Nobel Prize lecture: Drew Weissman, Nobel Prize in Physiology or Medicine 2023

The speaker introduces Dr. Drew Weissman, a Nobel laureate in physiology and medicine, highlighting his academic and professional journey. Born in Lexington, Massachusetts, Dr. Weissman obtained his MD and PhD from Boston University and completed his clinical training at Beth Israel Deaconess Medical Center at Harvard Medical School. His postdoctoral work was conducted at the National Institutes of Health with Dr. Anthony Fauci. In 1997, he joined the Perelman School of Medicine at the University of Pennsylvania, where he became a prominent figure in vaccine development. The speaker also shares an anecdote about Dr. Weissman's wife humorously referring to his late-night lab work as 'saving the world,' foreshadowing his significant contributions to the field.

This paragraph delves into the development of mRNA vaccines, focusing on their ability to elicit a robust immune response. The speaker discusses the history of vaccine technology, from live attenuated viruses to modern mRNA platforms. A pivotal moment in the development of mRNA vaccines was the discovery that encoding the hemagglutinin protein of influenza into mRNA and immunizing animals resulted in extraordinarily high neutralizing titers, far surpassing traditional vaccines. The speaker also explains the role of B cells and T follicular helper (Tfh) cells in the immune response, particularly the importance of germinal centers in producing long-lived plasma cells and memory B cells. The paragraph concludes with the revelation that the lipid nanoparticles (LNPs) used in mRNA vaccines act as an adjuvant, stimulating the immune system without the need for traditional antigen activity.

The speaker explores the concept of a universal influenza vaccine, which aims to provide long-lasting protection against various strains of the virus. They discuss the challenges of creating vaccines against a virus that mutates frequently and the need for annual updates. The paragraph details an experiment where animals were immunized with an mRNA vaccine encoding an H1 hemagglutinin and then challenged with a distant H5 strain, demonstrating complete protection. This suggests the potential for a vaccine that could offer immunity against a wide range of influenza strains. The speaker also addresses the importance of neutralizing antibodies and the surprising discovery that the mRNA vaccine induced a high number of antigen-specific plasma cells in the bone marrow, indicating long-term immunity.

This section investigates the underlying mechanism of mRNA vaccines, particularly the role of T follicular helper cells (Tfh) in generating a strong antibody response. The speaker describes an experiment using a monkey model to measure antigen-specific Tfh cells, revealing that mRNA vaccines induce a significantly higher proportion of Tfh cells compared to other types of vaccines. The paragraph also discusses the role of cytokines, such as IL-6, in stimulating Tfh cells and the importance of LNPs as an adjuvant in mRNA vaccines. The findings suggest that the unique formulation of mRNA vaccines, including the LNPs, contributes to their exceptional immunogenicity.

The speaker discusses the potential of mRNA vaccines to target a wide range of diseases and conditions. They describe the development of a vaccine containing multiple hemagglutinin types from different influenza strains, which was surprisingly effective in eliciting equal antibody responses to all antigens. This discovery challenges the conventional wisdom of antigen dominance in multicomponent vaccines and opens up new possibilities for vaccine design. The speaker also contemplates the future of vaccination, suggesting that a single mRNA vaccine could potentially replace multiple childhood vaccinations, simplifying immunization schedules and reducing the burden on healthcare systems.

This paragraph explores the customization of mRNA vaccines to elicit specific types of immune responses. The speaker discusses the differences between vaccines using modified and unmodified mRNA, particularly in the context of cancer vaccines. They highlight the importance of targeting T cells and the potential of combining mRNA vaccines with cytokine agents, such as IL-12, to enhance T cell responses. The speaker also describes experiments that demonstrate the ability to increase both antibody and T cell responses by modifying the vaccine composition, offering a promising avenue for developing more effective vaccines against various diseases, including cancer.

The speaker introduces the concept of targeting specific cell types with mRNA therapeutics, overcoming the limitation of lipid nanoparticles primarily targeting the liver and dendritic cells. They describe a method for attaching targeting molecules to the surface of LNPs, enabling the delivery of mRNA to a variety of cells and tissues, such as the heart, brain, and lungs. The paragraph also discusses the potential of this technology to modify immune cells, such as T cells, to perform various functions, including acting as a vaccine, delivering cytokines, or targeting tumor cells. The speaker emphasizes the broad applicability of this targeting technology to a wide range of therapeutic applications.

This section discusses the application of in vivo gene editing using mRNA therapeutics, particularly for targeting HIV latency in resting CD4+ T cells. The speaker describes a method known as the 'Cre-LoxP' system, which allows for the activation of a fluorescent protein in cells after the delivery of Cre recombinase mRNA. They present data showing high levels of gene recombination in both spleen and lymph nodes, indicating the potential for mRNA therapeutics to target and edit genes within specific cell types in vivo. The speaker also touches on the broader implications of this technology for treating other diseases, including genetic disorders and cancer.

The speaker explores the potential of mRNA therapeutics to revolutionize CAR T-cell therapy, a treatment that currently requires complex and costly procedures. They propose a method for creating CAR T-cells in vivo by targeting LNPs carrying CAR molecules to T cells, allowing the cells to take up the mRNA and express the CAR on their surface. The paragraph presents preliminary data showing the restoration of heart function in a mouse model of cardiac fibrosis, suggesting that a single injection of mRNA could potentially replace the need for CAR T-cell therapy. The speaker also discusses the broader implications of this approach for treating a variety of diseases, including the possibility of off-the-shelf drugs for conditions like heart disease.

The speaker discusses the potential of mRNA therapeutics to treat genetic diseases of the bone marrow, such as sickle cell anemia, by targeting and editing the genes of bone marrow stem cells. They describe an experiment using LNPs targeted to CD17 or c-kit, which were able to efficiently deliver mRNA to a high percentage of bone marrow stem cells in mice. The paragraph presents data showing long-term gene editing in the bone marrow, with the potential for a single treatment to cure diseases that currently require expensive and complex gene therapies. The speaker also contemplates the broader applications of this technology for treating other diseases and conditions, emphasizing the transformative potential of mRNA therapeutics.

In the concluding paragraph, the speaker reflects on the vast potential of RNA therapeutics for a wide range of applications, from vaccines and genetic diseases to therapeutic protein delivery. They highlight the ability to target various cells and tissues, including the brain, heart, and immune cells, and the potential for in vivo gene editing. The speaker expresses optimism about the future of RNA therapeutics and acknowledges the contributions of their team and collaborators in advancing this field. They also encourage their lab members to continue exploring the many possibilities that RNA therapeutics has to offer.