Thomas R. Cech (2024) 'The Catalyst: RNA and the Quest to Unlock Life's Deepest Secrets'

Thomas R. Cech is the discoverer of the enzymatic properties of RNA for which he was awarded the Nobel prize in 1989.

Thomas R. Cech (2024)
'The Catalyst'

The title of his book 'The catalyst' refers to the enzymatic properties of RNA. An enzym is a biological catalyst. A catalyst is a substance that increases the rate of a chemical reaction. An important goal of this book is explaining how the 'dogma' ALL ENZYMES ARE PROTEINS was overthrown by himself and subsequently by others. That dogma was the textbook truth at the time when he made his discovery. No exceptions to the rule were known at the time. Indeed, after the discovery of DNA and the establishment of the 'CENTRAL DOGMA OF MOLECULAR BIOLOGY', it was generally accepted that RNA was the messenger that carried genetic information from DNA to the site in the cell where protein synthesis takes place. That was the function of RNA: a messenger. Hence its name messenger-RNA or mRNA. Both dogmas were powerful [3]. They determined which kind of research was done, which research questions were asked and how results were interpreted. Even today one reads in the Wikipedia article Catalysis: "In biology, enzymes are protein-based catalysts". Later the name ribozyme was coined for enzymatic RNA's (enzymatic Ribonucleic acids).

His own discovery is told in chapter 3. The rest of the book is about other discoveries about RNA. Cech explains that the dogma ALL ENZYMES ARE PROTEINS [4] led scientists astray and hindered progress in biology more than once. But first his own discovery. When doing experiments with RNA, Cech himself assumed that splicing out introns from mRNA was being catalyzed by protein enzymes (the power of the received wisdom!). Frustratingly, finding that particular splicing enzym failed. Confusingly, several experiments showed that splicing occurred without protein enzymes. Afraid of making an unforgivable mistake, Cech repeated his experiments in order to be 100% sure that there was no protein contamination in his test tubes. Finally, many experiments later, in 1982, he was convinced that he discovered a self-splicing intron in a RNA sequence and published it [1].

structure of self-splicing intron (wikipedia)

Another example of the powerful influence of the ALL ENZYMES ARE PROTEINS dogma, occurred in the lab of Sidney Altman. A control experiment in Altman's lab was supposed to produce negative results because the sample contained no proteins, but only RNA. Mysteriously, the control did produce positive results! The enzymatic activity had to be attributed to RNA, not to protein. Again enzymatic RNA. So, Altman independently discovered a different enzymatic RNA and shared the Nobel prize in Chemistry with Thomas Cech in1989.

A third example (Chapter 5 The Mothership) of the refutation of the dogma is the ribosome machine which is enormously complex and made of proteins and ribosomal RNAs (rRNA). The ribosome is the site where proteins are produced. Naturally, when scientists started to investigate the structure and function of the ribosome, they assumed enzymatic proteins must do the job. However, things turned out differently. It appeared to be the ribosomal RNA, not one of the ribosomal proteins, that did the job of binding tRNAs. Chapter 4 was, unexpectedly, a pleasure to read and I learned a lot new and interesting facts.

A fourth example of enzymatic role of RNA is telomerase (Chapter 7). Telomerase is a complex molecule constructed of both RNA and proteins. According to the standard view proteins are the active enzymatic part. Contrary to the expectations, it appeared that Telomerase activity was destroyed by RNAse (Ribonuclease) treatment. Conclusion: Telomerase activity appeared to require RNA. "So now RNA had been found at the heart of yet another critical life process – building out chromosome ends to secure the integrity of the genome."  Another exception to the law ALL ENZYMES ARE PROTEINS.

There are many more interesting insights and facts about RNA, some of them breakthrough discoveries that were awarded the Nobel Prize [2]. Cech typically describes how discoveries are made and which scientists were involved. However, I will now focus on the long history of mRNA covid19 vaccines as I promised in my previous blog. 

 

Covid-19 vaccines

In Chapter 10 Cech tells how fundamental RNA research prepared the way for mRNA vaccines. There are two different ways to produce proteins in cells of a person: by DNA or by RNA. DNA-vaccins were already being developed. The disadvantage of DNA vaccines: DNA could incorporate into our chromosomes and that is something you don't want to happen. Another disadvantage of DNA vaccines is that one doesn't need permanent production of those proteins. Only a short period is enough for the immune system. The advantage of a mRNA vaccine is that it is not a permanent modification of our DNA. The mRNA cannot by its very nature be incorporated in DNA. The scientific principle underlying all these mRNA therapeutics is simple: in every case where a protein is needed to stimulate the immune system or to replace a missing or mutated protein, it seems possible to use the corresponding mRNA instead to instruct our bodies to make that protein. 

Cech emphasizes that mRNA is not a secret military invention that was used to repress the people or things like that. RNA, just as DNA, is in every living cell on earth. RNA is as old, and likely older than life itself (RNA-world). The only thing that is foreign to the human body is the viral Spike protein which is encoded in the RNA. In this case RNA is only the messenger. The original Spike protein is located on the outside of the SARS-CoV-2 virus. It is recognized by the human immune system. By including the genetic code for the Spike protein in an mRNA and letting our own cells decode the mRNA and produce Spike proteins, the immune system is prepared for attacking the real SARS-CoV-2 virus. It is better and safer to introduce only a foreign protein, than the complete but weakened SARS-CoV-2 virus. To introduce a harmless protein in our bodies instead of the whole virus, that's the whole idea of this vaccination. And the mRNA method is a smart way to do it.

However, making a vaccine out of RNA is not that simple. Nobody had done it before. There were many technical obstacles. For example, how do you deliver the RNA? RNA on its own is unstable. Forty year ago using lipid membranes (liposomes) was challenging and unproven. But in 1989 it was shown for the first time that a foreign gene (mRNA) could be expressed in cells in Petri dishes. Subsequently, it was shown that this also worked in living animals. Other problems appeared, such as how to avoid that the body attacked the RNA before it could produce the protein [7]. Expert biochemical knowledge and creative thinking solved the problem. It was a breakthrough discovery and was awarded the Nobel prize [5]. This was before the SARS-CoV-2 pandemic in 2019 caught the world by surprise. In 2018 the RNA technique was successfully used in a clinical trial as a therapy for the hereditary disease ATTR. Cech writes: "It turned out that siRNA delivery would be a dress rehearsal for mRNA delivery a few years later." As soon as the pandemic started, and the DNA sequence of the SARS-CoV-2 virus was known, BioNTech (Germany) [6] and Moderna (USA) abruptly switched their research programs to covid-19 vaccines based on their new RNA techniques. Remaining scientific and technical difficulties were overcome. 

"In November 2020, the directors of Pfizer Inc. were waiting in nervous anticipation. They were about to hear the results of the clinical trial of the mRNA vaccine they were developing with BioNTech. As the vaccine's 95 percent efficacy rate was announced, a collective gasp arose--and then the group erupted with applause and shouts of triumph. The board had been hoping for at least 70 percent efficacy, which would have been a public health success. That would have put the Covid-19 vaccine between the influenza vaccine somewhere between the influenza (flu) vaccine (averaging 40 percent effective), with a year-to-year range of 10 to 60 percent) and the measles vaccine (97 percent effective). Ninety-five percent was beyond most expectations."

It is clear from this description that pharmaceutical companies neither carry out the clinical trials themselves, nor do they determine the outcome, nor do they give themselves the permission to bring their products on the market (if anyone thought this would be possible).

Thomas Cech: 

"It had taken 30 years for mRNA therapeutics to evolve from being generally disparaged -- "too unstable", "too difficult to get into cells", "too immunogenic"-- to being heralded as "A shot to save the world."

While writing this blogpost, an article appeared in Nature:

"Over the past few decades, RNA’s place in biology has transformed from being a mere intermediate between DNA and protein to a fascinating molecule with diverse activities that go well beyond simple transcription of genetic information." Nature 14 Nov 24

Indeed! It just shows that 'The Catalyst' appeared at the right moment!

 

About the book

This book was written by a scientist and Nobelist, not by a science journalist. Although science journalists do very good work, its a rare and welcome event that a Nobel prize winner takes the trouble to write a book. It results in a lack of unnecessary lengthy and distracting anecdotes. Yes, there are short anecdotal remarks, but they help to understand how science is done. For example Cech mentions how his first coworker and lab technician Art Zaug "has golden hands". Cech kindly and rightly includes him as a co-author of the publication that reported the discovery of self-splicing RNA [1]. The style of the book is factual and to-the-point without too many technical details, but enough to explain the science. The book was a pleasure to read. I consider it a good example of a successful popular science book. A basic knowledge of the relation between DNA, RNA and proteins is helpful. Again, it turned out to be true that writing a book review takes more time than reading the book! 

 

Notes

1. K Kruger, P J Grabowski, A J Zaug, J Sands, D E Gottschling, T R Cech (1982)
   Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena, Cell.
2. Nobel prize 2024 (MicroRNAs) (postranscriptional gene reguation) gives a good and detailed explanation (with illustrations)
   
3. The Central Dogma of molecular biology. (wikipedia)
   
4. the reverse "all proteins are enzymes" is not true, because there are non-enzymatic structural proteins.
5. The 2023 Nobel Prize in Physiology or Medicine was awarded jointly to Katalin Karikó and Drew Weissman for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19. (Press release of the The Nobel Committee, with a good explanation of the science). 
6. BioNTech was founded to develop RNA-based cancer immunotherapies.
7. But how does the immune system distinguish its own RNA from foreign RNA especially when it is a mRNA of a new virus? My initial question was: why is this an issue, since the mRNA is located inside a liposome? So, it should be invisible for the immune system. However, this is (partly) explained on the Nobel prize page: "This was a paradigm change in our understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman immediately understood that their discovery had profound significance for using mRNA as therapy. These seminal results were published in 2005, fifteen years before the COVID-19 pandemic." This shows again that the Covid-19 vaccins were not rushed to market.
   

Previous blogs

• Tast het corona vaccin je eigen DNA aan? (update) 12 April 2021
• ASTRAZENECA is een vreemd vaccin. De onnatuurlijke werking van een DNA vaccin. 24 April 2021

Personal note: I have been vaccinated with the BioNTech/Pfizer mRNA  vaccin (5x) and Moderna mRNA vaccin (2x). (The Netherlands). Between vaccination #6 and #7 I tested positive for Corona and had a few days symptoms of corona (coughing).