Since its discovery in 1912, X-ray crystallography has become a most useful tool in physics, chemistry, material science, mineralogy, metallurgy, and even in the biological sciences. In 1914, Max von Laue was awarded the Nobel Prize “for the discovery of X-ray diffraction by crystals,” followed by the 1915 Nobel Prize to William Henry Bragg and William Lawrence Bragg “for their services in analysis of crystal structure by means of X-rays.” And these early Nobel prizes marked only the beginning of (...) X-ray crystallography as one of the most fruitful methods in the history of modern science. A 100 years after Laue’s Nobel Prize and 50 years after another Nobel Prize to Dorothy Hodgkin “for her determination by X-ray technique of the structures of important biochemical substances,” the UN proclaimed 2014 the International Year of Crystallography. “In all, 45 scientists have been awarded over the past century for work that is either directly or indirectly related to crystallo .. (shrink)

Scientific models share one central characteristic with fiction: their relation to the physical world is ambiguous. It is often unclear whether an element in a model represents something in the world or presents an artifact of model building. Fiction, too, can resemble our world to varying degrees. However, we assign a different epistemic function to scientific representations. As artifacts of human activity, how are scientific representations allowing us to make inferences about real phenomena? In reply to this concern, philosophers of (...) science have started analyzing scientific representations in terms of fictionalization strategies. Many arguments center on a dyadic relation between the model and its target system, focusing on structural resemblances and “as if” scenarios. This chapter provides a different approach. It looks more closely at model building to analyze the interpretative strategies dealing with the representational limits of models. How do we interpret ambiguous elements in models? Moreover, how do we determine the validity of model-based inferences to information that is not an explicit part of a representational structure? I argue that the problem of ambiguous inference emerges from two features of representations, namely their hybridity and incompleteness. To distinguish between fictional and non-fictional elements in scientific models my suggestion is to look at the integrative strategies that link a particular model to other methods in an ongoing research context. To exemplify this idea, I examine protein modeling through X-ray crystallography as a pivotal method in biochemistry. (shrink)

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, crosslinks two receptor (...) sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

The structures of protein and DNA were discovered primarily by means of synthesizing component-level information about bond types, lengths, and angles, rather than analyzing X-ray diffraction photographs of these molecules. In this paper, I consider the synthetic and analytic approaches to exemplify alternative heuristics for approaching mid-twentieth-century macromolecular structure determination. I argue that the former was, all else being equal, likeliest to generate the correct structure in the shortest period of time. I begin by characterizing problem solving in these cases (...) as proceeding via the elimination of candidate structures through the successive application of component-level information and interpretations of X-ray diffraction photographs, each of which serves as a kind of constraint on structure. Then, I argue that although each kind of constraint enables the elimination of a considerable proportion of candidate structures, component-level constraints are significantly more likely to do so correctly. Thus, considering them before X-ray diffraction photographs is a better heuristic than one that reverses this order. Because the synthetic approach that resulted in the determination of the protein and DNA structures exemplifies such a heuristic, its use can help account for these discoveries. (shrink)

Cryo‐electron microscopy allows the visualization of macromolecules in their native state. Combined with techniques of three‐dimensional reconstruction, cryo‐EM images of single molecules can be used to study macromolecular interactions. The ribosome, a large RNA–protein complex with multiple binding interactions, is an excellent test case illustrating the power of these new techniques. Conformational changes during the binding of tRNA and protein factors to the ribosome can now be studied without the interference of crystal packing. Now that the first X‐ray structures of (...) ribosomal subunits have become available, conformational changes observed by cryo‐EM in different functional states can be traced back to internal rearrangements of the underlying structural framework. Electron microscopy, X‐ray crystallography, and modeling should be used together in the endeavor to understand the functioning of the translational machinery. BioEssays 23:725–732, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The use of computers and the role of women in radio astronomy and X-ray crystallography research at the Cavendish Laboratory between 1949 and 1975 have been investigated. We recorded examples of when computers were used, what they were used for and who used them from hundreds of papers published during these years. The use of the EDSAC, EDSAC 2 and TITAN computers was found to increase considerably over this time-scale and they were used for a diverse range of applications. (...) The majority of references to computer operators and programmers referred to women, 57% for astronomy and 62% for crystallography, in contrast to a very small proportion, 4% and 13% respectively, of female authors of papers. (shrink)

Strong arguments are presented by Hargrave suggesting that the crystallization of visual rhodopsin for high resolution analysis by X-ray crystallography or electron microscopy is feasible. However, the effort needed to achieve this goal will most likely exceed the resources of a single laboratory and a concerted approach to the research is necessary.

DNA gyrase, an enzyme unique to prokaryotes, has been implicated in almost all processes that involve DNA. Although efficient inhibitors of this protein have been known for more than 20 years, none of them have enjoyed prolonged pharmaceutical success. It is only recently that the mechanisms of inhibition for some of these classes of drugs have been established unequivocally by X‐ray crystallography. It is hoped that this detailed structural information will assist the design of novel, effective inhibitors of DNA (...) gyrase. (shrink)

It was first suggested that the ribosome is associated with protein synthesis in the 1950s. Initially, its components were revealed as surface‐accessible proteins and as molecules of RNA apparently providing a scaffold for subunit shape. Attributing function to the proteins proved difficult, although bacterial protein L11 proved essential for binding one of the decoding protein release factors (RFs). With the discovery that RNA could be a catalyst, interest focussed on the rRNA that, in partnership with mRNA and tRNAs, could potentially (...) mediate the chemical reaction underlying protein synthesis. rRNA interactions and conformational changes were invoked as key elements that facilitated function. The decoding RFs, which are proteins, are exceptions to this rule because they usurp a tRNA function in mediating stop signal recognition. Cryoelectron microscopy and associated image reconstruction technology have now given dramatic snapshots of almost every step of protein synthesis, and X‐ray crystallography has revealed, at last, the subunits and monomeric ribosome in exquisite atomic detail. BioEssays 26:582–588, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

This paper presents a micro-history of an object in the collection of the Whipple Museum of the History of Science, with an emphasis on how Wh.3469 reflects a hybrid of two different interwar British X-ray crystallographic communities, namely those based in WL Bragg’s physics laboratory at the Victoria University of Manchester and the Crystallographic Laboratory at the University of Cambridge. It explores connections between Wh.3469’s final design and construction and the different interests each community had in X-ray crystallography.Keywords: Powder (...) camera; British X-ray crystallography; Object history. (shrink)

Mitchell & Gronenborn propose that we account for the presence of multiple models of protein structure, each produced in different contexts, through the framework of integrative pluralism. I argue that two interpretations of this framework are available, neither of which captures the relationship between a model and the protein structure it represents or between multiple models of protein structure. Further, it inclines us toward concluding prematurely that models of protein structure are right in their contexts and makes extrapolation of findings (...) from one context to another seem unwarranted. Instead, protein structure determination ought to be understood as modestly monistic. There is one model for every protein in each physicochemical context, and models of the same protein produced in different contexts are compatible with one another. ‘Integrating’ multiple models amounts to extrapolating from one context to another; this is possible because the effect of context on protein folding is relatively weak and predictable. Modest monism better describes the practice of protein structure determination than integrative pluralism and enables greater attention to how context affects protein folding. (shrink)

Change in scientific practice and its implications for the status of scientific claims, examined through an analysis of three episodes at a synchrotron laboratory. After World War II, particle physics became a dominant research discipline in American academia. At many universities, alumni of the Manhattan Project and of Los Alamos were granted resources to start programs of high-energy physics built around the promise of a new and more powerful particle accelerator, the synchrotron. The synchrotron was also a source of very (...) intense X-rays, useful for research in solid states physics and in biology. As synchrotron X-ray science grew, the experimental practice of protein crystallography, garnered funding, prestige, and acclaim. In Velvet Revolution at the Synchrotron, Park Doing examines the change in scientific practice at a synchrotron laboratory as biology rose to dominance over physics. He draws on his own observations and experiences at the Cornell University synchrotron, and considers the implications of that change for the status of scientific claims. Velvet Revolution at the Synchrotron is one of the few recent works in the sociology of science that engages specific scientific and technical claims through participant observation--recorded evocatively and engagingly--to address issues in the philosophy of science. Doing argues that bureaucratic change in science is neither "top-down" nor "bottom-up" but rather performed in and realized through recursively related forums of technical assertion and resistance. He considers the relationship of this change to the content of science, and the implications of this relationship for the project of laboratory studies begun in the late 1970s. (shrink)

Structural biology has experienced several transformative technological advances in recent years. These include: development of extremely bright X-ray sources and the use of electrons to extend protein crystallography to ever decreasing crystal sizes; and an increase in the resolution attainable by cryo-electron microscopy. Here we discuss the use of these techniques in general terms and highlight their application for biological filament systems, an area that is severely underrepresented in atomic resolution structures. We assemble a model of a capped tropomyosin-actin (...) minifilament to demonstrate the utility of combining structures determined by different techniques. Finally, we survey the methods that attempt to transform high resolution structural biology into more physiological environments, such as the cell. Together these techniques promise a compelling decade for structural biology and, more importantly, they will provide exciting discoveries in understanding the designs and purposes of biological machines. Structural biology is undergoing technological advancements that now reveal the structures of previously inaccessible biological machines. Microfocus synchrotron beamlines, X-ray free electron lasers, and MicroED cope with vanishingly small crystals, while cryo-electron microscopy targets single molecules at near atomic resolution. These advances promise an exciting decade for structural biology. (shrink)

ABSTRACT Rosalind Franklin is best known for her informative X-ray diffraction patterns of DNA that provided vital clues for James Watson and Francis Crick's double-stranded helical model. Her scientific career did not end when she left the DNA work at King's College, however. In 1953 Franklin moved to J. D. Bernal's crystallography laboratory at Birkbeck College, where she shifted her focus to the three-dimensional structure of viruses, obtaining diffraction patterns of Tobacco mosaic virus (TMV) of unprecedented detail and clarity. (...) During the next five years, while making significant headway on the structural determination of TMV, Franklin maintained an active correspondence with both Watson and Crick, who were also studying aspects of virus structure. Developments in TMV research during the 1950s illustrate the connections in the emerging field of molecular biology between structural studies of nucleic acids and of proteins and viruses. They also reveal how the protagonists of the “race for the double helix” continued to interact personally and professionally during the years when Watson and Crick's model for the double-helical structure of DNA was debated and confirmed. (shrink)

Werner Schuster was a doctor long before he became an artist--but it was a childhood fascination with photography that drove him to study radiology in the first place, so it's only fitting that he should now be one of the most versatile and interesting artists working with x-ray photography today. This volume presents full-color reproductions of Schuster's photographs along with those of other photographers, from the pioneering x-ray creators of 1895 to present-day artists working in the medium. An essay by (...) René Harather tells the history of x-ray photography and highlights the most important developments and proponents of the genre since its discovery. The second part of the book turns to Schuster's work, showing how he has expanded the boundaries of the medium and made creative use of the interplay between traditional and x-ray photography. A fascinating look at a stunning marriage of art and science, X-Ray is the first comprehensive representation of the history of x-ray photography. (shrink)

The gravitational waves from a binary black hole with masses \ can be detected with the Laser Interferometer Space Antenna once their orbital frequency exceeds 10\–10\ Hz. The binary separation at this stage is \R_{\mathrm{g}}\), and the orbital speed is \\). I argue that at this stage, the binary will be producing bright electromagnetic radiation via gas bound to the individual BHs. Both BHs will have their own photospheres in X-ray and possibly also in optical bands. Relativistic Doppler modulations and (...) lensing effects will inevitably imprint periodic variability in the EM light-curve, tracking the phase of the orbital motion, and serving as a template for the GW inspiral waveform. Advanced localization of the source by LISA weeks to months prior to merger will enable a measurement of this EM chirp by wide-field X-ray or optical instruments. A comparison of the phases of the GW and EM chirp signals will help break degeneracies between system parameters, and probe a fractional difference difference \ in the propagation speed of photons and gravitons as low as \. (shrink)

Historians have found it difficult to give a general account of the early medical use of X‐rays in medicine. While the rays were hailed by some as a miracle technology, their early medical application was patchy, often remaining subsidiary to traditional methods of diagnosis and treatment, and was of disputed value. In this essay, I argue that the selective appropriation of the new technology needs to be understood within the wider medical practice of the period. The argument is developed around (...) the case of orthopedic surgery in Germany, probably the first example in which doctors quickly made X‐rays indispensable as a medical tool. I show that value of X‐rays in this case was contingent upon an ongoing dispute, the theory and practice of surgical intervention, and the sociology of new surgical knowledge. (shrink)

We present the idea of searching for X-rays as a signature of the mechanism inducing the spontaneous collapse of the wave function. Such a signal is predicted by the continuous spontaneous localization theories, which are solving the “measurement problem” by modifying the Schrödinger equation. We will show some encouraging preliminary results and discuss future plans and strategy.

During the first half of the twentieth century, the mining industry in Britain was subject to recurrent disputes about the risk to miners’ lungs from coal dust, moderated by governmental, industrial, medical and mining bodies. In this environment, precise measurements offered a way to present uncontested objective knowledge. By accessing primary source material from the National Archives, the South Wales Miners Library and the University of Bristol's Special Collections, I demonstrate the importance that the British Medical Research Council (MRC) attached (...) to standardized instrumental measures as proof of objectivity, and explore the conflict between objective and subjective measures of health. Examination of the MRC's use of spirometry in their investigation of pneumoconiosis (miner's lung) from 1936 to 1945 will shed light on this conflict and illuminate the politics inherent in attempts to quantify disability and categorize standards of health. (shrink)

The author, who shared the 1959 Nobel Prize in Physics with Owen Chamberlain, offers impressions and recollections of the development of modern physics. Rather than a chronological approach, Segre emphasizes interesting, complex personalities who often appear only in footnotes. Readers will find that this book adds considerably to their understanding of science and includes compelling topics of current interest.

A 10 kHz pulsed X-ray generator utilising a hot-cathode triode in conjunction with a new type of grid control device for controlling X-ray duration is described. The energy-storage condenser was charged up to 70 kV by a power supply, and the electric charges in the condenser were discharged to the X-ray tube repetitively by the grid control device. The maximum values of the grid voltage, the tube voltage, and the tube current were −1.5 kV, 70 kV, and 0.4 A, respectively. (...) The duration of the flash X-ray pulse was primarily determined by the time constant of the grid control device and the cut-off voltage of thermoelectrons. The X-ray duration was controlled within a region of less than 1 ms; the X-ray intensity with a pulse width of 0.27 ms, a charged voltage of 70 kV, and a peak tube current of 0.4 A was 0.92 μC kg −1 at 0.5 m per pulse. The maximum repetition rate was about 10 kHz, and the size of the focal spot was about 3.5×3.5 mm. (shrink)