Art under the Microscope.

In March 2018, Greece issued five commemorative stamps that show a beautiful mélange of art and science. Images are, however, genuine views captured through light microscopy of stained human tissue during histopathological examination. Many will remember having drawn such diagrams in their histology and pathology journals during their medical school years. The microscopic images are photographed beautifully by Dr Maria Lambropaulou. She is an Associate Professor of Histology-embryology at the Medical Department of the Democritus University of Thrace, Greece.

Advances in Microscopy Tech Offer Better Views.

Microscopes have come a very long way since the 1600s when Henry Power, Robert Hooke, and Anton van Leeuwenhoek began publishing the first views of plant cells and bacteria. The major inventions of contrast, electron, and scanning tunneling microscopes didn't arrive until the 20th century, and the men behind them all earned Nobel Prizes in physics for their efforts. Today, innovations in microscopy are coming at a fast and furious rate with new technologies providing first-time views and information about biological structures and activity, and opening up new avenues for disease therapies.

Seeing clearly - Plant anatomy through Katherine Esau's microscopy lens.

Describing, naming and understanding the tissues and cell types composing biological organisms underpin myriad research endeavours in the biosciences. This is obvious when the organismal structure is a direct subject of the investigation such as in analyses of structure-function relationships. However, it also applies when structure represents the context. Gene expression networks and physiological processes cannot be divorced from the spatial and structural framework of the organs in which they operate. Atlases of anatomy and a precise vocabulary are therefore key tools on which modern scientific endeavours in the life sciences are based. One of the seminal authors whose books are familiar to nearly everyone in the plant biology community is Katherine Esau (1898-1997), a phenomenal plant anatomist and microscopist whose textbooks are still used daily around the world - 70 years after their first publication. Several technical innovations in microscopy have emerged since Esau's time and plant biological studies by authors who were trained using her books are shown side-by-side with Esau's drawings.

A Short History of Plant Light Microscopy.

When the microscope was first introduced to scientists in the 17th century, it started a revolution. Suddenly, a whole new world, invisible to the naked eye, was opened to curious explorers. In response to this realization, Nehemiah Grew, an English plant anatomist and physiologist and one of the early microscopists, noted in 1682 "that Nothing hereof remains further to be known, is a Thought not well Calculated". Since Grew made his observations, the microscope has undergone numerous variations, developing from early compound microscopes-hollow metal tubes with a lens on each end-to the modern, sophisticated, out-of-the-box super-resolution microscopes available to researchers today. In this Overview article, I describe these developments and discuss how each new and improved variant of the microscope led to major breakthroughs in the life sciences, with a focus on the plant field. These advances start with Grew's simple and-at the time-surprising realization that plant cells are as complex as animals cells, and that the different parts of the plant body indeed qualify to be called "organs", then move on to the development of the groundbreaking "cell theory" in the mid-19th century and the description of eu- and heterochromatin in the early 20th century, and finish with the precise localization of individual proteins in intact, living cells that we can perform today. Indeed, Grew was right; with ever-increasing resolution, there really does not seem to be an end to what can be explored with a microscope. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.

The vanishing link between animalcules and disease before the 19th century.

When Antoni van Leeuwenhoek began his work with microscopes in the late 17th century, western medicine was mostly based on the work of a Roman doctor called Galen (129-199 ad), theological interpretation, superstition, and folk remedies. During modern discussions of Van Leeuwenhoek's work, a common question from listeners is why it took so long for the link between Van Leeuwenhoek's discoveries and infectious disease to be accepted. Published literature, examples of which are discussed here, shows that many researchers, doctors, and others reported the link, even during Van Leeuwenhoek's lifetime. However, it was frequently not taken seriously by the most influential people. The scientific establishment included a faction of the Royal Society of London who called themselves the 'Mechanical Philosophers'. They ridiculed those reporting animalcule-linked infection, dismissing them as 'Contagionists'. The medical establishment also included many influential people with a lot to lose if they changed their established approaches, and many quack doctors. Most religious ministers were strongly orthodox, some even claiming that helping the sick angered God. A major problem, of course, was that technology and biological understanding also lagged far behind. Despite the fact that the use of vaccination was under active discussion in the Royal Society at the time of Van Leeuwenhoek's death and quarantine was in regular use, a possible microbial connection was apparently not considered. It was not until late in the 19th century, that Robert Koch (1843-1910) isolated Bacillus anthracis, proved that it caused anthrax, and was believed. This paper follows a lecture given during the online Microbe Forum in June 2021, and illustrates the difficulties of establishing the true link between Van Leeuwenhoek's animalcules and infectious disease in humans, animals, and plants.

Positioning Van Leeuwenhoek's microscopes in 17th-century microscopic practice.

The self-made nature of Antoni van Leeuwenhoek's discoveries and microscopes tends to obscure the rich and dynamic 17th-century culture of microscopy that preceded his work. Rather than being limited by available magnifications, 17th-century microscopy was shaped by philosophical paradigms, visual and preparation techniques, and observation conditions. Taking into account new insights into his lens making methods, a comparison of Van Leeuwenhoek's methodology with 17th-century predecessors reveals, on the one hand, how his work was rooted in existing traditions, while on the other hand it makes us appreciate his innovations better. Van Leeuwenhoek elegantly turned the viewing practice associated with high-magnification microscopy into a convincing narrative. In doing so, he reaffirmed the central role of the microscope in the 17th-century inquiry of nature. This allowed him to open up new vistas and become the founder of microbiology.

The new era of quantitative cell imaging-challenges and opportunities.

Quantitative optical microscopy-an emerging, transformative approach to single-cell biology-has seen dramatic methodological advancements over the past few years. However, its impact has been hampered by challenges in the areas of data generation, management, and analysis. Here we outline these technical and cultural challenges and provide our perspective on the trajectory of this field, ushering in a new era of quantitative, data-driven microscopy. We also contrast it to the three decades of enormous advances in the field of genomics that have significantly enhanced the reproducibility and wider adoption of a plethora of genomic approaches.

The Evolution of Single-Cell Analysis and Utility in Drug Development.

This review provides a brief history of the advances of cellular analysis tools focusing on instrumentation, detection probes, and data analysis tools. The interplay of technological advancement and a deeper understanding of cellular biology are emphasized. The relevance of this topic to drug development is that the evaluation of cellular biomarkers has become a critical component of the development strategy for novel immune therapies, cell therapies, gene therapies, antiviral therapies, and vaccines. Moreover, recent technological advances in single-cell analysis are providing more robust cellular measurements and thus accelerating the advancement of novel therapies.Graphical abstract.

Secretos detectados de la naturaleza por Antoine van Leeuwenhoek / Detected secrets for nature by Antoine van Leeuwenhoek

Resumen Una de las obras, probablemente menos conocidas, de Antoine van Leeuwenhoek (1632-1723) es su Arcana naturae detecta (Secretos detectados de la naturaleza) publicada en su primera edición en 1695. Esta obra es una recopilación de 38 cartas sobre temas científicos y está bellamente ilustrada. Una sección notable de ella es la observación y descripción por primera vez de levaduras de la fermentación y sus experimentos sobre la generación espontánea de microorganismos.

Abstract One of the works, probably less known, of Antoine van Leeuwenhoek (1632-1723) is his Arcana naturae detecta (Detected secrets of nature) published in its first edition in 1695. This work is a compilation of 38 letters on scientific issues and it is beautifully illustrated. A notable section of the work is the observation and description for the first time of fermentation yeasts and his experiments on the spontaneous generation of microorganisms.

Leeuwenhoek y sus animálculos / Leeuwenhoek and his little animals

Resumen Antoine van Leeuwenhoek (1632-1723) fue un comerciante de telas holandés y microscopista autodidacta, a quien se le considera el padre de la Microbiología. Sus sorprendentes lentes y agudas observaciones microscópicas durante casi cinco décadas posibilitaron por primera vez desentrañar los secretos del microcosmos. Este trabajo de investigación tiene como objetivo principal que el lector pueda acceder de manera directa a algunas de sus famosas cartas dirigidas a la Sociedad Real de Londres, anunciando el descubrimiento de sus celebérrimos animálculos.

Abstract Antoine van Leeuwenhoek (1632-1723) was a Dutch cloth merchant and self-taught microscopist who is considered the father of Microbiology. His marvellous lenses and keen microscopic observations over nearly five decades made it possible for the first time to unravel the secrets of the microcosm. The main objective of this work is that the reader can directly access some of his famous letters addressed to the Royal Society of London, announcing the discovery of his famous little animals.

A brief history of how microscopic studies led to the elucidation of the 3D architecture and macromolecular organization of higher plant thylakoids.

Microscopic studies of chloroplasts can be traced back to the year 1678 when Antonie van Leeuwenhoek reported to the Royal Society in London that he saw green globules in grass leaf cells with his single-lens microscope. Since then, microscopic studies have continued to contribute critical insights into the complex architecture of chloroplast membranes and how their structure relates to function. This review is organized into three chronological sections: During the classic light microscope period (1678-1940), the development of improved microscopes led to the identification of green grana, a colorless stroma, and a membrane envelope. More recent (1990-2020) chloroplast dynamic studies have benefited from laser confocal and 3D-structured illumination microscopy. The development of the transmission electron microscope (1940-2000) and thin sectioning techniques demonstrated that grana consist of stacks of closely appressed grana thylakoids interconnected by non-appressed stroma thylakoids. When the stroma thylakoids were shown to spiral around the grana stacks as multiple right-handed helices, it was confirmed that the membranes of a chloroplast are all interconnected. Freeze-fracture and freeze-etch methods verified the helical nature of the stroma thylakoids, while also providing precise information on how the electron transport chain and ATP synthase complexes are non-randomly distributed between grana and stroma membrane regions. The last section (2000-2020) focuses on the most recent discoveries made possible by atomic force microscopy of hydrated membranes, and electron tomography and cryo-electron tomography of cryofixed thylakoids. These investigations have provided novel insights into thylakoid architecture and plastoglobules (summarized in a new thylakoid model), while also producing molecular-scale views of grana and stroma thylakoids in which individual functional complexes can be identified.

Antoni van Leeuwenhoek and measuring the invisible: The context of 16th and 17th century micrometry.

This article explores the impact of 16th and 17th-century developments in micrometry on the methods Antoni van Leeuwenhoek employed to measure the microscopic creatures he discovered in various samples collected from his acquaintances and from local water sources. While other publications have presented Leeuwenhoek's measurement methods, an examination of the context of his techniques is missing. These previous measurement methods, driven by the need to improve navigation, surveying, astronomy, and ballistics, may have had an impact on Leeuwenhoek's methods. Leeuwenhoek was educated principally in the mercantile guild system in Amsterdam and Delft. He rose to positions of responsibility within Delft municipal government. These were the years that led up to his first investigations using the single-lens microscopes he became expert at creating, and that led to his first letter to the Royal Society in 1673. He also took measures to train in surveying and liquid assaying practices existing in his time, disciplines that were influenced by Pedro Nunes, Pierre Vernier, Rene Descartes, and others. While we may never know what inspired Leeuwenhoek's methods, the argument is presented that there were sufficient influences in his life to shape his approach to measuring the invisible.

When botany inspired pathology of the peripheral nervous system.

Medicine and botany are 2 distinct disciplines of "natural science," one focusing on humans, the other on plants. However, among the life sciences, both were quite close in earlier times. Moreover, the history of neuropathology, especially in the field of the peripheral nervous system, has been marked by many examples of "botanical images" used to describe certain histopathologic structures. We propose to better understand the reasons why neuropathologists used these botanical terms from a number of interesting anecdotes.

Twenty years of t-loops: A case study for the importance of collaboration in molecular biology.

Collaborative studies open doors to breakthroughs otherwise unattainable by any one laboratory alone. Here we describe the initial collaboration between the Griffith and de Lange laboratories that led to thinking about the telomere as a DNA template for homologous recombination, the proposal of telomere looping, and the first electron micrographs of t-loops. This was followed by collaborations that revealed t-loops across eukaryotic phyla. The Griffith and Tomáska/Nosek collaboration revealed circular telomeric DNA (t-circles) derived from the linear mitochondrial chromosomes of nonconventional yeast, which spurred discovery of t-circles in ALT-positive human cells. Collaborative work between the Griffith and McEachern labs demonstrated t-loops and t-circles in a series of yeast species. The de Lange and Zhuang laboratories then applied super-resolution light microscopy to demonstrate a genetic role for TRF2 in loop formation. Recent work from the Griffith laboratory linked telomere transcription with t-loop formation, providing a new model of the t-loop junction. A recent collaboration between the Cesare and Gaus laboratories utilized super-resolution light microscopy to provide details about t-loops as protective elements, followed by the Boulton and Cesare laboratories showing how cell cycle regulation of TRF2 and RTEL enables t-loop opening and reformation to promote telomere replication. Twenty years after the discovery of t-loops, we reflect on the collective history of their research as a case study in collaborative molecular biology.

A Brief History of Phagocytosis.

This chapter outlines some of the more significant steps in our understanding of the phenomenon and mechanism of phagocytosis. These are mainly historical, ranging from near the advent of microscopy in the seventeenth and eighteenth century up to the period before the Second World War (1930s). During this time, science itself moved from being the domain of the wealthy enthusiast to the professional and funded university scientist. Not surprisingly progress was slow of the first two centuries of phagocytic research, but accelerated around the late nineteenth century and the turn of the twentieth century. Since then progress has accelerated still further. This chapter however aims to put our current progress into a historical context and to explore some of the interesting personalities who have set the ground work for our current understanding of the subject of this book, namely phagocytosis.

Of Molecules and Mechanisms.

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.

From magnifying glass to operative microscopy - the historical and modern role of the microscope in microsurgery.

The modern computer-assisted microscope, being a hallmark of microsurgery, has become a standard piece of equipment in the operating theatre. Its introduction enabled visualisation of fine anatomical structures, obscure to the unaided eye, and revolutionised many surgical specialties, such as neurological, ophthalmological, or vascular. These astounding achievements have been the culmination of a century of constant progress in optical engineering and microsurgery, since 1921, when a microscope was first used during surgery. Long before surgery, pathology adopted microscopes, and they have become its most prominent diagnostic tools. We traced the evolution of this important invention and discussed its present status and future prospects.

Story telling of myocarditis.

Myocarditis was discovered as heart disease at autopsy with the use of microscope. In 1900, with the name of acute interstitial myocarditis, Carl Ludwig Alfred Fiedler first reported the history of a sudden cardiac heart failure, in the absence of coronary, valve, pericardial disease or classical specific infections with multiorgan involvement. He postulated a peculiar isolated acute inflammation of the myocardium with poor prognosis due to invisible microorganisms, which years later would have been identified as viruses. Subsequent revision of Fiedler original histologic slides by Schmorl showed cases with either lymphocytic or giant cell infiltrates. The in vivo diagnosis became possible with the right heart catheterism and endomyocardial biopsy. Employment of immunohistochemistry and molecular techniques improved the diagnosis and etiology identification. The mechanism of myocyte injury by coxsackie virus was identified in protease 2A coded by the virus and disrupting the dystrophin in the cytoskeleton. Both RNA and DNA viruses may be cardiotropic, and coxsackie and adenovirus share a common receptor (CAR). Unfortunately, vaccination is not yet available. Cardiac Magnetic Resonance is a revolutionary diagnostic tool by detecting edema, of myocardial inflammation. However endomyocardial biopsy remains the gold standard for etiological and histotype diagnosis, with limited sensitivity due to sampling error. Viral lymphocytic fulminant myocarditis may not be fatal and the employment of mechanical assistant device - ECMO in acute phase for temporary support may be lifesaving with good prognosis.

From the Popularization of Microscopy in the Victorian Age: A Lesson for Today's "Outreach".

In the latter half of the Victorian Age (1837-1901) microscopy was introduced as popular past-time. Many books were published aimed at general audiences, both adult and juvenile, on microscopy. Here I consider 5 of these popular books of particular interest to protistologists as they included presentations of 'infusoria' or 'animalcules'. I focus on the scientific backgrounds of the authors, from what we know of them, and the approaches taken to engage the reader based on their texts and illustrations. The possible lesson to be drawn from this exercise concerns our oft-mandated efforts in "Outreach". The methods used by 19th century popularizes of the 'wonders of the microscopic world' can likely be used today. They appealed to the imagination, to empowerment, and gave very practical instructions on how to see the invisible. I conclude that we should likely target the very young and describe our organisms with the enthusiasm that brought us to Protistology to begin with, but which we often conceal.