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François Gros, a biologist by training, began his research at the Institut Pasteur. In 1961, he discovered the molecular nature of the proposed intermediary between the gene and the protein, a so-called messenger RNA (mRNA), and determined its main characteristics. The author of numerous books, François Gros has helped shape and enlightened the birth of molecular biology and the development of related biotechnologies since the 1970s. He was Professor at the Collège de France and Permanent Secretary of the French Academy of Sciences. Within the Academy, he initiated the creation of a committee for developing countries (COPED). François Gros was a humanist driven by moral rigour and an unfailing sense of commitment., (CC BY)

This Reflections article is focused on the 5 years while I was a graduate student (1964-1969). During this period, I made some of the most significant discoveries of my career. I have written this article primarily for a protein biochemistry audience, my colleagues who shared this exciting time in science, and the many scientists over the last 50 years who have contributed to our knowledge of transcriptional machinery and their regulation. It is also written for today's graduate students, postdocs, and scientists who may not know much about the discoveries and technical advances that are now taken for granted, to show that even with methods primitive by today's standards, we were still able to make foundational advances. I also hope to provide a glimpse into how fortunate I was to be a graduate student over 50 years ago in the golden age of molecular biology., Competing Interests: Conflict of interest The author declares that he has no conflicts of interest with the contents of this article., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

Ever since the first structures of proteins were determined in the 1960s, structural biologists have required methods to visualize biomolecular structures, both as an essential tool for their research and also to promote 3D comprehension of structural results by a wide audience of researchers, students, and the general public. In this review to celebrate the 50th anniversary of the Protein Data Bank, we present our own experiences in developing and applying methods of visualization and analysis to the ever-expanding archive of protein and nucleic acid structures in the worldwide Protein Data Bank. Across that timespan, Jane and David Richardson have concentrated on the organization inside and between the macromolecules, with ribbons to show the overall backbone "fold" and contact dots to show how the all-atom details fit together locally. David Goodsell has explored surface-based representations to present and explore biological subjects that range from molecules to cells. This review concludes with some ideas about the current challenges being addressed by the field of biomolecular visualization., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Integrative modeling is an increasingly important tool in structural biology, providing structures by combining data from varied experimental methods and prior information. As a result, molecular architectures of large, heterogeneous, and dynamic systems, such as the ∼52-MDa Nuclear Pore Complex, can be mapped with useful accuracy, precision, and completeness. Key challenges in improving integrative modeling include expanding model representations, increasing the variety of input data and prior information, quantifying a match between input information and a model in a Bayesian fashion, inventing more efficient structural sampling, as well as developing better model validation, analysis, and visualization. In addition, two community-level challenges in integrative modeling are being addressed under the auspices of the Worldwide Protein Data Bank (wwPDB). First, the impact of integrative structures is maximized by PDB-Development, a prototype wwPDB repository for archiving, validating, visualizing, and disseminating integrative structures. Second, the scope of structural biology is expanded by linking the wwPDB resource for integrative structures with archives of data that have not been generally used for structure determination but are increasingly important for computing integrative structures, such as data from various types of mass spectrometry, spectroscopy, optical microscopy, proteomics, and genetics. To address the largest of modeling problems, a type of integrative modeling called metamodeling is being developed; metamodeling combines different types of input models as opposed to different types of data to compute an output model. Collectively, these developments will facilitate the structural biology mindset in cell biology and underpin spatiotemporal mapping of the entire cell., Competing Interests: Conflict of interest The author declares that he has no conflicts of interest with the contents of this article., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

The past 4 decades have seen remarkable advances in our understanding of the structural basis of gene regulation. Technological advances in protein expression, nucleic acid synthesis, and structural biology made it possible to study the proteins that regulate transcription in the context of ever larger complexes containing proteins bound to DNA. This review, written on the occasion of the 50th anniversary of the founding of the Protein Data Bank focuses on the insights gained from structural studies of protein-DNA complexes and the role the PDB has played in driving this research. I cover highlights in the field, beginning with X-ray crystal structures of the first DNA-binding domains to be studied, through recent cryo-EM structures of transcription factor binding to nucleosomal DNA., Competing Interests: Conflict of interest The author is a member of the scientific advisory board of Thermo Fisher Scientific., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

My personal and professional journeys have been far from predictable based on my early childhood. Owing to a range of serendipitous influences, I miraculously transitioned from a rebellious, apathetic teenage street urchin who did poorly in school to a highly motivated, disciplined, and ambitious academic honors student. I was the proverbial "late bloomer." Ultimately, I earned my PhD in biophysical chemistry at Yale, followed by a postdoc fellowship at Berkeley. These two meccas of thermodynamics, coupled with my deep fascination with biology, instilled in me a passion to pursue an academic career focused on mapping the energy landscapes of biological systems. I viewed differential energetics as the language of molecular communication that would dictate and control biological structures, as well as modulate the modes of action associated with biological functions. I wanted to be a "molecular linguist." For the next 50 years, my group and I used a combination of spectroscopic and calorimetric techniques to characterize the energy profiles of the polymorphic conformational space of DNA molecules, their differential ligand-binding properties, and the energy landscapes associated with mutagenic DNA damage recognition, repair, and replication. As elaborated below, the resultant energy databases have enabled the development of quantitative molecular biology through the rational design of primers, probes, and arrays for diagnostic, therapeutic, and molecular-profiling protocols, which collectively have contributed to a myriad of biomedical assays. Such profiling is further justified by yielding unique energy-based insights that complement and expand elegant, structure-based understandings of biological processes., Competing Interests: Conflict of interest The author declares that he has no conflicts of interest with the contents of this article., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

I am deeply honored to receive the International Society for Experimental Hematology (ISEH) 2020 Donald Metcalf Lecture Award. Although I am not a physician and have had no formal training in hematology, I have had the privilege of working with some of the top hematologists in the world, beginning in 1970 when Dr. David Nathan was a sabbatical visitor in my laboratory and introduced me to hematological diseases.  And I take this award to be given not just to me but to an exceptional group of MD and PhD trainees and visitors in my laboratory who have cloned and characterized many proteins and RNAs important for red cell development and function. Many of these projects involved taking exceptionally large risks in developing and employing novel experimental technologies. Unsurprisingly, all of these trainees have gone on to become leaders in hematology and, more broadly, in molecular cell biology and molecular medicine. To illustrate some of the challenges we have faced and the technologies we had to develop, I have chosen several of our multiyear projects to describe in some detail: elucidating the regulation of translation of α- and β-globin mRNAs and the defect in beta thalassemia in the 1970s; cloning the Epo receptor and several red cell membrane proteins in the 1980s and 1990s; and more recently, determining the function of many microRNAs and long noncoding RNAs in red cell development. I summarize how we are currently utilizing single-cell transcriptomics (scRNAseq) to understand how dividing transit-amplifying burst-forming unit erythroid progenitors balance the need for more progenitor cells with the need for terminally differentiated erythroid cells, and to identify drugs potentially useful in treating Epo-resistant anemias such as Diamond Blackfan anemia. I hope that the lessons I learned in managing these diverse fellows and projects, initially without having grants to support them, will be helpful to others who would like to undertake ambitious and important lines of research in hematology., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Rosalind Franklin provided the key data for deriving the double helix structure of DNA. The English chemist also pioneered structural studies of colloids, viruses, and RNA. To celebrate the 100 th anniversary of Franklin's birth, I summarize her work, which shaped the emerging discipline of molecular biology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A systematic search for non-conventional open reading frames in human DNA reveals a large number of small ORFs encoding peptides generally smaller than 100 amino-acids. These ORFs are transcribed and translated into small proteins, which are demonstrated to have functional significance by bulk CRISPR inactivation. Evidence is also found for bicistronic mRNAs including such a small ORF upstream of a canonical coding sequence. These findings add a new facet to our understanding of biological processes., (© 2020 médecine/sciences – Inserm.)

In 1970, John Maynard Smith published a letter, entitled "Natural Selection and the Concept of a Protein Space," that proposed a simple analogy for the incremental process of adaptive evolution. His "Protein Space" analogy contains the substrate for many central ideas in evolutionary genetics, and has motivated important discoveries within several subdisciplines of evolutionary science. In this Perspectives article, I commemorate the 50th anniversary of this seminal work by discussing its unique legacy and by describing its intriguing historical context. I propose that the Protein Space analogy is not only important because of its scientific richness, but also because of what it can teach us about the art of constructing useful and subversive analogies., (Copyright © 2020 by the Genetics Society of America.)

Forty years ago, Horace Judson's The Eighth Day of Creation was published, a book vividly recounting the foundations of modern biology, the molecular biology revolution. This book inspired many in my generation. The anniversary provides a chance for a new generation to take a look back, to see how science has and hasn't changed. Many central players in the book, including Sydney Brenner, Seymour Benzer, and François Jacob, would go on to be among the founders of modern cell biology, developmental biology, and neurobiology. These players come alive via their own words, as complex individuals, both heroes and anti-heroes. The technologies and experimental approaches they pioneered, ranging from cell fractionation to immunoprecipitation to structural biology, and the multidisciplinary approaches they took continue to power and inspire our work today. In the process, Judson brings out of the shadows the central roles played by women in many of the era's discoveries. He provides us with a vision of how science and scientists have changed, of how many things about our endeavor never change, and of how some new ideas are perhaps not as new as we would like to think.

Without question, molecular biology drives modern neuroscience. The past 50 years has been nothing short of revolutionary as key findings have moved the field from correlation toward causation. Most obvious are the discoveries and strategies that have been used to build tools for visualizing circuits, measuring activity, and regulating behavior. Less flashy, but arguably as important are the myriad investigations uncovering the actions of single molecules, macromolecular structures, and integrated machines that serve as the basis for constructing cellular and signaling pathways identified in wide-scale gene or RNA studies and for feeding data into informational networks used in systems biology. This review follows the pathways that were opened in neuroscience by major discoveries and set the stage for the next 50 years., (Copyright © 2020 the authors.)

The invention of partition chromatography by the biochemists Archer Martin and Richard Synge in 1941 offered crucial insights into the structure and function of DNA, insights at least as important as those from X-ray crystallography. Even so, the role that partition chromatography played in molecular biological studies is far less well known. Using new archival material, this article describes the origins of Martin and Synge's work, arguing that their achievement was far more than a new technical innovation; it went on to have a profound impact on the development of molecular biology to an extent that scholars have insufficiently appreciated., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Protein synthesis and its regulation are central to all known forms of life and impinge on biological arenas as varied as agriculture, biotechnology, and medicine. Otherwise known as translation and translational control, these processes have been investigated with increasing intensity since the middle of the 20th century, and in increasing depth with advances in molecular and cell biology. We review the origins of the field, focusing on the underlying concepts and early studies of the cellular machinery and mechanisms involved. We highlight key discoveries and events on a timeline, consider areas where current research has engendered new ideas, and conclude with some speculation on future directions for the field., (Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved.)

The discovery of the three eukaryotic nuclear RNA polymerases paved the way for serious biochemical investigations of eukaryotic transcription and the identification of eukaryotic transcription factors. Here we describe this adventure from our vantage point, with a focus on the hunt for factors that regulate elongation by RNA polymerase II.

The discovery of RNA polymerases I, II, and III opened up a new era in gene expression. Here I provide a personal retrospective account of the transformation of the DNA template, as it evolved from naked DNA to chromatin, in the biochemical analysis of transcription by RNA polymerase II. These studies have revealed new insights into the mechanisms by which transcription factors function with chromatin to regulate gene expression.

Transcription regulation is critical to organism development and homeostasis. Control of expression of the 20,000 genes in human cells requires many hundreds of proteins acting through sophisticated multistep mechanisms. In this Historical Perspective, I highlight the progress that has been made in elucidating eukaryotic transcriptional mechanisms through an array of disciplines and approaches, and how this concerted effort has been driven by the development of new technologies.

The landmark 1969 discovery of nuclear RNA polymerases I, II and III in diverse eukaryotes represented a major turning point in the field that, with subsequent elucidation of the distinct structures and functions of these enzymes, catalyzed an avalanche of further studies. In this Review, written from a personal and historical perspective, I highlight foundational biochemical studies that led to the discovery of an expanding universe of the components of the transcriptional and regulatory machineries, and a parallel complexity in gene-specific mechanisms that continue to be explored to the present day.

Restriction enzymes have been identified in the early 1950s of the past century and have quickly become key players in the molecular biology of DNA. Forty years ago, the scientists whose pioneering work had explored the activity and sequence specificity of these enzymes, contributing to the definition of their enormous potential as tools for DNA characterization, mapping and manipulation, were awarded the Nobel Prize. In this short review, we celebrate the history of these enzymes in the light of their many different uses, as these proteins have accompanied the history of DNA for over 50 years representing active witnesses of major steps in the field.