A year after the Nobel Prize, Penn’s mRNA research is revving up

In the early hours of October 2, 2023, the phones of Katalin Karikó, PhD, and Drew Weissman, MD, PhD, rang out like bells celebrating the ultimate recognition of their life’s work: modified mRNA as a tool to treat and prevent disease. On the other end of the phone were representatives of the Nobel Prize organization calling from Sweden. Nearly two decades after their research was published and four years after COVID-19 struck the world and their technology saved countless lives through new vaccines, Karikó and Weissman were the recipients of the 2023 Nobel Prize in Physiology or Medicine. 
One year later, the Penn Institute for RNA Innovation, led by Weissman, bustles with individuals in crisp white lab coats carrying vials of carefully mixed compounds. They are some of the world’s foremost medical experts and the sharpest young investigators, both eager to add to Karikó and Weissman’s monumental research and to bring RNA innovation to new areas of research. The flurry of new innovation in mRNA beyond COVID-19 vaccines began prior to Weissman and Karikó’s Nobel, but the award certainly has only built on the wave of enthusiasm for mRNA research. 
As mRNA scientists look to the future, the mRNA successes from the past 12 short months at Penn help paint the picture of how medicine is changing rapidly as a result of the prize-winning discovery. 
“In the last year, our lab at Penn has roughly tripled in size,” said Weissman, whose formal title is the Roberts Family Professor in Vaccine Research. “When Kati and I started our research in the 90s, it was just us. We were the ones running around in lab coats with pipettes in our hands. Now here and all over the world, there are teams of scientists moving mRNA research forward. It’s incredible to see.” 
The lab often welcomes visitors. On any typical day, there may be a very recognizable journalist and her camera crew interviewing Weissman and his colleagues under glowing lights, or there may be a class of students from a local Philadelphia high school invited to see the lab and ask questions of a Nobel-Prize winning scientist about what life as a researcher is like. (One piece of advice he and Karikó always give young people: don’t become a scientist if you can’t handle failure…and a lot of it.)  
Some of the scientists working in the lab, like Thomas Egwang, PhD, MBA, from Uganda, are themselves thousands of miles from home and visiting Philadelphia for a few months essentially to learn the “recipe” for the mRNA vaccine platform. The goal for Egwang and many others is to then go back to their home country with the knowledge of how to construct an mRNA vaccine platform that can treat the diseases most prevalent there. That, says Weissman, is critical to better vaccine access worldwide and ultimately less disease. For Egwang, who’s working under Elena Atochina-Vasserman, MD, PhD, his focus is to develop an mRNA malaria vaccine. 
After the world learned of the safety, efficacy, and manufacturing ease of the mRNA COVID vaccines from Pfizer/BioNTech and Moderna, one of the next key goals for mRNA researchers is treating communicable diseases from myriad viruses, bacteria, parasites, and fungi. Weissman and colleagues are developing new mRNA vaccines for the influenza, COVID, and other common viruses.  
One ongoing approach is to find a way to create “pan” vaccines, or vaccines that would prevent multiple variations of a virus or a set of viruses that fall under the same umbrella. For example, Penn’s RNA Institute would like to create a vaccine that would prevent all coronaviruses likes COVID, SARS, MERS, and other coronaviruses. And a successful pan-flu vaccine would perhaps mean our current need to get a new flu shot every year due to changing strains, would be a thing of the past.   
At the same time, scientists are continuing to use the mRNA vaccine platform to make targeted vaccines for specific infectious diseases. Weissman and Edward (Ted) Kreider, MD, PhD, an Infectious Diseases Instructor in Weissman’s lab, have set the stage for HIV human vaccine trials. An mRNA vaccine to prevent herpes simplex virus 2 (HSV2), is currently in Phase 1 clinical trials thanks to the work of Weissman, Harvey Friedman, MD, a professor of Infectious Diseases, and Gary Cohen, PhD, a professor of Basic and Translational Sciences at Penn Dental. Right before the Nobel announcement, Weissman and Norbert Pardi, PhD, an assistant professor of Microbiology, created a vaccine against Lyme disease that they hope to bring to clinical trials. In March, Weissman and Scott Hensley, PhD, a professor of Microbiology, developed a vaccine to prevent avian flu virus H5N1. The results from that work were published in Nature Communications.  
Weissman and Atochina-Vasserman created a vaccine against norovirus, which they hope to bring to clinical trials.  The results from this work were published in the journal npj Vaccines. Weissman and Atochina-Vasserman are also leading research on tweaking the existing mRNA vaccine platform, specifically making the lipid nanoparticles out of a single component, in order to make mRNA vaccines even faster and easier to make. 
And most recently, Weissman and Mohamad-Gabriel Alameh, PhD, an assistant professor of Pathology and Laboratory Medicine, developed an mRNA vaccine that effectively prevents Clostridioides difficile (previously called Clostridium difficile and abbreviated C diff), an infection well-known for being difficult to treat and highly contagious. All attempts to make a vaccine against the bacteria had failed, Alameh said, including one developed and trialed by Pfizer just two years ago. However, none have used modified mRNA, he said. 
“C diff is difficult to treat because it lives outside the body (on the outer surface of the mucosa) and forms biofilms that protect it from antibiotics,” said Alameh. “Our approach was to create a tetravalent vaccine, or a vaccine that targets two of the toxins from the bacteria as well as two other factors that allow it to thrive. That kind of vaccine is easier to make using an mRNA platform.” The results of the research were published in Science. 
With the goal of bringing the latest RNA developments to a broad scientific community and an investment by the National Science Foundation (NSF) of $18 million, the Penn Institute for RNA Innovation is now part of the NSF’s Artificial Intelligence-driven RNA Foundry, which will manufacture RNA and use AI to do it. The initiative aligns researchers from Penn Engineering, the Institute, the University of Puerto Rico–Mayagüez (UPR-M), Drexel University, and Children’s Hospital of Philadelphia (CHOP). Not only will RNA be made for research purposes, but leaders will use AI to help design better particles and research and make predictions on what approaches might yield the best results.  
Not only can modified mRNA be used to prevent infectious diseases, but Weissman and colleagues are figuring out ways it could prevent and even treat cancerous tumors. When tumors develop in the body, surrounding them are small extracellular vesicles (sEVs) that block the body’s natural defenders or drugs that attack tumors. In new research published in Nature Materials in September, Weissman, along with Michael Mitchell, PhD, an associate professor of Bioengineering at Penn’s School of Engineering, and Wei Guo, PhD, the Hirsch Family President’s Distinguished Professor in the Penn School of Arts and Sciences, found that a particular mRNA concoction, which includes specific gene-interfering RNA, can lower the tumor’s defenses. If these results hold true in animal and human trials, oncologists’ cancer treatments could be more likely to destroy tumors. 
Humans aren’t the only species that can benefit from mRNA vaccines. Penn Vet proudly announced its mRNA Research Initiative, a partnership with the Penn Institute for RNA Innovation. One of its key elements is to develop a pipeline to test the immunologic response of mRNA vaccines in swine and poultry. Understanding how mRNA vaccines can keep animals healthy, especially those on which humans depend for food, and creating veterinary mRNA vaccines, like the one developed by Weissman and Hensley, could prevent animal pandemics and viruses being passed from animals to humans.  
Another aspect of the Initiative is a basic science investigation into ways to make mRNA vaccines generate better immune responses within barrier tissues like the skin, lungs, and intestines.  
Near Weissman’s office are shelves that house the beautiful, unique trophies from too many awards to count and an official replica of his Nobel medal.  But surrounding the lab benches and tacked to the walls of the lab are personal messages of thanks. Some are letters from people who say the COVID vaccine saved their lives and the lives of their loved ones. Some are thank-you drawings from kids. All of them are reminders that scientific work done in a lab has an unbridled potential to benefit real people. 
And in the shadow of all those letters of thanks, the work continues.