Dr. Drew Weissman, Lessons in mRNA Science

The Research & Discoveries Guarding Humanity From Covid-19

In a series of interviews covering the most significant scientific discoveries, Param Malik and Dr. Weissman's conversation discusses remarkable advancements in mRNA science, vaccines, and his journey in research. Featured below is a selected segment of the full interview.

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Param: Thanks for your time Dr. Weissman. You've been researching the use of mRNA in vaccines and other applications for many years, including the COVID mRNA-based vaccines. What did your research prior to COVID entail and what had interested you in working with mRNA specifically?

Dr. Weissman: I'm a basic science researcher, and so I’m mainly interested in understanding science, understanding mechanisms. When I first started working on RNA with Katie Kariko, the first thing we observed was that RNA was highly activating, and this is 1998.

That was completely unexpected because we didn't know about toll receptors or any other receptors that recognize RNA, and RNA is in our cells, so there was no reason to think it should be inflammatory, but it was. So we spent seven years trying to figure out why RNA was so inflammatory. We identified a bunch of receptors that recognized RNA and made the inflammation, and then we figured out how to make it non-inflammatory.

And that was really the critical finding because you can't use a therapeutic that makes people sick, and RNA, just regular RNA, makes mice sick. So when we figured out how to make it non-inflammatory, that's when we started to work on therapeutic development. We delivered erythropoietin, which is an anemia drug, we delivered monoclonal antibodies, we delivered cytokines, we delivered lots of different therapeutic proteins.

And I also started using it in vaccines, and those vaccines are what led Moderna and BioNTech to want to use the platform to make RNA vaccines for COVID-19.

Param: What made the mRNA vaccines different from other inactivated or attenuated vaccines that are generally administered?

Dr. Weissman: Yeah, so the main thing is that they're much more potent, and they're much easier and faster to make. So for an inactivated vaccine, first you have to isolate the virus that causes the disease. Then you have to grow it up, then you have to inactivate it.

With RNA vaccines, we only needed the sequence from the virus. We didn't need the virus, we didn't need anything, just the sequence. And the next day we were making RNA vaccines, and Moderna and BioNTech did the same thing.

So that's why it took two months after the sequence was released to inject the first people. It's just a quick, easy platform.

Param: Going a little bit back, when you were a student and an aspiring scientist, what influenced you to enter the biomedical field and pursue mRNA in particular? But generally, what inspired you to pursue this field? And did you always know you wanted to enter this field?

Dr. Weissman: Yes. My father is actually an engineer, and my entire life growing up, my mother would say, you can be anything you want, just don't be an engineer. So I guess that biased me away from being an engineer. But I was interested in basic research. And starting in college, I did basic research in labs every summer, and just fell in love with it. I didn't know that that's what I wanted to do.

Param: Going back to your research, how does the mRNA vaccine interact with the immune system?

Dr. Weissman: Yeah, so what happens is that the lipid nanoparticles are an adjuvant. They activate dendritic cells in the immune system, warning them that something is wrong. Then the RNA encodes COVID, the spike protein, so the immune system recognizes that as foreign. So the combination of the inflammation from the LNPs and the foreign spike protein stimulate the immune system to make a response.

Param: Would you mind going into more depth about how you transitioned into COVID research? You’ve mentioned that Pfizer and BioNTech approached you because of your promising technology, but more specifically, how did that process go?

Dr. Weissman: My lab was actually working on a variety of vaccines. We had five phase one clinical trials started before COVID hit. So we were bringing this vaccine platform into clinical development. In November of 2019, we started hearing about a strange pneumonia in Wuhan, China. I talked to friends at the Wuhan Virologic Institute, and the story they gave me was a lot worse than what the Chinese government was releasing, that a lot of people were getting sick and a lot of people were dying, and it was being transmitted very quickly. So that told me that this had the potential to be a big pandemic. What we didn't know at the time was what was causing it, what the virus was. And in mid-January, we found out that it was a coronavirus. And in the minute we found that out, we started making the vaccine.

Param: That's an interesting journey. You also mentioned that you already had four or five different clinical trials happening before the COVID work. What are some other applications of your mRNA technology, including these other applications you mentioned?

Dr. Weissman: The technology has a really wide application. For vaccines, we're working on probably two dozen different types, including treating things like HIV, hepatitis C, malaria, norovirus, C. diff, influenza, universal influenza, genital herpes, and many others. So it's a platform technology, and it has applications in many different disease areas. We're working on vaccines for food allergies. We're also developing other types of therapy. So we've delivered RNA to the brain to treat stroke. We've delivered RNA to the liver to treat genetic deficiencies. And we've delivered RNA to the lung for cystic fibrosis. We've made CAR T-cells in vivo. That's an enormous new technology for treating cancer, autoimmune diseases, and other maladies. We've got a program to do gene therapy in vivo. For sickle cell, our plan is to inject RNA LNPs into a person and cure sickle cell anemia with just a simple injection, no taking bone marrow out of the patient, no lentiviruses, no complicated, expensive procedure. Just a single injection will cure them.

Param: That's very interesting, actually. So for these more ambitious examples, sickle cell anemia or cancer, how long should it take for mRNA vaccine-based technology to be adequate and ready?

Dr. Weissman: So for the in vivo CAR T-cells, we're hoping to have clinical trials in about two years. The gene therapy will probably be similar.

Param: Wow.

There's been a lot of debate over the effectiveness of vaccines, and there's been studies that have shown longer-term side effects. Do you think these side effects stem from the mRNA technology?

Dr. Weissman: Yeah, so the problem is people don't look at the denominator. For the adenoviruses, there's a clotting side effect that occurs in a couple per 100,000 people. That's incredibly rare. But it's concerning because those people can get very sick. But if you do a risk analysis, one in 200 people are terminally affected by COVID-19, and the vaccine prevents that. So the risk by not taking the vaccine is logs and logs higher than the risk of getting a clotting disorder. 

I understand why the adenoviruses aren't given to young women because of that clotting risk. For the mRNA vaccines, they've seen two main adverse events. One is an anaphylactoid-like reaction that occurs in two per million doses that is treated and goes away in half an hour. The other is the myocarditis that occurs in adolescent boys. And that, again, is a mild disease that's easily treated. And things that are happening in one per million or one per 100,000 people are incredibly rare. We see them because 3 billion people have gotten the RNA vaccine, but they're incredibly rare. And for RNA, they're not life-threatening.

Param: It’s clear that mRNA technology is both promising and effective. Do you foresee that mRNA technology will be more prevalent for severe conditions in the future? Or are you seeing more potent preventative technologies?

Dr. Weissman: I mean, new technologies are always going to appear. And I'm sure someday something will be better. Right now, RNA vaccines are incredibly potent and very easy to make. So both of those advantages would make RNA sort of the lead for any new vaccine development.

Param: Do you see any possible future work with mRNA-based technology and researching diabetes or with whole insulin resistance?

Dr. Weissman: So it's possible. Well, the problem with diabetes is that we don't know the etiology. We think it might be a coxsackie virus infection that usually happens in young children. They can sometimes be older. And that causes a cross-reaction in the pancreas. So people have done studies of giving drugs that block the immune system. when symptoms first appear. And that has mild effects. We are developing drugs for autoimmune diseases that block antigen-specific immunity, like what occurs in diabetes. So if we can identify people likely to develop diabetes, then we could treat them. We could vaccinate them and induce that response. Diabetes is incredibly rare. So it doesn't make sense to immunize the entire world to prevent diabetes that occurs in 1 in 100,000 people. It's possible to develop. I don't know how the CDC or other organizations would apply it.

Param: Could mRNA-based technology be used to help people who are genetically predisposed to a particular disease (assuming they've had genetic sequencing, and they know they're going to develop a certain disease)?

Dr. Weissman: Yeah, so it's probably applicable to certain genetic cancers where we know the antigens and we know an immune response should be protective. For many other genetic diseases, however, there isn't a big immune component to it. So cystic fibrosis is a deficiency of a protein. The immune system has nothing to do with initiation of the disease. So an RNA therapy won't be able to address that. It has to be a disease where the immune system can block formation or modulate formation of the disease.

Param: Finally, what advice would you offer to aspiring scientists who want to follow in your footsteps and help advance the medical field?

Dr. Weissman: Yeah, so probably the most important thing is to expose yourself to research. Spend a summer in a research lab while you're in college or high school. Talk to scientists. Expose yourself so you can see what research is all about and see if it interests you. And if it does, go for it.

Param: Thanks Dr. Weissman for your time.