2023 Nobel Prize in Physiology or Medicine In-Depth Analysis

News

2023 Nobel Prize in Physiology or Medicine In-Depth Analysis

Major Announcement! 2023 Nobel Prize in Physiology or Medicine In-Depth Analysis.

October 2, 2023 – The results of the 2023 Nobel Prize in Physiology or Medicine were announced.

This year, Katalin Karikó and Drew Weissman have been awarded for their groundbreaking discoveries in nucleoside modification, which made the development of effective mRNA vaccines against COVID-19 possible.

2023 Nobel Prize in Physiology or Medicine In-Depth Analysis

The Nobel Prize website provides an introduction to the research achievements of Katalin Karikó and Drew Weissman:

“The discoveries of the two Nobel laureates were crucial in the development of effective mRNA vaccines to prevent COVID-19 during the pandemic that began in early 2020. Their groundbreaking findings fundamentally changed our understanding of how mRNA interacts with the immune system. Thus, in a time when modern human health faced one of its greatest threats, these two Nobel laureates made a significant contribution to the rapid development of vaccines.”

Vaccines Before the Pandemic

Vaccination stimulates the body to form an immune response against specific pathogens, allowing the body to fend off the pathogen when exposed later. Vaccines based on inactivated or attenuated viruses, such as the polio vaccine, measles vaccine, and yellow fever vaccine, have long been in use. In 1951, Max Theiler received the Nobel Prize in Physiology or Medicine for developing the yellow fever vaccine.

In recent decades, advances in molecular biology have led to the development of vaccines based on individual viral components rather than the whole virus. Portions of the viral genetic code, typically encoding viral surface proteins, are used to manufacture proteins that stimulate the production of antibodies against the virus. Vaccines for hepatitis B and human papillomavirus are examples.

Another approach involves transferring portions of the viral genetic code to harmless viral vectors. This method is employed in the development of the Ebola virus vaccine. When the vector vaccine is administered, selected viral proteins are produced within cells, eliciting an immune response against the target virus.

Production of whole virus, protein, and vector vaccines requires large-scale cell culture, a resource-intensive process that limits the rapid production of vaccines in response to disease outbreaks and pandemics. Researchers have long sought to develop vaccine technologies independent of cell culture, which has proven to be a challenging task.

2023 Nobel Prize in Physiology or Medicine In-Depth Analysis

Figure 1. Pre-COVID-19 pandemic vaccine production methods

mRNA Vaccines: A Promising Idea

In our cells, the genetic information encoded in DNA is transcribed into messenger RNA (mRNA), which serves as a template for protein production. An effective method for producing mRNA without the need for cell culture, known as in vitro transcription, was proposed in the 1980s, marking a pivotal step in the advancement of molecular biology in various fields. The idea of using mRNA technology for vaccines and therapies also emerged but faced obstacles.

mRNA produced via in vitro transcription is unstable and difficult to deliver, requiring the development of complex lipid carriers to encapsulate the mRNA. Additionally, in vitro-produced mRNA can trigger an inflammatory response. As a result, enthusiasm for developing mRNA technology for clinical use was initially limited.

These challenges did not deter Hungarian biochemist Katalin Karikó, who was dedicated to developing mRNA therapies. In the early 1990s, while serving as an assistant professor at the University of Pennsylvania, she persevered despite struggling to convince research funders of the significance of her project: realizing mRNA therapy.

Karikó’s new colleague at the university was immunologist Drew Weissman, who was interested in dendritic cells, critical for immune surveillance and the induction of immune responses by vaccines. With the impetus of a new idea, the two quickly began collaborating, focusing on how different types of RNA interacted with the immune system.

The Breakthrough

Karikó and Weissman noticed that dendritic cells recognized mRNA transcribed in the extracellular environment as foreign material, leading to the activation of dendritic cells and the release of inflammatory signaling factors. They were puzzled as to why extracellularly transcribed mRNA was recognized by dendritic cells, while mammalian cell-transcribed mRNA did not trigger the same response. Karikó and Weissman realized that dendritic cells must rely on specific features to distinguish between different types of mRNA.

RNA is composed of four bases abbreviated as A, U, C, and G, while the genetic code carrier DNA is composed of four bases abbreviated as A, T, C, and G. Karikó and Weissman knew that RNA nucleotides in mammalian cells often carried chemical modifications, whereas extracellularly transcribed mRNA did not. They were also surprised that the absence of base modifications in extracellularly transcribed mRNA could explain unexpected inflammatory reactions.

To investigate this, they synthesized various types of mRNA, each with unique modifications on the bases, and delivered these mRNAs to dendritic cells. The results were astonishing: when base modifications were introduced into the mRNA, inflammatory reactions almost disappeared. This discovery changed our conventional understanding of how cells recognize and respond to different types of mRNA.

Karikó and Weissman soon realized that their findings would have a significant impact on mRNA therapy, and their groundbreaking research, of great significance, was published in 2005, 15 years before the COVID-19 pandemic.

2023 Nobel Prize in Physiology or Medicine In-Depth Analysis

Figure 2. mRNA contains four different bases, abbreviated as A, U, G, and C. The Nobel Prize winner discovered that nucleoside base-modified mRNA can be used to block the activation of the inflammatory response (secretion of signaling molecules) and increase protein synthesis when the mRNA is delivered to cells.

In subsequent studies published in 2008 and 2010, Karikó and Weissman elucidated that base-modified mRNA, compared to unmodified mRNA, significantly increased protein synthesis. This effect was attributed to reduced activation of enzymes that regulate protein synthesis. Through these findings, namely that base modification could simultaneously reduce inflammation and increase protein synthesis, Karikó and Weissman overcame key barriers in the clinical application of mRNA.

Unleashing the Potential of mRNA Vaccines

Interest in mRNA technology began to heat up, and in 2010, several companies started developing this therapy, focusing on vaccines against the Zika virus and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), closely related to SARS-CoV-2.

Following the outbreak of COVID-19, two base-modified mRNA vaccines encoding the surface protein of SARS-CoV-2 were developed at a record pace. Reports indicate their efficacy to be approximately 95%, and these vaccines were granted approval as early as December 2020.

The flexibility and speed with which mRNA vaccines were developed have been impressive, paving the way for the use of this new platform in the development of vaccines for other infectious diseases. In the future, this technology can also be employed for delivering therapeutic proteins and treating certain types of cancer.

Several other SARS-CoV-2 vaccines based on different approaches were swiftly introduced, and over 13 billion COVID-19 vaccine doses have been administered globally.

These vaccines have saved millions of lives, prevented more severe diseases, and allowed societies to reopen and return to a semblance of normalcy.

This year’s Nobel laureates, through their fundamental discovery of the importance of base modification in mRNA, made a significant contribution to this transformative development during one of the greatest health crises of our era.