Live Blogger: Matthew Blacksmith
Editors: Sadie Schaus and Ryan Schildcrout
This piece was written live during the 8th annual RNA Symposium, “Unmasking the Power of RNA: From Structure to Medicine” hosted by the University of Michigan’s Center for RNA Biomedicine. Follow MiSciWriters’ coverage of this event on Twitter with the hashtag #umichrna.
What do measles, the flu, and most recently, COVID-19 have in common? Each of these viruses has vaccines which have been developed to prevent infection, reduce the severity of symptoms, and promote faster recovery. So what are vaccines and how do they work? The answer varies from vaccine to vaccine. Historically, vaccines have been created by weakening or outright killing viruses before injecting them into patients to expose them to viral proteins. Once injected, the body attacks the virus, priming the immune system for a later date where you’re exposed to the virus at full strength. However, the process of creating a vaccine from a weakened virus can be long and difficult. Fortunately, scientists have been hard at work trying to create vaccines which are as effective as the current vaccine standard, but can be produced more quickly in response to global needs.
For a long time this work fell below public notice, but was thrust into the spotlight during the COVID-19 pandemic. If you’ve heard of Moderna or Pfizer’s COVID-19 vaccines, then you are familiar with the new class of vaccines which have been referred to as “mRNA vaccines.” These vaccines are fundamentally different from older vaccines in that they contain a lipid nanoparticle that surrounds messenger RNA (mRNA) that can be used to make viral proteins without the need for full viruses.
mRNAs are biological molecules which encode information for making proteins. Our bodies also produce mRNAs and our cells use this information to create proteins which are indispensable for our bodies working properly. In the case of mRNA vaccines, the viral proteins encoded by the mRNA are then produced within the body to prepare the immune system to fight against the virus if you’re infected later on. Lipid nanoparticles can be thought of as a biological capsule which carries the mRNA to the cells of the immune system. Without a lipid nanoparticle, cells do not efficiently take up the mRNA.
Enter Dr. Drew Weissman and his research group, who have been working to develop and test mRNA derived vaccines. Dr. Weissman began his talk by noting that when speaking with non-scientists, people will frequently mention a concern that the COVID-19 vaccine was created in a mere 10 months. This is ultimately a misconception where people are unaware of the amount of time and effort that went into these vaccines. So today, he delved into the history of his work with vaccines, lipid nanoparticles, modified mRNA, and where the research is heading in the future.
For Dr. Weissman, much of his time as a young faculty member at the University of Pennsylvania was spent at the Xerox machine printing off scientific literature or waiting in line while others printed papers for themselves. It was here that he met Dr. Katalin Karikó, who would become a long time collaborator, and fellow awardee of the Nobel Prize in Physiology or Medicine in 2023. Today’s retrospective began with an observation – when RNAs are introduced to dendritic cells (a specialized cell within the immune system), the immune system is activated. This helps our cells eliminate foreign mRNAs which have entered the body before they can be translated and cause harm. However, desirable RNA therapies would undergo the same fate which limits how useful RNA-based therapeutics could become. However, when testing different classes of RNAs for immunogenic properties, it was revealed that a class of RNAs called transfer RNAs showed reduced ability to activate dendritic cells. A potential cause of the non-immunogenic properties of transfer RNAs is that they possess a naturally occurring chemical modification in which some uridines, one of the four building blocks that comprise RNA, are converted into pseudouridine. When previously immunogenic RNAs were modified to contain pseudouridine in place of uridine, the dendritic cells were no longer strongly activated upon exposure. Additionally, the pseudouridine containing RNAs were used by the cells to faithfully produce proteins.
This realization would have profound implications. Protein-based therapies can be difficult to produce and often have to be grown in vats of cells in giant tanks located within facilities. These facilities are expensive to run and require generating the proteins outside of the body before using them as therapies. However, if mRNA therapies can be created, the patient’s cells can be used to create the proteins themselves, allowing for therapies to bypass the need to generate proteins outside of the body. Additionally, proteins are rapidly cleared out of the body upon injection. This reduces the amount of time that the immune system can spend preparing itself for future viral invaders. By contrast, as shown in experiments studying influenza in mice, proteins that are made from mRNA that was injected can be readily found for 10-14 days after injection. This gives the body much more time to activate the immune system.
Just because protein is being made within the host doesn’t mean that the immune system is ready to attack it. To verify if injected mice were actually protected from influenza, several confirmation experiments were performed. One experiment looked at antibody production. Antibodies are produced by the immune system as it prepares to fight an infection, and the immune system “remembers” how to create these so that similar infections can be fought again later if necessary. Mice injected with influenza mRNA vaccines had a 50 times stronger immune response as compared to vaccines containing dead viruses. Additionally, mice injected with an mRNA vaccine against influenza were protected not just from the same strain of influenza that the mRNA vaccine was designed to protect against, but were also partially protected against another subtype of influenza. If this result is translatable to humans, it could represent a major breakthrough which reduces the need for annual flu shots and replaces them with a single vaccine with protection lasting multiple years. While this vaccine is not yet ready for testing in humans, it shows promise for developing vaccines which protect from a wide array of influenza strains. Dr. Weissman’s group and others are working to generate mRNA vaccines for a host of other diseases including malaria.
Moving forward, mRNA technology may allow us to look beyond disease prevention and towards treating other conditions. But to do so, scientists had a new problem to overcome. Is it possible to target the lipid nanoparticle to specific cell types? Throughout the body different types of cells are designed to interact with different molecules. One way that they are able to do this is through receptors on the outside of the cell that bind to specific molecules (called ligands). In this way, ligands and their receptors can be thought of as locks and keys. Ligands which attach to cells of interest can be placed on the outside of the lipid nanoparticle to enable specific binding of nanoparticles to cells. Once the lipid nanoparticle is bound to its target cell, it can be pulled into the cell where the mRNA treatment can be released. For instance, in human patients, the medical impact of stroke is made worse by brain inflammation in the days following the stroke. Injecting a lipid nanoparticle with an mRNA encoding an anti-inflammatory protein was able to reduce inflammation in the mouse brain. This suggests that mRNA treatments, when administered encapsulated in lipid nanoparticles, have the potential for reducing stroke severity. So far, lipid nanoparticles have been able to target cells in the brain, lungs, and immune system and are showing great promise in someday being used for conditions such as treating cancer, allergies, and autoimmune conditions.
In summary, while mRNA vaccines feel like they only recently entered public consciousness, scientists like Dr. Weissman have been working on the foundation that enabled RNA vaccines for decades. Incremental steps taken to develop these technologies include placing RNA in a lipid nanoparticle, replacing uridine with pseudouridine, and targeting lipid nanoparticles to specific cell types. mRNA treatments offer several advantages over protein based therapies. mRNA therapies bypass the need for producing proteins outside of the body, and instead allow patients to produce required proteins themselves in the relevant parts of the body.
mRNA vaccines have already proven to be advantageous during the COVID-19 pandemic where a new vaccine was needed quickly, and shows promise for other contagious diseases such as influenza, where animal testing suggests that mRNA vaccines can protect against multiple disease subtypes. Furthermore, this technology is currently being tested for effectiveness against many other conditions including reducing brain swelling after strokes and may potentially be able to be leveraged for treating cancer, allergies, and autoimmune conditions.
Dr. Drew Weissman earned a B.A. and M.A. from Brandeis University before earning an M.D. and Ph.D. from Boston University in 1987. He next completed a residency in medicine at Beth Israel Hospital in Boston, Massachusetts. He then spent time as an allergy and immunology fellow and subsequently allergy and infectious diseases fellow at the National Institutes of Health. In 1997, he was appointed as an Assistant Professor of Medicine at the University of Pennsylvania School of Medicine; where he has risen to Professor of Medicine and ultimately received the Roberts Family Professor in Vaccine Research endowment from the University of Pennsylvania School of Medicine. He has held or still holds appointments at the Chulalongkorn University as a Professor, at Philadelphia Veterans Administration Medical Center as an attending physician, and as the Director at the Institute for RNA Innovation at the University of Pennsylvania. His work has been highly influential in developing vaccines using mRNA encased in a lipid nanoparticle. Dr. Weissman is a highly decorated scientist who in 2023 won the Nobel Prize in Physiology or Medicine with Dr. Katalin Karikó. For more information feel free to view his University of Pennsylvania faculty page.
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