Senior Scientist at the University of Zurich
Dr. Steve Pascolo, immunologist and co-founder of CureVac, pioneered work on synthetic mRNA production and first human mRNA trials. At the University of Zurich, he leads a research group dedicated to mRNA therapeutics. His group advances synthetic mRNA technologies, enhancing protein expression, therapeutics, and next-generation vaccine innovations inspired by COVID-19 mRNA successes.
This Transcript is AI-Generated
Steve Pascolo: I wanted to make sure that the mRNA is safe in human. Dr. Benjamin, we from the dermatology department, has injected me mRNA coding for Firefly Luciferase. So this mRNA is translated into protein that emits light, you know, like the Firefly does.
Micah: Back in 2003, Steve Pascolo Pascalo made history as the first person ever injected with Messenger RNA.
Chai: But it wasn't until the COVID-19 pandemic that mRNA really burst into the spotlight, offering up a potential treatment beyond infectious diseases.
Steve Pascolo: There is a theoretical solution for any disease using mRNA, any disease you can think about autoimmune auto inflammation, degenerative injuries, even aging.
Micah: In this episode, we'll explore why it took so long for mRNA to be taken seriously. We'll hear Steve Pascolo's story as its first human test subject, and we'll look ahead to the exciting possibilities this technology could unlock.
Chai: I'm Chai Nussbaumer.
Micah: And I'm Mike Schweitzer. This is Balancing the Future from METTLER TOLEDO.
Chai: On this show, we delve into the world of science and technology and explore its transformative impact on our lives.
Micah: Just for context, Steve Pascolo, what is mRNA and how does it work in the body?
Steve Pascolo: So mRNA in the body is a copy of a gene that is contained in DNA, so any cell of our body contains all the information to make anything an hepatocyte neuro skin cell of the skin.
Chai: That's Dr. Steve Pascolo Pascal. He's a senior scientist in the Department of Dermatology at the University of Zurich, and the former co-founder of CureVac, a biopharmaceutical company pioneering mRNA research.
Micah: CureVac is where Steve Pascolo was working when he was first injected with mRNA.
Steve Pascolo: But of course it's cell type. Depending on what it has to do. We'll use some of the genes, not all of them. And this decision is made on mRNA. So for example, the cell of the skin will copy the gene coding for keratin so that the skin cells make keratin, but over cells will not make keratin.
So mRNA is in every cell. It makes the cell being specific, expressing the genes that it needs to express and it's transient. So. The mRNA is always made, is translated into proteins, and then it's degraded. So you have a dynamic whereby the cells can also then adapt. If you are a wound on the skin, then the cells will start to make mRNA coding for proteins that will repair the skin, for example, and this is transient.
Chai: So before COVID-19, the discussion around mRNA was relatively obscure. So what took so long for this technology to gain widespread recognition?
Steve Pascolo: The whole problem of MRN at that time. Was the prejudice, but people said it's fragile. As I said, mRNA is stringent in the cells. It's made and then it's degraded.
So we have a lot of proteins in the body called RNAs. And RNAs is a protein that degrade mRNA. And when you work in laboratory with mRNA, you have to put gloves, you have to have special solutions, special plastic, which are. Free of RNAs is because RNAs are everywhere, on every surface in your body, everywhere.
And so people knew that it's difficult to work with mRNA. So when you say, I will make a drug with mRNA, most people say it's impossible. It's fragile, it's terrible to work with mRNA in the lab, you have to have all specific things. How would you want to make a drug with something that is so difficult to work with?
And this is a misunderstanding. Of people doing research on medicine. They don't know most of the time how you produce a drug. And when you produce a drug, you have gloves. When you produce a drug, you use special plastic. When you produce a drug, you use special solutions. It's of course in the lab, it makes the life a bit harder to make mRNA, but DNA proteins.
But in pharmaceutical production, whatever you produce, pharmaceutically, you have seen people are very protected. The old space is very clean. So the production of mRNA as a drug. Is not more difficult than producing a peptide or DNA in a lab. Yes. But you know, people making decisions. Are people eventually coming from the lab or from the clinics?
Micah: My understanding is that you are the first person who ever received an mRNA injection.
Steve Pascolo: Yeah, that's correct. So, um, CureVac, we had three goals. So one was to optimize the mRNA vaccine because it was working but not as good. As, for example, protein vaccines. So we wanted to optimize it. The second goal was to produce it.
At that time we went to companies doing pharmaceutical products. We asked them, could you do mRNA? And then all of them, they said, you know, you guys are are nice, but you're completely crazy. There will be no market ever for this. mRNA molecule. So we improved mRNA vaccine, the production formulation, we did the pharmaceutical production in CureVac.
So we made clean rooms and uh, and I designed a suite. It was like six years of work, but we finally got the certification for mRNA production in pharmaceutical grade. And then going to human was to make clinical studies in cancer patients because this was initially my, my goal to induce. T-cell responses in, uh, in cancer patients.
And so we had everything ready for the clinical studies, but I wanted to make sure that the mRNA is safe in, in human, it was safe in animals, but, and also I wanted to make sure that it's functionally, it was really a clinical study in the dermatology clinic of the university hospital of where Dr.
Benjamin from the dermatology department has injected me mRNA coding for Firefly Luciferase. So this Mr. A. Translated into protein, but emits light, you know, like the firefly does. So I think I'm the first human also has expressed, uh, firefly, uh, Luc array. So the idea was to, and and did you light up or did Yes, yes, yes.
At this pieces from my skin. So we injected. Skin. And then a few hours later, or one day later, we, we repeated a few times. We looked at the site of injection of, I didn't have side effects. I didn't feel fever or something like that, so, so of course we recorded the side effects. And then at the site of injections or away from the site of injections, we met punch biopsy.
So you take small pieces of the skin under local anesthesia, and then in the biopsies we could record in a so-called luminometer. It's a machine that measures the light emission. Then we could record light emission. From the skin taken at the site of injection, but not away. You know, we made small holes the more and more away from the site of injection so we could show that the expression of this, uh, firefly, luciferase what was at the site of injection of the mRNA and not away, we could monitor that it's was coming quite quickly and disappearing after two days.
We published that in 2007. So these are published data. I sent it to big journals and said, you are crazy guys. I mean, what are you doing? So even though
Micah: you lit
Steve Pascolo: up Yes. And
Micah: you, you would think that, that even just, that would get some attention. Right.
Steve Pascolo: We were young, we didn't have political network, you know, to publish Hi, you need to have like a big name or you need to know the editors or to invite them or whatever, you know.
And um, I was very young so I send it, you know, to big journals and they immediately said. Crazy. You, I mean, go away. So then I went down with the impact factors and finally published it, uh, in a lower impact factor. But I think if I would've been somebody a little bit famous or it also helps if you are in a big American, uh, university or you know, in a site connected to some journals, um, you see some people manage to to, to publish their things.
Chai: In the time between Steve Pascolo's injection and the COVID-19 pandemic researchers worked to make mRNA stronger and safer, tweaking its chemical building blocks to reduce inflammation, cleaning up impurities, and developing lipid nanoparticles or LMPs to deliver it efficiently into cells.
Micah: These LMPs would later prove critical in making the COVID-19 vaccines possible by the 2010s.
Animal studies and early human trials showed that mRNA vaccines could protect against viruses like flu and rabies.
Chai: In 2019, scientists had all the tools ready for rapid vaccine development, safe optimize mRNA effective delivery using LMPs and evidence that it could trigger a protective immune response.
Micah: So when the COVID-19 pandemic hit mRNA vaccines could be developed quickly and effectively.
So fast forward to 2021 or 2020, what changed? Why did the pandemic have such a dramatic effect on the uptake and recognition of mRNA vaccines?
Steve Pascolo: I need to mention that in 2001, we were partner of immigrant for vaccines against ine, uh, flu. At that time, there was a fear that, uh, there would be, uh, this kind of flu, uh, coming from, from animals.
And so there were some programs to develop vaccines. We joined the program where they tested. Peptide virus protein vaccines, and I could add mRNA vaccines in it. So because we already postulated in 2000 that mRNA could be good in terms in case of pandemics. So we had that in mind in January, 2020. Then people thought, okay, let's do mRNA coding for the spike.
And they just, you know, within few days basically. Got it. And while the over doing proteins or peptides took months. To, to eventually design, produce, and test their protein. So the speed of production, what we have claimed already 20 years ago was there, and it was funny to see in, let's say February, 2020, nobody knew about mRNA except the small group of, you know, people doing mRNA vaccines.
And then in, uh, October, 2020, everybody was speaking about mRNA. It has gone from night to spotlights within four, five months. This is rare for technology. Normally technologies, you know, monoclonal antibodies, siRNA always take quite some years and they move through the studies and the public starts to get acquainted.
The medical people start to get acquainted with the technology. And here, within six months. A technology that nobody knew, including medical people. Suddenly they were all exposed to it and then exposed first in terms of information and then in terms of being really injected with it.
Chai: So after scaling up production and millions of people being vaccinated with an Mr.
NA vaccine, what were the learnings from that? Whether good, bad, were there any necessary changes or adjustments that needed to be made?
Steve Pascolo: So, um, you can always improve vaccines. You know, we spoke about the injections I received in 2003. We were happy. There were no side effects, but we were also a little bit concerned because we were like, you know, if you activate your immune system, you should feel a bit tired, you should feel a bit fever, and I felt nothing.
And the first clinical study in patients was also, you know, safety was super, but when you do vaccines and there is no systemic side effect, you think your vaccine might be a bit weak because a strong vaccine will, at least in some people, if you inject. 10 or 20 people. You should have some people reporting.
Some kind of side effects, local or systemic. The side effects of the COVID vaccines compared to other vaccines are very good, so the immune response is very strong. One thing that can be improved is the duration. Immune response. So we have seen that the immune response induced by the R NNA vaccines as they are so far is vanishing away within few months is decreasing.
And this is the same with many vaccines people forget, but the flu vaccines, the protein-based flu vaccines also give immune response that vanishes over time. So it's not something new that some immune response you get by vaccine is tend to go down. And mRNA platform is so versatile. But you have many ways to make mRNA vaccine, and there's one way called self amplifying mRNA vaccine, and this is done by several companies, including one called Aus in the us.
And this kind of complicating mRNA vaccine has shown to give. More prolonged immune response. So I think for prophylactic vaccines in the future, we may switch from the non replicating. So mRNA that gives a protein and goes away to a replicating mRNA, which is a kind of mini virus in a way. And this.
Works really well. You need less. The injection is only a few micrograms, like five micrograms. The normal vaccines with mRNA, like 30 micrograms, and what actually has shown that is its vaccine is approved and they have shown that the antibody response remain, uh, high for longer time using this replicating mRNA compared to the previously approved, uh, mRNA vaccines from Bion, Pfizer and, and Moderna.
So. I think, you know, there are still improvements you can make to, to keep the safety, to keep the efficacy, but to increase maybe the duration of immune response. And people need to know that mRNA is a platform. So it's not, you know, one product is a platform and you can, by changing a little bit, the the structure of mRNA, the formulation, maybe the delivery route, we can make it always better.
Chai: So you would say that the benefits do outweigh the risk in short.
Steve Pascolo: Totally. Yes. And I think, I mean, that is published, you know, and again, if you have like one country or one place publishing clinical studies, okay, it's good, but you know, you know that you have to look again, now you have clinical studies.
Have been done first in Israel, who has a post-approval, you know, in, uh, in January, 2021. People have continued in so-called phase four studies. So every country has its own way to do pharmaco, to, to check side effects of even approved products. Medical doctors can report side effects they would see in their patients, and it's not centralized.
Every country does it. So it's a safe vaccine.
Chai: mRNA wasn't just safe, it could be made at scale. Before COVID-19, production was tiny. We're talking about milligrams or grams. But during the pandemic, pharmaceutical companies ramped up to kilograms within months, even while battling supply chain chaos and logistical hurdles.
Micah: If you're interested in hearing about a successful scale up of LMPs for mRNA vaccines, then we've linked to a webinar with process manufacturer Merck, KGAA in the show notes.
Chai: So here's the big question. If mRNA can already work at scale and prove so effective, what else could it do?
Steve Pascolo: Yes, and I think vaccines is the tip of the iceberg for mRNA. The part underwater is therapies, which is even bigger than vaccines because as I said at the beginning, mRNA tells the cells what to do. So in theory with mRNA, we can do anything, and I'm a saying there is a theoretical solution for any disease using mRNA.
Any disease you can think about, autoimmune auto inflammation, degenerative. Injuries, even aging. Now, of course, you know, from theory to approval, you need like many years and a lot of efforts and money. But normally I ask people challenge me. You know, I mean, tell me a disease and I will tell you which mRNA in theory could help in Parkinson disease, in Alzheimer's disease, in how disease in skin disease.
Normally it's a game I like to do because then, you know, you always end up to say, okay, with this mRNA coding for this protein, you could do that, or that, or that. And so in theory, I mean, the next years and decades, we'll probably, uh, get approval of more and more therapies we have seen already, you know, a small baby, a newborn baby being corrected from a genetic defect using mRNA.
Mr. NA coding for enzyme, but can repair DNA. And so genetic defects, uh, everything can be in theory, uh, controlled by some mRNA, RNA formulation that we inject in people. And the genetic medicine is huge. I mean, so we have a program called the Reg EU Program to repair the heart after a heart infarct. And yes, we, we use mRNA that can, but look.
Cardiomyocytes. So muscle cells of the heart to proliferate. So to regenerate a muscle at the site of necrosis of the heart. So ultimately, you know, this will work at one point, maybe not in two years, maybe not in five years, but let's say maybe in 10 years or earlier or later. It's always difficult to to plan and to know when it'll be successful, but at one point it'll be successful.
So, mRNA. It is used to regenerate the skin, the heart, the lungs, co genetic disease, regenerate neurons, so the possibilities are nearly
Micah: unlimited. You're working in with a chemical synthesis of mRNA as well. What benefits does this offer over enzymatic synthesis?
Steve Pascolo: This is mostly for cancer patients because for cancer patients, what we are doing at the moment is to do individualized vaccine.
So each cancer patient get treated with its own product. It's totally individualized medicine. So what we do is that you take a biopsy of a cancer and you make the genetic profile of this cancer, you find mutations compared to healthy cells. In each individual and then you make a vaccine that will allow your body to make.
Immune response against the mutation of your own cancer. So this is in phase three, studies by Moderna, studies by bion. So each patient get its own mRNA vaccine against his own mutations. So this is a process that takes like three months from the. The entry of the patient in the clinical study, you need to sequence the genome of the tumor.
You need to sequence the healthy genome of the patient. You need to, to compare by informatic, uh, the two genomes, find the mutations, then conceived by informatic, um, vaccine, and then produce it. And the in vitro production of mRNA, like it is done in the vaccines, in approved vaccines. Is easy to make it in big amount, but when you want to make it for each patient, it takes some time because you need people to, to be involved, to, to, to make the different steps of production.
So you can make one gram or one kilogram with the same equipment and with the same people, but you need like one person per production, let's say. So if you have 20 patients, you may need 20% working on it, and especially some parts of the production needs. To have people looking at it. By moving to chemical synthesis, we can have a production automated, 'cause the chemical synthesis is fully automated on some kind of chemical synthesizers that are kind of robots.
So I started to think about using chemical synthesis of mRNA in this context of individualized anticon concern vaccines, because there's really. A big workload, so we, which means also a big price for making one vaccine for one person. So it's feasible. It's in phase three. It's hopefully will be approved within two years.
But it's big workload. It's big cost. It takes three, four months. And by moving from the normal enzymatic synthesis to chemical synthesis, we can reduce, uh, the timeframe and go faster and think the cost by having the whole production and formulation automated.
Chai: Remember how we talked about LMPs earlier?
They were the breakthrough that made COVID to 19 vaccines possible, helping mRNA reach lymph nodes and trigger strong antibody responses. Something older formulations couldn't do.
Micah: The next challenge is designing LMPs that deliver mRNA precisely to specific tissues. Researchers are refining lipid chemistry and formulations paving the way for more effective vaccines and therapeutic uses in the years ahead.
Steve Pascolo, I can imagine that the passion that you have for this topic has inspired at least some of our listeners, and if somebody is interested in being a part of the future of mRNA therapies, what advice would you have in terms of career and in terms of research focus? What is needed to advance this field or who is needed to advance this field?
Steve Pascolo: What I see is that collaborations are needed. So as I say, you know, the chemists synthesize a lot of lipids, and then you need biologists and, and you need physicians because yeah, a chemist will not know, for example, that the liver takes everything. A physician will know that the liver takes everything but will not know how to get away from it.
Biologists will know. Okay? Lipid, uh, nanoparticle shape, structure charge will dictate its bio distribution. So you need a few people to work together. To manage to have solutions to this lever, uptake, to the targeting, the mRNA itself will still improve it, and so it's kind of important collaborations and to be horizontal.
I think one person alone will not have the solution. You will need to, to work with colleagues from other fields to, to find new formulations, mostly to to manage, to, to, to treat the disease you want to treat. So exciting opportunities for collaboration. Yes. And also a lot of, of course, artificial intelligence to predict a little bit better, um, what will happen to the RNA, what will happen to the particles.
We still know very little what happens to a mRNA. You know, we think cells are full of proteins that interact with mRNA full of. A that interacts with RA. We have long non RNA, we have macro RNAs. We have a lot of things. We don't know what they do, but they are there because we don't know what they do. We think they do nothing, but they do something.
And when you make mRNA going in the cells. It'll interact. All these things in a good or bad way, we don't know, and only artificial intelligence can help us maybe better to predict. Okay. This mric once will interact with this protein and it'll destabilize your mRNA. So you rather mutate here, your mRNA in order to avoid to interact with this protein in this cell type.
This is so complicated so far we cannot predict it, but with artificial intelligence kind of putting in place networks, you know, from the sales interaction between RNA protein. We can better say, okay, now we'll make this mRNA design and ask, you know, is there a chance to artificial intelligence? Is there a chance that this mRNA will not perturb the cell physiology, cut for the protein for a long time?
And by knowing better, the microRNAs, the RNAs, the proteins, the structure of the mRNA. Then we will manage also by prediction to make better mRNA. So artificial intelligence should be also part now of the decisions of how to make the mRNA, which sequence to make and how to formulate it. So it's really multi-domain work that will need to take place.
Micah: We've been speaking with Dr. Steve Pascolo Paolo. He's a senior scientist in the Department of Dermatology at the University of Zurich. Kai, what were your key takeaways from this conversation?
Chai: Well, when we hear about mRNA, we usually think of COVID-19, but they have potential for treating so much more.
Researchers have realized that you can treat a wide range of illnesses. There's some research done about regenerating the skin, the heart, the lungs, and even going into the area of genetic diseases.
Micah: But of course if we think back that Steve Pascolo was the first person to receive an mRNA injection all the way back in 2003, this research has been going on for a long time.
And as an aside guy I should say, I think Steve is probably going to be the only guest on this show whose skin has ever glowed. Yeah. But you know, for more than a decade after that, and of course leading up to that, there was all kinds of work. Being done on mRNA vaccines, and yet they were considered impractical because of stability issues.
And then once COVID came around, we realized actually that's not the case. And it sort of entered our vocabulary at that point.
Chai: Yeah. People like Dr. Steve Pascolo really laid the groundwork, making sure that large scale production is possible.
This has been. Balancing the Future from METTLER TOLEDO.
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