Foreword to the Fourth Edition

Fifteen years ago (2006) the 3rd Edition (3E) of Nucleic Acids in Chemistry and Biology was published by the Royal Society of Chemistry. In the decade and a half since then, one could expect that there might have been only a few new developments in this field and that only perhaps brief addendums to 3E should have been necessary. This is far from the case: One can only marvel at how far the chemistry and biology of the nucleic acids has progressed during these intervening years, above all in the RNA world. Consequently, it is most refreshing to have a dramatically updated 4th Edition (4E). In particular, what makes each chapter worth a serious and rewarding read is how the authors present their topics in a uniform style from start to finish. In each chapter, the first section opens much like an introductory, undergraduate textbook. After that brief start, the development of each topic is intensely focused on many new advances up to the present, including superb full-colour illustrations, and concludes with a section speculating on future developments. Such a format leads the reader to seriously want this book not only as a guide for future research but also as a reference for classrooms, manuscript preparation and lectures.

It is important for the first chapter of a major book to grab your attention, to be informative, and also to be entertaining. This is the case for Nucleic Acids in Chemistry and Biology 4E. The first chapter launches by describing the rich history surrounding the discovery that nucleic acids are the hereditary molecules of life. I find its narrative to be exciting. Starting with Friedrich Miescher's 1868 discovery of a substance he called nuclein and through further research over the ensuing decades, that was fortified by the key experiments of Avery in 1944, we now know that nuclein is the inheritable molecule of life, which, after a complex history, became known as deoxyribonucleic acid (DNA). In this opening chapter, the story of the nucleic acids field is displayed in all its glory from Miescher onwards to span 150 years to the present time. The editors of this book themselves cover three generations of research activity. Their experience ranges from first-hand apprehension of many of the important discoveries in the nucleic acids field – the Watson–Crick structure of DNA, Sanger's development of RNA and DNA sequencing methodologies and other initial, important discoveries in molecular biology associated with the DNA–RNA–protein scientific dogma – to the current applications of nucleic acids in medicine. This background leads to a very encompassing chapter that, for me, was one of the most entertaining and important highlights of the book.

Among so many new advances, it is difficult to single out the most important from all the developments that are pinpointed in this book – and each reader will have different choices. I am especially excited about the coupling of the new, extremely rapid, sequencing methodologies to bioinformatics. This has created entirely novel tools that will dramatically help us focus on such important yet poorly understood topics as how entire genomes are regulated through both temporal and spatial organization. Bioinformatics coupled with rapid sequencing techniques will also help us develop innovative concepts including the function of all the noncoding RNA that is expressed, which some estimates put at approximately 90% of the genome. Already, through burgeoning studies on noncoding RNAs, we have begun to develop our understanding of their potential as their unimagined biological roles are discovered and we learn that these roles will lead us to novel therapeutic and diagnostic targets.

The development of therapeutic and diagnostic applications for DNA and RNA since 3E has been so dramatic that it merits specific comment. By the end of 2020, 12 oligonucleotides and two gene therapies have been approved for clinical use, there have been many applications of DNA and/or RNA for diagnostic purposes and, most recently, two mRNA vaccines have found much-needed success in the battle against Covid-19. What therapeutic applications await RNA development following these successes as a vaccine? In the wings is the clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR associated protein (Cas) system. Shall we be able to deliver therapeutic applications for this recently developed technology?

Perhaps Chapter 14 best summarizes how rapidly RNA has come to the forefront when we consider potential future developments. Here we discover that RNA and its associated proteins play essential roles in nearly all cellular processes (post-transcriptional processing and regulation of RNAs, splicing, polyadenylation, mRNA turnover, localization and translation) and therefore we must carefully examine these roles for possible therapeutic and diagnostic applications. One of the first examples of how these processes have been tapped is the treatment of spinal muscular atrophy (SMA) in patients that have a defective survival of motor neuron 1 (SMN1) gene along with a functional but unstable SMN2 gene. A thorough understanding of how certain proteins interact with these mRNAs and their associated genes has led to the development of an antisense oligonucleotide that is approved by the Food and Drug Administration (FDA) for treatment of SMA as described in Chapter 9. And now, as outlined in that Chapter, there are small molecules that also are active relative to enhancing expression of the SMN2 gene. This is simply one of several examples on how our knowledge of protein–RNA interactions can be utilized for therapeutic and diagnostic purposes.

The four editors have assembled an excellent set of authors who are experts in the science presented in the fourteen substantive chapters, topped by a composite electronic chapter on the basic physical and structural techniques on which current research progress depends, notably for cryo electron microscopy. This would be expected as Michael Blackburn, Martin Egli, Michael Gait and Jonathan Watts are among the most highly respected and experienced research scientists in this field. Thus, it is not surprising that the science presented is both current and focused on important concepts. I enthusiastically recommend this book as a foundation, as a reference source, and as a guide for further research in the field of nucleic acids.

Marvin H. Caruthers

Distinguished Professor, Chemistry and Biochemistry,

University of Colorado, Boulder

National Medal of Science (2006)

Co-founder, Amgen Inc.