A Nobel Journey: Triumph over Adversity, Serendipity, BioNTech’s Rise, and mRNA Marvels

  • Katalin Karikó and Drew Weissman were awarded the 2023 Nobel Prize for Physiology or Medicine for pioneering the use of messenger RNA (mRNA) as a therapeutic tool for vaccines
  • mRNA translates genetic instructions from DNA to cellular machinery, driving essential protein synthesis in cell biology
  • Karikó and Weissman’s innovations led to the development of the first mRNA vaccine to combat the Covid-19 virus
  • Katalin Karikó overcame significant professional and personal setbacks before becoming a world-renowned scientist
  • Her life changed after a chance meeting with Weissman, which resulted in their ground-breaking contribution to biomedical science and the Nobel Prize
 
A Nobel Journey: Triumph over Adversity, Serendipity, BioNTech’s Rise, and mRNA Marvels
 
On Monday 2nd October 2023, Katalin Karikó and Drew Weissman were awarded the Nobel Prize in Physiology or Medicine for their contributions to messenger RNA (mRNA) biology that led to the unprecedented rate of vaccine development during the Covid-19 pandemic.
 
In this Commentary

This Commentary has four sections. In Part 1, Triumph over adversity, we highlight the journey of Katalin Karikó, which is a testament to her indomitable spirit. Despite facing entrenched prejudices and significant setbacks, Karikó's brilliance eventually triumphed, earning her the respect she deserved. As her work gained prominence, she emerged as a passionate advocate for women in science. Part 2, Serendipity, briefly describes a chance encounter between Karikó and Drew Weissman, which triggered a collaboration that defied the odds, and resulted in a major contribution to biomedical science that safeguarded the health and wellbeing of billions throughout the world and gained them the Nobel Prize. Part 3, “BioNTech doesn’t even have a website”, outlines the role played by a German start-up founded in 2008 by a husband-and-wife team, which leveraged Karikó's expertise and developed the first mRNA vaccine for the Covid-19 virus - a significant feat with global ramifications. The concluding Part 4, mRNA marvels, explains the science and describes the early contribution of Roger Kornberg, which enhanced our understanding of the molecular machinery that underpins mRNA’s functions. Also, we focus on how Karikó and Weissman championed the practical implications of mRNA for its use as a therapeutic. The combined endeavours advanced the field of molecular biology and opened unprecedented frontiers in both basic research and transformative therapeutic innovations. Takeaways follow.
 
Part 1

Triumph over adversity

Born in 1955 in a small town in central Hungary, Katalin Karikó grew up in a household devoid of running water, a refrigerator, or a television. From a young age she became fascinated with science, which led to her developing a passion for biology.
 
In 1982, she obtained a PhD from the University of Szeged, Hungary. Her research explored how mRNA could be used to target viruses: an innovative endeavour as gene therapy was in its infancy. Recognizing the therapeutic potential of mRNA, Karikó secured a postdoctoral position at the Biological Research Centre (BRC) of the Hungarian Academy of Sciences, where she embarked on a journey to advance her research.
 
At this time, Hungary was under Communist rule as part of the Eastern Bloc. The prevailing socio-political environment presented challenges for Karikó, which included glass ceilings that were obstacles for her scientific ambitions. After two years of research, her funding abruptly ceased: an illustration of the volatile and uncertain conditions she faced during those early years.
 
Buoyed by a boom in mRNA research taking place in the US, Karikó turned her gaze towards America and landed a research position at Temple University in Philadelphia. She sold her car, converted the proceeds into 900 British pounds on the Black Market, and sewed the currency into her two-year-old daughter's teddy bear to facilitate taking them out of Hungary. In the US in the late 1980s, she entered a male-dominated scientific community and encountered the prevalent gender biases and stereotypes: unequal opportunities, limited representation in leadership roles, and both subtle and overt discrimination.
 
In 1988, Karikó accepted a position at Johns Hopkins University in Baltimore without notifying Temple University. This prompted her sponsor to report her to the US immigration authorities, accusing her of being "illegally" in the country. After successfully challenging the resulting extradition order, Karikó faced another setback as Johns Hopkins withdrew her job offer. However, she secured a research position at the Uniformed Services University of the Health Services in Bethesda, Maryland.
 
A year later, in 1989, the University of Pennsylvania recognized her talent and hired her. Karikó dedicated her research to exploring the therapeutic potential of mRNA, envisioning its use to stimulate protein production within the human body. Her research faced scepticism during a time when synthetic mRNA applications for therapeutics were met with doubt. During clinical studies, the injection of mRNA-based therapies into animals triggered a severe inflammatory response, resulting in the death of the subjects, thereby eliminating any possibility of human trials.
 
Consequently, the excitement around mRNA as a therapy faded, and securing funding for such research became impossible. Karikó received multiple rejections from funding agencies. Her inability to raise research monies led the university in 1995 to suggest that she was "not of faculty quality" and presented her with an ultimatum: "leave or be demoted". This was a devastating and demeaning blow for Karikó who was on a tenured career path to become a full professor. She decided to accept an untenured position with a reduced salary and persevered in her research.

Even in the face of demotion and funding rejections, Karikó showed resilience. Overcoming doubts and questions from the scientific community is no small feat. It demands an unusual form of persistence and a deep belief in the value of one's research. She had to reconcile staying true to her visionary ideas and adapting to the feedback around her. What makes Karikó’s story even more remarkable is the personal adversity she faced. Amidst her professional challenges, her husband encountered visa problems, which obliged him to return to Hungary for six months. During this period, she was diagnosed with cancer, underwent two operations while simultaneously caring for her daughter and maintaining her research.
 
Part 2

Serendipity

Serendipity played a significant role in Karikó's scientific journey, as her fascination with mRNA had to endure a time when its potential was largely doubted by the scientific community. A critical turning point for her was a chance encounter with Drew Weissman, a senior professor of immunology at the University of Pennsylvania, who was well-endowed with research funds.
 
In the late 1990s, Karikó and Weissman bumped into each other at a photocopier. At that time, scientists copied the latest research from journals. Their meeting led to a recognition of a shared vision and complementary skills, and together, they pushed the boundaries of what was deemed possible. Their collaboration addressed challenges associated with using synthetic mRNA as a therapeutic tool. Weissman's expertise in immunology, combined with Karikó's focus on mRNA and protein synthesis, led to breakthroughs in modifying mRNA to reduce its inflammatory response and increase its stability.
 
In retrospect, Karikó's journey, coupled with her collaboration with Weissman, not only showcased scientific acumen but also emphasised the transformative potential of collaborative efforts in advancing the boundaries of knowledge. Their partnership became a catalyst for ground-breaking discoveries, particularly in the development of modified mRNA.
 
Part 3

“BioNTech doesn’t even have a website”

BioNTech, a German start-up founded in 2008 by a dynamic husband-and-wife team, Uğur Şahin and Özlem Türeci, was launched without a website but had a mission to disrupt healthcare. In 2013, Karikó accepted an invitation to join the company as a senior vice-president. When she told her University colleagues they are reported to have laughed at her saying that the company does not even have a website. Later Karikó and Weissman licenced the mRNA technology they developed to BioNTech, which later partnered with Moderna and Pfizer. BioNTech’s partnership with Pfizer, a giant pharmaceutical company experienced in vaccine development and distribution, led to a global clinical trial of Karikó and Weissman’s mRNA tool as a therapy, which involved >43,000 individuals across six countries. The joint venture became a linchpin in the fight against the Covid-19 virus. Today, BioNTech is a Nasdaq traded company with a market cap of ~US$23bn, annual revenues of >US$18bn, >4,500 employees and research centres in San Diego and Cambridge, Massachusetts.
  
Unknown to Karikó and Weissman, in 2005, Derrick Rossi, while a postdoctoral researcher in molecular biology at Stanford University in California was impressed with a paper they published describing a modified form of mRNA that did not induce an immune response. In 2010, Rossi, together with colleagues from Harvard and MIT, founded Moderna, which, between 2011 and 2017, raised US$2bn in venture capital funding and later formed its partnership with BioNTech. In the throes of the global Covid-19 pandemic, BioNTech emerged as a pioneer, developing the first authorized mRNA vaccine by leveraging Karikó and Weissman's mRNA technology. This breakthrough had a competitive edge over traditional vaccines because it offered a faster and more efficacious solution. In April 2020, as the world clamoured for a solution to the Covid-19 virus, Moderna secured a significant boost, receiving US$483m from the US Biomedical Advanced Research and Development Authority to fast-track its Covid-19 programme. Today, Moderna, based in Cambridge, Massachusetts, is a Nasdaq traded company with a market cap >US$30bn, annual revenues of ~US$20bn, and a workforce of ~4,000.
 
From a humble start without a website to shaping the future of medicine, the stories of BioNTech and Moderna exemplify the transformative power of scientific innovation and unwavering determination.
 
Part 4

mRNA marvels
 
The molecular messenger: mRNA
mRNA functions act like a postal service of the genetic world, which takes instructions from the DNA in the cell’s nucleus and delivers them to the protein-producing machinery called ribosomes in the cell’s cytoplasm [a jelly-like substance that fills the cells and surrounds the nucleus]. Think of it as a template that guides the creation of proteins in a process known as translation. So, mRNA is the messenger that ensures the right genetic instructions reach the protein-making machinery, which helps cells produce specific proteins needed for different tasks.
 
Importance of mRNA in protein synthesis
mRNA plays a crucial role in protein synthesis, serving as the intermediary that carries genetic instructions from DNA to the ribosomes. This process is significant for several reasons: mRNA transfers the genetic code from DNA to the ribosomes in the cytoplasm, ensuring the accurate transmission of instructions for protein synthesis. Each mRNA molecule corresponds to a specific protein, providing the specificity needed for the synthesis of diverse proteins with distinct functions. The regulation of mRNA production allows cells to control when and how much of a particular protein is synthesized, contributing to the adaptation of cellular processes. Proteins are essential for the structure, function, and regulation of cells. The diversity and specificity of proteins determine the many functions that cells can perform. Thus, mRNA acts as a messenger, translating the genetic information stored in DNA into functional proteins, thereby influencing all cellular activities and maintaining the integrity and functionality of living organisms.
 
The transcription process and the role of RNA polymerase II
Transcription is the first step in the flow of genetic information, where a segment of DNA is used as a template to synthesize a complementary RNA molecule. RNA polymerase II plays an important role in this process, particularly in the transcription of protein-coding genes. Let us give a brief overview. Transcription begins with the binding of RNA polymerase II to a specific region of DNA called the promoter. This signals the start of the gene to be transcribed. Once bound to the promoter, RNA polymerase II unwinds the DNA double helix and starts synthesizing an RNA molecule complementary to one of the DNA strands. As it progresses along the DNA, RNA polymerase II adds nucleotides to the emerging RNA chain, always extending it in the 5’ to 3’ direction. Transcription continues until the RNA polymerase II encounters a termination signal in the DNA. This signals the end of transcription, and the RNA polymerase II detaches from the DNA template. The newly synthesized RNA molecule, called pre-mRNA, undergoes processing steps like capping, splicing, and polyadenylation to form mature mRNA. These modifications enhance stability, functionality, and transport of the mRNA. RNA polymerase II is responsible for transcribing protein-coding genes (mRNA). It recognizes the promoter sequences of these genes and catalyses the synthesis of the complementary mRNA strand. The precision and regulation of this process are vital for ensuring accurate gene expression and the production of functional proteins in cells.
Science made easy

Importance of mRNA in protein synthesis
Think of mRNA as a messenger in the protein-making factory of your cells. It is like the delivery person that carries important instructions from the cell's recipe book (DNA) to the protein-making machines (ribosomes). Here is why this messenger - mRNA - is important: (i) Accurate Delivery: mRNA ensures that the instructions from the recipe book (DNA) are accurately delivered to the protein-making machines (ribosomes) in the cell's kitchen (cytoplasm). (ii) Specific Recipes: Each mRNA molecule has a specific recipe for a particular protein. This specificity is important because it helps in making different proteins with different jobs in the cell. (iii) Controlled Production: Cells can control when and how much of a protein is made by managing the production of mRNA. It is like having control over how often and how many times a specific recipe is used in the kitchen. And (iv) Cellular Teamwork: Proteins are like the workers in the cell - they build structures, carry out functions, and regulate processes. mRNA, by delivering the right protein recipes, ensures that the cell's team is diverse and has the skills needed for various tasks. So, mRNA is the messenger that translates the genetic information stored in DNA into practical instructions for making proteins. This process is like the secret sauce that keeps the cell running smoothly and maintains the overall health and function of living organisms.

The transcription process and the role of RNA polymerase II
Imagine your DNA is like a cookbook, and you want to make a specific recipe from it. Transcription is the first step in this cooking process. RNA polymerase II is like the chef who reads the recipe and makes a copy of it.  The chef (RNA polymerase II) starts by finding the beginning of the recipe, which is called the promoter. Then, s/he reads the instructions in the recipe (DNA) and creates a matching copy in the form of RNA. This copy, known as pre-mRNA, undergoes some additional steps to become the final recipe (mature mRNA). The chef follows the recipe precisely from start to finish, and when s/he reaches the end of the instructions or sees a "stop" sign (termination signal), s/he finishes the job. The final recipe (mature mRNA) is then ready to be used in the kitchen (cell) to make a delicious dish (functional protein). This whole process is crucial to ensure that the right recipes are selected and copied accurately, leading to the creation of the correct proteins needed for the cell's functions.
Synthetic mRNA
Beyond its natural role, synthetic mRNA acts as a vaccine, directing cells to produce specific viral proteins, prompting an immune response without inducing illness. Initially, challenges arose with unwanted inflammation caused by early versions of these genetic instructions. Katalin Karikó and Drew Weissman addressed this issue by making adjustments, preventing inflammation, and enhancing target protein production. This breakthrough laid the groundwork for vaccine development.
 
mRNA, Roger Kornberg, Katalin Karikó and Drew Weissman
We have described how mRNA serves as a critical messenger, shuttling genetic instructions from the cell's nucleus to the protein-building ribosomes. Now, let us briefly describe the contribution to the field of Roger Kornberg, an American biochemist who, in 2006, was awarded the Nobel Prize in Chemistry for his research on RNA polymerase II, the enzyme central to transcribing DNA into mRNA. In the video below Kornberg explains his research interest in how biological information, encoded in the human genome, is accessed to inform all human activity.
 

Kornberg's research went beyond simply decoding genetic information; he illuminated the intricacies of transcription - the process translating DNA into RNA. Specifically, his work dissected the structure of RNA polymerase II uncovering the nuances of how RNA polymerase II interacts with DNA during transcription. This detailed molecular blueprint is central to understand how genetic instructions in DNA are accurately transcribed into mRNA, which, as we described above, is a crucial step in the cellular flow of genetic information.
 
Katalin Karikó and Drew Weissman built upon Kornberg’s insights and spearheaded the application of mRNA for therapeutic purposes. While they championed the practical implications of mRNA, Kornberg’s contributions enhanced our understanding of the molecular machinery that underpins mRNA’s functions. Their combined endeavours advanced the field of molecular biology and opened unprecedented frontiers in both basic research and transformative therapeutic innovations.
 
Takeaways
 
This Commentary tells a story of science, resilience, serendipity, and a ground-breaking achievement. We described the scientific intricacies of mRNA, flagging Roger Kornberg's pioneering contributions. A testament to the triumph of the human spirit, portrayed Katalin Karikó's journey: her brilliance, overcoming prejudice and blossoming into advocacy for women in science. The unexpected collaboration between Karikó and Weissman, which led to a biomedical breakthrough that transcended expectations, ultimately garnering the Nobel Prize. We introduced BioNTech, where a husband-and-wife team harnessed Karikó and Weissman’s innovative research to pioneer the development of the world's first mRNA vaccine to combat the Covid-19 virus. This not only marked a historic moment in biomedical science but also exemplified the power of collaboration, determination, and visionary leadership. As we reflect on this journey - from the molecular intricacies of mRNA to the global impact of a life-saving vaccine - it becomes clear that the convergence of scientific curiosity, individual tenacity, and collaboration can be a catalyst for transformative change. The 2023 Nobel Prize for Physiology or Medicine awarded to Katalin Karikó and Drew Weissman stands as recognition of their central role in reshaping the landscape of biomedical science and, more importantly, in safeguarding the health and wellbeing of billions throughout the world. In scientific discovery, their story serves as an inspiring chapter, encouraging us to embrace the boundless possibilities that arise when science and humanity join forces in the pursuit of a healthier, more resilient future.

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