"The Catalyst
By Thomas R. Cech
Norton, 304 pages, $28.99
Initially dismissed as a wealthy and frivolous socialite, Charles Swann in Marcel Proust's "In Search of Lost Time" eventually transforms from a figure of minor significance to an important one. Were biology a novel, ribonucleic acid (RNA) would be the Charles Swann of living systems.
For decades the biological sciences barely acknowledged the existence of RNA, consigning it to relative obscurity. Researchers accepted that it performed some important functions -- messenger RNA, for instance, carries genetic information from the nucleus to the cell cytoplasm, while transfer RNA transports amino acids to the ribosomes that assemble them into proteins -- but it was not considered to be of general importance beyond these discreet cameo roles.
It was RNA's attention-seeking cousin, DNA, that long held center stage, bathing in celebrity indulgences while RNA skulked around uncomfortably and awkwardly in the shadowlands. And then suddenly, catching us all unaware, RNA stormed into the spotlight. It now appears as the apotheosis of everything essential to life, with an unexpected versatility and ubiquity.
In Thomas Cech's lively and entertaining "The Catalyst: RNA and the Quest to Unlock Life's Deepest Secrets," the Nobel laureate and professor of biochemistry describes the story of how RNA intersected with his own personal scientific journey, and recounts the important role he played in elevating this modest character to its rightful place within the pantheon of biological molecules. In the RNA renaissance he describes, the molecule emerges as both the colorful and mercurial protagonist of biology and as a "wondrous molecule of limitless possibilities." Mr. Cech, who has made it his mission to "demystify" this elusive molecule, counsels us to "never underestimate RNA."
DNA has been likened to the source code of a computer program, containing the basic chemical building material of genomes and encoding life's core information.
RNA performs its functions using a near-identical language. It is made in part from a sugar called ribose, whereas DNA uses deoxyribose. This is significant, we learn, as the extra oxygen atom incorporated into ribose "makes RNA chemically much less stable than DNA."
This inherent instability confers RNA with an ephemeral nature, enabling it to perform its regulatory and information-transfer functions.
While DNA is double stranded and locked into a double-helical structure, RNA contorts itself into a plethora of "origami-like shapes." This ability to generate a structurally diverse and stable repertoire of three-dimensional architectures allows RNA to function -- like proteins -- as the components of molecular machines. RNA is used, for example, to build the "mothership" ribosome machines that make "all the proteins in all living things."
While only 11/2 % of the human genome codes for proteins, we now know that almost all the rest of the genome, sometimes referred to as its "dark matter," acts as a template for the synthesis of special types of RNA molecules. These so-called long noncoding RNAs outnumber the protein-encoding genes and, we learn, appear to transact a diverse range of essential functions. Many of these relate to gene regulation, while others are still being discovered. The agency of long noncoding RNA molecules explains in part how near-identical gene kits are able to produce organisms as different as, say, a human and a mouse, or a fish and a fly.
Perhaps most striking is how Mr. Cech demonstrates that nearly all the key RNA discoveries of the past have been the product of curiosity-driven research on esoteric species. The examination of Tetrahymena thermophila, found in pond scum and shaped like a "miniscule watermelon," for instance, led to the discovery in 1982, by Mr. Cech and his colleagues at the University of Colorado Boulder, that some RNAs have enzyme-like functions once thought to be the exclusive domain of proteins. Such catalytic RNAs, with dual informational and structural functions, known as ribozymes, may have played a key role in the origin of life. They also, among other things, allow genes to be cut and spliced, in a process known as alternative splicing, that diversifies the genome's information content.
There is a hidden treasure trove of useful biology residing within the genomes of even the humblest species. The study of a transparent worm barely 1 millimeter long, for example, led to the discovery of the phenomenon of RNA interference, which has been harnessed to therapeutically silence genes.
The unassuming bacteria E. coli, similarly, led to the discovery of the Crispr system that has since been used to develop techniques for gene editing and manipulating gene expression for therapeutic purposes. Who would have imagined that the apparently insignificant microscopic bacteria living in, on and all around us would have played such a pivotal role in unlocking the secret of how to engineer human genomes and alter their regulation?
Mr. Cech wistfully reminds us of the importance of preserving life's biodiversity, as "yet-to-be-discovered RNAs" are likely lurking within their genomes and have the potential to unlock new opportunities. He reminds us that "the biggest breakthroughs in biomedicine almost always come from fundamental research that's being done to understand how nature works, without any medical application in mind."
The author also teaches us some of the trade secrets of successful scientists, demonstrating, for example, the importance of selecting the right model systems. The discovery of telomerase would not have been possible were it not for the decision to study Oxytricha nova, another pond-scum species, which has tens of millions of chromosomes.
In this "educated citizen's guide" to this intriguing molecule, the machinations of RNA emerge as a core feature of what makes us human. We appear to be at the beginning of a conceptual enlightenment in biology -- an "age of RNA," as Mr. Cech calls it. Biology will never be the same.
Mr. Woolfson is the author of "An Intelligent Person's Guide to Genetics."" [1]
1. The RNA Renaissance. Woolfson, Adrian. Wall Street Journal, Eastern edition; New York, N.Y.. 06 June 2024: A.15.
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