovations that you are most excited to see the center tackle in the upcoming year or two , as you set out to be COO right To operationalize all of these , uh , all of the goals you guys have , are you most excited about anything that you guys are going to be working on in particular ?

There were a lot of things that I saw at the meeting in Boston last week . Was that last week ?

I'm really eager to see what happens in that space , just how mRNAs are used in areas where they haven't been used before , such as new antigen therapy Sorry , I'm getting a cold . No , no , you jinxed me . I wonder where that came from . Yeah , or for delivering enzymes and base editing and perspiring . So I think a lot of people are trying to switch to that .

So I think that's a really important area . We're probably going to see a lot of people asking us about that . But , yeah , I think self-amplifying rna is an interesting space . I know jeff and I have talked about that before . It has its pros and cons , but , um , it's nice because you can deliver less um and potentially get more expression .

That's a lot of RNA .

But if you can get it and what I've heard from some of the self-amplifying folks is that they're down to like 0.25 micrograms , so it's a pretty significant you know difference and you know , and that puts you into a new realm of where you can start mixing and matching different strands for complex processes , whether that's like some sort of gene editing or if it

is a pan viral vaccine that you want to generate . So you can have five or six different transcripts in there , you know , to try and get the best response that you can possibly get . So those are all things that we really need to explore .

And I'm curious about that , cause I don't think it can be overstated that this isn't just an academic exercise and that you two both bring to the table a bunch of industry and vendor supplier experience . You both worked in the biotech space . You've got , like I said , supply experience .

So I'm just curious about what kind of mind share that industry experience you're bringing to bear as you form the center up and create the vision and , you know , make it what you intend it to be . How , of those experiences that you've had in the industry the business of biotech informed , the way that you're setting up to help other companies build and grow .

You want to start there , michelle .

So bringing the center in existence was a , you know , that was no small feat .

And then here getting operations going at the micro scale , I think because of my experience before in a small startup and then in a larger company , it was an eye opener to me , coming from grad school and a postdoc , excuse me where you're in a very academic mindset , it's very different than when you're in a company , like when you are trying to sell something

or help people . You have to be very customer oriented . You need to know how to keep stakeholder engagement . You need to know never to say no or never to say it with that word . You need to understand like you're trying to understand what do people need and then how can you deliver to them and how can you describe to them what you can and can't deliver .

So I think those are the skill sets that I bring from my previous experience and I hope it pays off . Yeah , I mean I can just add on that and .

But one thing you do learn in talking to investors and talking to other players in the space leaders in the space and it goes to why this center really is important is that you have to hit the ground running . When you start a new startup , you have a very limited time , and so you have to identify a niche that you can occupy , that you bring value to .

And that's really where I think we can help in this arena is if you have investigators that are coming to us and they , hey , they want to do this , that or the other thing , you know it's . It's fine if you're getting a publication , great , but if you actually want to spin that out to make a company , well then what is the real value of that product ?

What does it bring to the table ? And we can help with that narrative by saying well , you know we understand the mRNA space and we know that you know that you have lots of competition over here , but you might have a singularity here that could be explored and provide value that investors would be very interested in seeing .

So you know we don't and we don't work alone in that regard . I mean we have the tremendous support of , you know , johns Hopkins Technical Ventures and as well as our own , you know contacts in the field . So you know I anticipate that the center will provide . You know we do more than just science at the center .

You mentioned we're part of this alliance for mRNA medicines and that is another aspect because it allows us to really connect people with other industrial leaders and we have over 60 to 70 members of that alliance now that we're part of and that network is very valuable and will be valuable to our clientele as we move forward .

And there's a lot of best practices , I think , in terms of you know , how you can launch a business and best leadership practices that are really modality agnostic .

But I'm curious , you know , with your background , both of your backgrounds being in this RNA world- and having seen the RNA world pre-COVID , when no one really gave it the respect that it was due right , are there any RNA-specific insights that you think are really important for folks to keep in mind as they are launching an RNA business ?

That genie's out of the bottle and there's a lot of issues around vaccines and political things , blah , blah , blah , but it's not going to go away . It's just too easy , works too well , and not that it works too well , it works great . But I think where we're really seeing incredible promise is in neoantigen therapy or mRNA .

Again , the idea that you can design a personalized therapy for an individual with pancreatic cancer and have that . You know the successes that we're seeing in the last two years in pancreatic cancer with neoantigen approaches is really tremendous .

That you know this was a disease where it's really a death sentence but was leading at least to half the people in that study were still alive several years later and so that's going to continue and there's a very clear path to using mRNA in the new antigen approaches . It's not going to work . You know mRNA is another modality in our therapeutic arsenal .

It's not going to work for everything but it is going to work for these other applications and I think and I don't think this is a crazy vision , think this is a crazy vision I think you're going to see in the next five to 10 years sort of point of care therapeutic development where you have major medical centers like Johns Hopkins or Sloan Kettering or Houston

Methodist creating their own programs to make personalized medicines on site . Where you get diagnosed with some rare disease or rare cancer , you go there and they , they help design a therapy in the house and you , you , you get that therapy . Now how that all gets paid for that's a different issue .

But you know the the technology is such that we can do it as point of care and you know that's going to expand . That will expand beyond the medical community also into like agriculture and starting to treat you know , our food supply before some of these pathogens emerge into the human population .

Mrna is a very low-cost , viable approach to start using on some of our livestock and animal products .

If and I'm going to ask you a hard question to answer right now- and I apologize for it in advance If you're going to put your next paycheck on a bet .

Each of them have their own uh you know , own glimpse of of of commercial promise down the road . Um , but you got to put your money on what's going to go wrong , Cause you've seen it go wrong before . Like what's that knowledge gap , or that you know that that missing piece that that so often do dooms these projects early . Yeah .

You know , we've as everybody's said and you probably heard a million times in this podcast is that it's really easy to cure a mouse . There's you , we've eliminated cancer and most genetic diseases in mice a thousand fold , um , but applying academic research to the human body is much more difficult , and so getting good efficacy and low talks is what is critical .

Um , without that you , you don't get out the door . And um , so if I was betting , you know , in the place where I think a lot of people have made these bets historically is always in the cancer space , because the risk , the benefit ratio is so different versus other places . You know prophylactic vaccines .

You've got a huge risk benefit analysis that has to be done you cannot cause harm there at all and it has to be efficacious . And there's a lot of political aspects about that too . But in the cancer space , oh really . I haven't heard any political influence on the vaccine space . We could go down a whole different podcast for that one .

We can take a lot more risk there because the benefit is so high and that allows for innovation that then can eventually allow us to do things like monogenetic gene replacement , and which has its has its challenges . You know , the challenge there is the , the durability of the mRNA , the mRNA . The reason why I study mRNA is because it goes away .

That is my job . I've studied mRNA stability for decades and it goes away , and it goes away fairly quickly . And so for protein replacement strategy , unless we improve the durability , or we improve or have , or if it's an indication that allows for repeat dosing , then we're sort of limited there .

So from a betting standpoint , if somebody had a really good cancer neoantigen treatment , that's where I'd be betting .

You know we've talked about why academia is a great place to do some of the R&D that we really need today , Right , and so I'm curious , just as we're looking forward into the future and just in your experience so far with the center , you know , have you seen an increasing amount of interest from industry in partnering more closely with academia over the past year

, two years , and do you see that ? You know , now that the center's fully fledged and formed and exists , do you see that interest continuing to increase ?

But when I was in PacBio , I mean they and other companies that I had spoken with , like everybody , is understanding or realizing the real value of academic centers for discovery , right , because you know , as we've talked about earlier , it's just it's an inhibited prospect if you're at a biotech company or pharma company when you have timelines and deadlines and

programs , if you're a biotech company or pharma company when you have timelines and deadlines and programs .

So I think I think companies are going to continue to grow their interest in trying to partner with academic institutions to help foster these early ideas and , you know , with the idea that it's going to come back to them so they can work on the other end of the research pipeline .

And but we can , you know , it is the messenger of the genetic code and we can get it to communicate any information we want . And so that's where , um , why industry is so fascinated by this technology and why they're approaching places like us in order to say , well , what can we do together ?

And I only see that interest continuing to go up and up and up in the next few years . This is a technology that's simply not going to go away . It's not .

Maybe there are things that we can do outside of the individual , but also of the bigger industry as a whole .

We're going to have to revisit down the road and learn about some of that project work and stay up to date with the progress of the RNA Innovation Center and any number of these things . You know the vaccine conversation . I'd welcome that . Vaccine politics there's a lot .

We have a lot of challenges ahead of us and it's important that the public realizes that these technologies are not there . As you know , they're not bad technologies that are meant to just make people money . They , they are technologies that actually are saving people's lives and , uh , they're going to become very important in the next few years .

And it's a technology that really started with Operation Warp Speed during the Trump administration , and it was launched during that time , and we have to embrace it and we really have to rally around it as a technology .

You get your podcasts and go to the videocast page under the Listen and Watch tab at bioprocessonlinecom , where you can not just listen to Anna Rose and I , but you can watch us .