Continued innovation and investment is vital to maintaining the U.S.'s leadership in the biopharma sector. Rob and Jackie sit down with Andrew Geall, Chief Development Officer at Replicate Bioscience, and Deborah Barbara, strategic advisor to Primrose Bio, to discuss the development and potential of mRNA as the fourth pillar of pharmaceutical innovation.

Mentioned

• Sandra Barbosu, “Harnessing AI to Accelerate Innovation in the Biopharmaceutical Industry,” (ITIF, November 2024)
• Richard Fleischer, dir. Fantastic Voyage, (20th Century-Fox, 1966).

Related

• Stephen Ezell and Meghan Ostertag, “The Bayh-Dole Act’s Role in Stimulating University-Led Regional Economic Growth,” (ITIF, June 2025).

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Rob Atkinson: Welcome to Innovation Files. I'm Rob Atkinson, the founder and president of the Information Technology and Innovation Foundation.

Jackie Whisman: And I'm Jackie Wiman. I head development at ITIF, which I'm proud to say is the world's top ranked think tank for science and technology policy.

Rob Atkinson: This podcast is about the kinds of issues we cover at ITIF. Which these days is a lot. Everything from the broad economics of innovation to regulatory questions about new technologies. So, if you're into this stuff, please be sure to subscribe and rate us.

Jackie Whisman: Today we're talking to Andrew Geall and Deborah Barbara. Dr. Geall is the Chief Development Officer at Replicate Bioscience and RNA, an mRNA vaccine production startup, and he co-founded the company. He is also the board chair of the Alliance for mRNA Medicines and Deb Barbara is the inaugural board chair of the Foundation for mRNA Medicines and a strategic advisor to Primrose Bio, an mRNA manufacturing and production systems company.

And we're excited to have you both here.

Deborah Barbara: Thank you for the invitation. We believe this conversation is timely. So appreciate the opportunity to join the podcast.

Andy Geall: Yep. Thank you very much.

Jackie Whisman: Deb, maybe we'll start with you. You described in a column last year how mRNA is the fourth pillar of pharmaceutical innovation. Can you tell us what you meant by that and how mRNA compares to other innovative medicines?

Deborah Barbara: Yeah, sure. Thanks for the question. So, when you think about the evolution of the pharmaceutical sciences, there are four foundational innovations that actually stand out. They are small molecules. These are the molecules that are standing in your medicine cabinet, your aspirin, if you will.

There are biologics. You see them on your TV at night. Keytruda, Opdivo, Humira, cell and gene therapies. You see those in the form of the first approved cell and gene therapies to combat liquid tumors in the form of Kymriah, and then Luxturna for eye indications. And the last evolution was mRNA.

And we saw that in the form of the COVID vaccine. So why are these pillars well, and what do they share in common? It really is what are they made of? How are they made? How do they work, and whether they have this potential of covering a breath of disease. And in the case of mRNA. The composition is the same.

It is all ribo nucleic acids. Some might be modified tweaks here and there. They're all made through a common three-unit core, three-unit operation platform, manufacturing process. They all work by expressing a protein in the body that will have a pharmaceutical effect. And they have the potential of covering a broad disease category.

Everything from infectious diseases like we saw with COVID vaccines to rare diseases, to cardiovascular diseases, to cancer, and, and onward.

Rob Atkinson: So, I have a question, which is, I will have to admit, for me as well as listeners, what does the M stand for? And, and the second question is, I, you know, I study this stuff. I still don't know how any of this stuff works. I mean, you got these cells in your body, and you got these proteins on and then you put something else in and it does something and it changes it like it is crazy.

Andy Geall: I'll take that question. So, the M stands for Messenger. Messenger RNA. And so if you go back into your biology books and we bring it up a layer up, the central dogma of biology is a genetic code. It's contained in DNA, a double stranded helix. This is a stable molecule, that tests, you know.

Whatever's thrown at it, it's able to maintain that genetic code within our cells, that needs to be translated into a protein. We are made of proteins; enzymes are made of proteins. Our biology is about protein and how that functions. And so we need to get from DNA to protein, and we do that through Messenger RNA.

It's a transient message that is designed to vaporize, to hydrolyze very quickly. It's not designed to hang around. And so our double helix opens up, in comes stuff. Messenger RNA is made, our ribosomes take that messenger RNA, make protein and protein does stuff, but then once we stop making the RNA, it all disappears.

So, it's a transient message. It's designed to hydrolyze. We have mechanisms in our bodies, enzymes called RNAs that are designed to inactivate RNA. So, it's a transient message we can get it into a cell, hijack that machinery to get a protein made, but transiently. And then the RNA disappears, so it doesn't integrate into the genome as some of the conspiracy sites will say it.

The central dogma of biology is, it's a transient message and poof, it's designed to disappear. The pharmaceutical industry got excited, particularly vaccines. I switched careers in 2008 to kind of industrialize this. We could manufacture a vaccine without cell culture. So, if you look at any of the traditional technologies, a protein vaccine or a live attenuated vaccine, you need cells, you need big stainless steel fermenters.

It's like brewing beer. You need dedicated facilities. So, for instance, in Holly Springs, in 2012, Novartis vaccines commissioned a modern cell flu culture facility, 900 people running this facility, over 400,000 square feet at a cost of a billion dollars. And all it did was make one type of vaccine for influenza, either a seasonal influenza vaccine or a pandemic, if we had a pandemic. The reason you need big infrastructure is it's like making beer. You have to brew, you have to culture these cells. And in the case of the flu, the virus grows in the cells. These are mammalian cells. And then you have to purify that virus away from all of the debris of the cells. And then you have to inactivate it, split it, prepare it into a vaccine. For RNA, you don't need any of that. All you need is an enzymatic reaction. So, you're starting off in a very pure system that can And how do you make RNA? Well, you have a piece of DNA as your template that encodes the mRNA. You add an enzyme called T seven polymerase, and if everything is right in that template it binds on a promoter sequence and it reads along, makes a messenger. RNA comes back, it reads, it drops off, and it keeps doing this two-, three-hundred times, and you end up with messenger RNA because it's unstable. You need to then process it very quickly, purify it and freeze it down, get it outta solution, and then formulate it so you can deliver it.

But so, for the first time, we had a very small-scale production system that didn't have the complications of cell culture. And that's why we saw a lot of innovation happening, in the RNA space back in early 2008, I switched careers. We saw the US government get involved. The defense Advanced Research Project Agency pushed about a billion dollars into the technology.

People like BioNTech, Moderna, Sanofi. I was a principal investigator on a large grant at Novartis Vaccines. That early innovation drove the technology to a point where we started to see venture capital investment coming in, big pharmaceutical companies investing. And so, by the time the technology had been scaled and it was ready for implementation I don't think anyone really expected, global implementation, but Pfizer, Biotech and Moderna were ready and they scaled to capacity, to meet global demand.

Rob Atkinson: That's really a great explanation. There's a great line by the famous science fiction writer, Arthur C. Clark, which you may know of. And it’s basically, “Any sufficiently advanced technology, it seems like magic”. And that's what this seems like to me. Like you just described something and I'm like, yeah, whatever.

Andy Geall: That’s the problem. It's magic. Therefore, we don't understand it. Therefore, there's a lot of misinformation. But as a scientist, why am I excited? The safety aspects of this technology compared to older cell culture technologies are far in advance. I work at Replicate Biosciences.

We work on the next iteration of the technology and based on recent clinical data, the second-generation systems we're looking at being able to produce from a one-liter bioreactor, somewhere around 50 million human doses per liter in a few hours. And so that, if you can imagine that cell culture facility in Holly Springs for flu that cost a billion dollars, that barrier has gone.

So, the barrier to vaccine innovation was about, could you afford to build that one facility to make the vaccine, that is all gone now. We're looking at countries around the world thinking of implementing mRNA technology even in the developing world.

I spent a week embedded in a university in Brazil teaching on mRNA to enable the next generation of scientists to be trained, ready to fill positions in those new facilities. And so those barriers to vaccine innovation are now gone and removed. The financial burden of building those big production facilities have been leveled.

They don't exist anymore.

Rob Atkinson: That's a little bit like saying, you know, we have this new technology to brew beer and we don't need Budweiser to have these massive brewers. We got like, an apartment in New York.

Andy Geall: Yeah, you have all of these micros now making fantastic beer.

Rob Atkinson: Sure.

Andy Geall: Obviously those vaccine producers are gonna be regulated, by the governing bodies in their countries. And it's not gonna be like brewing beer. It's gonna be highly controlled and done in a safe, and effective manner.

Rob Atkinson: Although, even brewing beer brewing is regulated. So, you basically, essentially you have this new molecular tool. How do you say, well, I want to go for that thing. I wanna do this thing. Where in that process do you identify what the target is and how to design the RNA molecule for the target?

How does that work in a computer?

Deborah Barbara: Yeah, it's great. I think, when you're looking at targets, you're looking at where can we treat an unmet disease and do we know from the Human Genome Project what those targets might look like when we think about innovation, AI is being deployed, quickly to do target discovery. If we think about one of the most exciting applications for mRNA, which is personalized cancer vaccines, what happens in that process is AI is used to identify neoantigen specific to your tumor. And then they're able to build a vaccine that's highly personalized with precision to treat your cancer.

And that's one way that AI is being used. It's also being used for sequence optimization to make sure that we are building, stable and efficacious. Vaccines and therapeutics, and it's also being used to inform on how to formulate different delivery systems. So, it's gonna be, it is, and going to continue to be a very impactful force from an innovation perspective.

Rob Atkinson: You know our colleague Sandra Barbosu recently wrote a whole long report on the role of AI in drug discovery, and that's something that's super important. It's something, frankly, Washington policymakers need to be more aware of how this nexus of, so you talk about an amazing new technology of mRNA. And then on top of that, AI to enable it and support it.

Andy Geall: But you know, we can look back at what happened during COVID-19, a lot was known about coronavirus in 2002, there was an outbreak, of SARS. In 2012 there was an outbreak of MRSA and research scientists had taken isolates of the virus begun to understand them, try and develop animal models and vaccines against them, and they determined that one particular protein on the virus could be a target for vaccines.

And if you could neutralize it, then you had an effective vaccine. By the time 2020 came, we had, you know, SARS COV to two started to spread A lot was known about, if we have to make a vaccine very quickly, we know it should be centered around the spike protein, modern, sequencing, systems for viruses, highly efficient now.

And so sequence information is shared globally. So, we were able to go from that sequence into an mRNA vaccine very, very quickly. Traditional technologies, you'd learn how to make the protein in cells a subunit vaccine, or you would try and grow the virus, in cell culture. Again, takes sometimes six to eight months to happen with the RNA sequence to a vaccine.

And we saw within 60 days of that vaccine, of the sequence being available, vaccines were going into clinical trials. And so we saw the speed of innovation, of mRNA and its key advantage. You don't need the cell culture systems anymore that bring a burden of time, before they can be optimized.

Jackie Whisman: The best thing about drug development is that it only gets better. So, I'd love to hear from both of you on what are some of the most exciting kind of recent innovations in mRNA technology and potential future applications you find most promising.

Deborah Barbara: Yeah, I'll let Andy talk about self-replicating RNAs. I think from my perspective, it's targeted drug delivery systems. They're starting to take those lipid bubbles that. Andy was talking about that protect the mRNA and starting to think about how do we make them more targeted. It comes down to a combination of what lipids you put together, but also there's opportunities to decorate those lipid bubbles with different molecules that target specific tissues or cells. So, I think that to me is very exciting because you can make mRNA, but unless you're able to get it to the right cell in the right time for the right disease, you don't have a medicinal effect.

Delivery is coming a long way.

Andy Geall: I work in the manufacturing side for mRNA vaccines. And you know what we did during COVID is really in the dark ages now. We would never, you know, the processes that were designed there are what known as a batch process. We're five years on now and we're starting to see innovation on that production system. So, the first layer of innovation is automation. So rather than having highly trained people, running a process, now you have a robot running the same process and you program the robot. So, there's companies like Quantum who have robot systems to perform that in vitro transcription reaction.

Then the next layer down from that is flow chemistry. Rather than having a batch reaction where you make RNA for two hours, as I told you, RNA hydrolyzes. The molecule you make at time one minute, will hydrolyze over the next two hours. And you kind of optimize your batch to produce, as potent material as you can in flow chemistry. Now, within two minutes, the reaction happens and you harvest, and inactivate, that product. And so the quality of material using flow chemistry, and this is now available GMP, from companies like Centillian and Nature's Toolbox. So that can be implemented in the clean room today. Downstream from that, all of the purification technologies, there's been a lot of innovation and process design.

And so when we design a process now to make an mRNA vaccine, it's completely different to that kind of batch process that we developed, five years ago, during COVID. So, we're seeing rapid innovation. We're seeing the cost of goods, of the materials come down. One of the reasons we're seeing that implemented now in the developing world directly.

Rob Atkinson: Yeah, that's amazing. I don't know if you ever remember that movie from the seventies with Raquel Welch, Invisible Voyage. So, it's basically like the president or somebody has a tumor or something and he is gonna die. The scientists figure out a way to get a submarine and shrink it.

They inject the submarine into the body, and then Raquel Welch and these other, they go out and they try to kill the actual tumor, but in a way that's a predecessor to what you're talking about.

Andy Geall: No, and we've talked a lot about vaccines, but, you know, probably one of my areas that I'm watching heavily is gene editing or base editing. And this is an mRNA-based technology. There are a lot of rare liver diseases where there are mutations that can be corrected. And so you can take an enzyme most people may have heard of, you know, CRISPR/Cas9, but there are other types of enzymes. So, you encode your enzyme in the mRNA. You need a guide RNA, that guides that enzyme to the correct place where the mutation is. In the DNA, you encapsulate it in a lipid nanoparticle, you do a single dose administration into a patient, and you correct that genetic mutation, and then they're cured.

And so this technology is in clinical trials with multiple companies. I happen to be lucky enough to sit on the scientific advisory board at Ver Therapeutics in Cambridge, Boston. And so I'm getting to see the technology roll out. It's remarkable that after a single administration, you're seeing cures for incurable diseases that patients are on multiple pharmaceutical interventions for the rest of their life.

And now we're seeing them potentially come off them after a single dose of a medicine.

You know, historically, things have gone wrong in the gene therapy world with viral vector vaccines, and so there's a lot of scrutiny and analysis from the regulators on what happens if there's an off target read. Data coming from those early clinical trials is very compelling.

And it will be great to see it become mainstream in the near future, once those regulatory concerns are addressed.

Deborah Barbara: Yeah, I think it's interesting. Andy, you know, rare disease, right? There's multiple ways of approaching it. We are just talking about CRISPR, but Moderna's developing an approach, which is a protein replacement approach.

Acidemia has a missing protein or a defective protein, and they're able to create mRNAs that actually create this enzyme and correct for that enzyme deficiency. Protein replacement in addition to CRISPR, is a way to attack rare diseases.

Rob Atkinson: Yeah, this is really phenomenal. We were talking earlier at the beginning of the show, you know, there's so many things one can now look at the world and go, oh gosh, this is awful. There's so many bad things happening depending on whether you're a Republican or Democrat or whatever.

But this is one area where you're like, I'm optimistic. I'm so like, wow, this is so great for humanity. The world's gonna be better. Let me close by switching over perhaps to a policy question and, maybe, Deb, that you could sort of answer that.

You know, Andy, you were talking about production and one of the things that ITIF, I think we're very proud of it, we were the think tank that really spurred the launch of a thing called the Manufacturing USA Institutes at NIST.

They have a bio made one, one's in Delaware and it's partly about production, early-stage collaborative R&D for production. And, you know, we've long argued we need to have stronger NIH funding and we need to have, better, faster, but accurate drug approval.

We need strong IP protection for our innovators. We were big supporters of the Bayh-Dole Act that lets universities move their technology. There's so many important policy questions that we have to have because we're the leader in biopharma.

So, I'm just curious, a couple off your top of your head, if you were advising a member of Congress, or secretary Kennedy now, what would you suggest or what are the things they should be thinking about?

Deborah Barbara: I think it's all of the above, right? You know, this is where the Alliance for mRNA Medicines comes into play. We're advocating for that funding. We are advocating for regulatory framework clarity. We're advocating for international cooperation to advance science. We're advocating for the technology and you know, we're coming up against a lot of barriers. In January we heard all this wonderful news come out of the White House. President Trump, when I think it was day three, had the tech guys at the White House, and Larry Ellison gets up and talks about Stargate.

And Stargate is the AI infrastructure initiative where there's a commitment to invest $500 billion. Well, what does Larry Ellison propose earlier and say? He says, think about it guys. We can create an mRNA medicine in a day. Now that would be lovely. That's not reality right now.

But the thinking was there. The innovative thinking was there, and the promise was there. And of course he's got an AI lens on it. So, you can start seeing how important AI is gonna be. Well, in March we had whiplash. Right, and the whiplash came in the form of the NIH grants being terminated for those that were, funding vaccine hesitancy and uptake. After that, there was an email sent out to NIH grantees demanding that there be a disclosure of whether their grant funds mRNA innovation. And that was followed by a study, or an article by the Kaiser Family Foundation that cited that a couple of investigators have been advised to strip their grant applications of the word or of the phrase mRNA.

And then, like that wasn't enough, we lost our greatest advocate for patients. And greatest advocate for innovative medicines in the form of Peter Marks being asked to be fired. So, what does that say about the future and what it does it say about what we all have to do to advocate for this medicine?

Because it's not just infectious diseases, it's gonna be a whole bunch of other diseases we will potentially be able to conquer as we discussed earlier.

Rob Atkinson: Yeah, it's weird because, if you really want to think about the worst of it. Secretary Kennedy is like, you know, if you just eat a lot of carrots and don't put fluoride in your water, all the diseases go away. I mean, I'm vastly exaggerating—

Deborah Barbara: No, that sounds accurate.

Rob Atkinson: — but the idea that somehow that, that eliminates diseases that we need molecular intervention is just…

Andy Geall: I work in a small 20-person biotech in San Diego. We started in 2020. We have unbelievably good phase one clinical data. We run on venture capital. That's how we achieve our innovations. Venture capital wants certainty.

In the regulatory review process so that they can do risk assessments on how quickly they can predict whether their investments are gonna return. You create regulatory uncertainty, that money disappears. Right now, the US is leading this field. Quickly, we will not be leading this field, and we'll see that investment happening elsewhere.

And that would just be catastrophic. For the US we need to lead this field and push it forward and do what we've always done, innovate and show the world how great America is in the biopharmaceutical sector.

Rob Atkinson: Make American mRNA—

Deborah Barbara: Great again.

Andy Geall: There we go.

Rob Atkinson: We could keep going. God, this is so fascinating. But, unfortunately we do need to wrap up. I learned a lot. This is gonna be a good day 'cause I'm happy and optimistic to start the day, so thank you.

Andy Geall: Wonderful.

Deborah Barbara: Thank you for having us.

Jackie Whisman: And that’s it for this week. If you liked it, please be sure to rate us and subscribe. Feel free to email show ideas or questions to [email protected]. You can find the show notes and sign up for our weekly email newsletter on our website itif.org. And follow us on X, Facebook, and LinkedIn @ITIFdc.

Rob Atkinson: We have more episodes and great guests lined up and we hope you'll continue to tune in.

Jackie Whisman: Talk to you soon.