What is it like to pursue a scientific theory for more than 20 years, in the face of doubts from colleagues and funders that it would ever work, and see it produce a vaccine that saves countless lives around the globe? Then to win the highest scientific honor in the world for forging ahead?
Drew Weissman, MD, PhD, will tell you. Weissman and Katalin Karikó, PhD, his colleague at the Perelman School of Medicine at University of Pennsylvania, won the 2023 Nobel Prize in Physiology or Medicine for research that culminated in the development of vaccines using RNA to protect people from COVID-19 as it spread into a pandemic that took at least three million lives around the globe. An estimated 13 billion doses of COVID-19 vaccines, built on this and other technologies, have been administered worldwide.
“Through their groundbreaking findings, the laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times,” the Nobel Assembly said in announcing the awards last fall.
The breakthrough, in a nutshell and expanded upon below: Scientists had long experimented with creating vaccines that employ RNA (ribonucleic acid) to make proteins to fight viral infections, as opposed to the standard process of creating vaccines with snippets of a virus (usually inactive or attenuated) in order to help the body subsequently recognize that virus and fight it off. The form of RNA used in the COVID-19 vaccines (called messenger RNA, or mRNA) delivers instructions for the body to make proteins.
The benefit: It’s faster, easier, and less expensive to create a vaccine using RNA. The problem: It was difficult to get RNA into a cell, RNA caused severe inflammation, and low levels of protein were made because the body saw it as an alien substance and attacked it. Weissman and Karikó used synthetic RNA that the body’s immune system doesn’t recognize, and encased the RNA in lipid nanoparticles (fat bubbles) that easily slip into cells.
The interview, which Weissman conducted from his home, has been edited for clarity and brevity.
My first question sounds rather typical, but how does it feel? Going to Stockholm with your wife and daughters to receive the Nobel Prize? Even before that, seeing the impact of your work on RNA in helping to bring the pandemic under control?
Weissman: The impact of the work is probably the biggest shock, because Kati [Karikó] and I spent 25 years working on this, with people telling us the whole time, “Give it up. It isn’t going to work. Why are you bothering?” The NIH [National Institutes of Health] not giving us money, people not wanting to publish our papers. And then, to suddenly see it come out to the market and be the major vaccine that has tamed the pandemic is a fantastic experience. My dream has been to develop something that helps people and I think I’ve done that.
I’ve never gotten used to getting awards. They’re things that Hollywood people like to get, to march down the red carpet and to show off. I’m happy back in the lab and working. The Nobel is certainly the crown of all of them. It was a great experience and my family loved it as well.
What does one do with the Nobel Prize medal itself? I don’t see it hanging behind you on the wall.
Weissman: My wife won’t allow me to keep any awards at the house. They’re all in my office.
(A smiling Mary Ellen Weissman, PhD, hearing the conversation, walks up behind her husband, wraps her arms around his neck, and looks into the camera.)
Why can’t he keep his awards at home?
Mrs. Weissman: (Nodding slowly for emphasis.) It’s a lot of awards. And they’re all heavy! You need reinforced glass shelves. We don’t have those here.
Okay, that makes sense! Thank you!
(Mrs. Weissman, a child psychologist, pats her husband's shoulders and walks away.)
You’ve helped us explain the science behind the role of RNA in vaccines and therapeutics. Can you explain, perhaps for non-scientists, the key developments in your research with Dr. Karikó? What impediments did you resolve?
Weissman: RNA was used in clinical trials in the late 90s and early 2000s for cancer, but it failed. It didn’t provide any protection to cancer patients. Biotechs and pharmaceutical companies decided that this isn’t going to work. It’s too hard to work with. It doesn’t make enough protein [which helps form responses to fight infection and disease]. The world essentially gave up on RNA.
Kati and I started working on it in 1997. We identified that, immunologically, the RNA was seen by the body as foreign, so the body responded with an extreme immune response that induced severe inflammation. That made no sense to us because our cells are full of RNA. We spent about eight years figuring that out. Eventually, we modified some elements of the RNA to make it not look foreign, and as a result it didn’t set off that inflammation and made much more protein.
The second key was that you have to have some sort of delivery system for RNA to work. We found that lipids that had been developed for siRNA [small interfering RNA, which is used to impede the expression of certain genes] worked for mRNA. Coating the mRNA with that lipid allowed it to penetrate the cell. It’s pure luck that the lipids stimulated antibody production. It increased the amount of protein [that the body made under instructions from the mRNA] by about a thousandfold.
When you published those findings in the journal Immunity in 2005, I read that you told Dr. Karikó, “our phones are going to ring off the hook.” What happened?
Weissman: I thought we had solved the problem of delivering RNA. So I thought the world would see that, and biotechs and pharmaceuticals and researchers would want to start using it. But the phone didn’t ring for three or four years. Random scientists did start to pick it up in their own experiments, and we kept working on it and we kept publishing papers about it. It was a slow build until Moderna started up, and biotech became interested in our RNA work. Things started taking off from there.
(The pharmaceutical and biotechnology company Moderna was founded in 2010 to focus on developing therapeutics built on the mRNA that Weissman and Karikó developed.)
I wonder what this achievement says about the value of basic science research. You and Dr. Karikó worked for many years on this, and scientists usually don’t know if something they’re working on will come to fruition.
Weissman: There are thousands and thousands of crazy ideas, and it’s impossible to know which crazy ideas are going to work. There just isn’t enough money to fund all of those ideas. I understand why we couldn’t get funded, because they [funders] considered it a crazy idea.
What does that say about the mindset you have to have to do basic science research? What would you tell a room full of young scientists?
Weissman: I can tell you what my wife says about my mindset.
But I think it’s more that Kati and I saw the potential. We saw that this wasn’t just one treatment; it had the potential to treat thousands of diseases. We weren’t willing to give up. We knew that it was just a matter of solving all the problems that had plagued researchers before us. But if we could solve those problems, we would have a new type of therapeutic with really broad applicability.
Since you baited me, I’ll ask: What does your wife say about your mindset?
Weissman: She calls me a pain in the butt with an incredibly stubborn approach to everything.
I imagine a stubborn approach might be a necessary condition for a scientist to pursue a project for decades.
You’ve said that research on the potential of using RNA in vaccines was growing before COVID-19. [By 2017, according to an analysis in Nature, human trials were underway to test mRNA vaccines against HIV, influenza, Zika, and rabies.] Then came the pandemic. The urgency to combat the disease drove governments, foundations, and corporations to pour money into experimental vaccine research and development, including RNA.
What are the conditions that make something that’s experimental move to real world application? We won’t always have a pandemic.
Weissman: It’s purely based on the data and on the market. A pharmaceutical company has less interest in developing a malaria vaccine than they do an influenza vaccine. A malaria vaccine doesn’t generate money because the disease primarily affects poor countries, and they need money to pay for the trials and everything else that goes into vaccine development.
But if you develop interesting data that catches the attention of VCs [venture capitalists], biotech, NIH reviewers, then you’ll get funding. It’s based on how good the data is, and what the potential of the research is.
A lot of the stories about your RNA research refer to the serendipitous moment when you and Dr. Karikó happened to be standing at a copy machine in the offices at Penn, got to talking about your research, discovered a mutual commitment to the potential of RNA, and a partnership was born.
I imagine you might be a fan of colleagues working in the same place, as opposed to remotely, because of the kinds of spontaneous interactions that are more likely to occur in person.
Weissman: Yes, that’s something we’ve been pushing for in the lab. I’m in the lab and my office usually four or five days a week. We just moved into a new building because we needed more space for my lab. But I had extra space where I brought in other researchers we collaborate with. Now in this building, I’ve got some of my closest collaborators from Penn — on the floor above us, bioengineers who we work with on delivery systems; on the floor below, neurologists who are working on neurologic therapies. We’re bringing researchers together so they can interact.
All of our labs are open labs. There aren’t walls. You don’t have to walk through a door to talk to your neighbor. We spur interactions between everybody in the lab — the technicians, the undergrads, the PIs [principal investigators], and everybody in between. Through those kinds of interactions, new projects keep popping up.
When we spoke about the RNA vaccines during the pandemic you said, “I’m already thinking about what we’re going to do next.” What RNA research shows the most promise for vaccinations or therapeutics for other diseases?
Weissman: We’ve got five or six vaccines in Phase 1 clinical trials, for things like HIV, genital herpes, influenza, norovirus, malaria. Also, we’ve had great success in our in vivo gene therapy in pre-trial research. We published a paper about how we could deliver gene-editing with an IV injection of RNA that targets blood stem cells to fix broken genes. We’re moving to develop that therapy for sickle cell anemia.
That would have worldwide use. You don’t need a fancy laboratory that can grow stem cells. You give people with sickle cell an IV injection to repair the genetic defect that causes the disease and they’re cured. Nothing could be better for treating genetic diseases.