Santiago Ramon y Cajal (1852 – 1934)

Santiago Ramon y Cajal. Spanish Nobel laureate in medicine.

Photo credit: Original photo is anonymous although published by Clark University in 1899. Restoration by Garrondo – Cajal.PNG, Public Domain, https://commons.wikimedia.org/w/index.php?curid=12334552

  

Santiago Ramon y Cajal was a Spanish neuroscientist and pathologist, specializing in neuroanatomy, particularly the histology of the central nervous system. He won the Nobel prize in 1906, becoming the first person of Spanish origin who won a scientific Nobel prize. His original investigations of the microscopic structure of the brain made him a pioneer of modern neuroscience. Hundreds of his drawings illustrating the delicate arborizations of brain cells are still in use for educational and training purposes.

 

Santiago Ramon y Cajal was born 1 May 1852 in the town of Petilla de Aragon, Navarre, Spain. His father was an anatomy teacher. As a child, he was transferred many times from one school to another because of behavior that was declared poor, rebellious, and showing an anti-authoritarian attitude. An extreme example of his precociousness and rebelliousness at the age of eleven is his 1863 imprisonment for destroying his neighbor’s yard gate with a homemade cannon. He was an avid painter, artist, and gymnast, but his father neither appreciated nor encouraged these abilities, even though these artistic talents would contribute to his success later in life. In order to tame the unruly character of his son, his father apprenticed him to a shoemaker and barber.

 

Ramon y Cajal as a young captain in the Ten Years’ War in Cuba, 1874.

Graphic credit: Izquierdo Vives, Public Domain, https://commons.wikimedia.org/w/index.php?curid=32562868

 

 

Over the summer of 1868, his father hoped to interest his son in a medical career, and took him to graveyards to find human remains for anatomical study. Sketching bones was a turning point for him and subsequently, he did pursue studies in medicine. Ramon y Cajal attended the medical school of the University of Zaragoza, where his father was an anatomy teacher. He graduated in 1873, aged 21. After a competitive examination, he served as a medical officer in the Spanish Army. He took part in an expedition to Cuba in 1874-75, where he contracted malaria and tuberculosis. In order to heal, he visited the Panticosa spa-town in the Pyrenees. After returning to Spain, he received his doctorate in medicine in Madrid in 1877. In 1879, he became the director of the Zaragoza Museum, and he married Silveria Fananas Garc?a, with whom he had four daughters and three sons. Cajal worked at the University of Zaragoza until 1883, when he was awarded the position of anatomy professor of the University of Valencia. His early work at these two universities focused on the pathology of inflammation, the microbiology of cholera, and the structure of epithelial cells and tissues.

 

In 1887 Cajal moved to Barcelona for a professorship. There he first learned about Golgi’s method, a cell staining method which uses potassium dichromate and silver nitrate to (randomly) stain a few neurons a dark black color, while leaving the surrounding cells transparent. This method, which he improved, was central to his work, allowing him to turn his attention to the central nervous system (brain and spinal cord), in which neurons are so densely intertwined that standard microscopic inspection would be nearly impossible. During this period he made extensive detailed drawings of neural material, covering many species and most major regions of the brain. In 1892, he became a professor in Madrid. In 1899 he became director of the National Institute of Hygiene , and in 1922 founder of the Laboratory of Biological Investigations , later renamed to the Cajal Institute. He died in Madrid on October 17, 1934, at the age of 82, continuing to work even on his deathbed.

 

Ramon y Cajal made several major contributions to neuroanatomy. He discovered the axonal growth cone, and demonstrated experimentally that the relationship between nerve cells was not continuous, but contiguous. This provided definitive evidence for what Heinrich Waldeyer coined the term neuron theory as opposed to the reticular theory This is now widely considered the foundation of modern neuroscience. Cajal was an advocate of the existence of dendritic spines, although he did not recognize them as the site of contact from presynaptic cells. He was a proponent of polarization of nerve cell function and his student, Rafael Lorente de N?, would continue this study of input-output systems into cable theory and some of the earliest circuit analysis of neural structures. By producing excellent depictions of neural structures and their connectivity and providing detailed descriptions of cell types he discovered a new type of cell, which was subsequently named after him, the interstitial cell of Cajal (ICC). This cell is found interleaved among neurons embedded within the smooth muscles lining the gut, serving as the generator and pacemaker of the slow waves of contraction which move material along the gastrointestinal tract, mediating neurotransmission from motor neurons to smooth muscle cells. In his 1894 Croonian Lecture, Ramon y Cajal suggested (in an extended metaphor) that cortical pyramidal cells may become more elaborate with time, as a tree grows and extends its branches.

 

Cajal devoted a considerable amount of time studying hypnosis which he used to help his wife during labor and parapsychological phenomena. A book he had written on these topics was lost during the Spanish Civil War. Cajal received many prizes, distinctions, and societal memberships during his scientific career, including honorary doctorates in medicine from Cambridge University and Wurzburg University and an honorary doctorate in philosophy from Clark University in the United States. The most famous distinction he was awarded was the Nobel Prize in Physiology or Medicine in 1906, together with the Italian scientist Camillo Golgi “in recognition of their work on the structure of the nervous system“. This caused some controversy because Golgi, a staunch supporter of reticular theory, disagreed with Ramon y Cajal in his view of the neuron doctrine. He published more than 100 scientific works and articles in Spanish, French and German. Among his most notable works were:

 

Rules and advice on scientific investigation

Histology

Degeneration and regeneration of the nervous system

Manual of normal histology and micrographic technique

Elements of histology

 

A list of his books includes:

 

Ramon y Cajal, Santiago (1905) [1890]. Manual de Anatomia Patologica General (Handbook of general Anatomical Pathology) (in Spanish) (fourth ed.).

Ramon y Cajal, Santiago; Richard Greeff (1894). Die Retina der Wirbelthiere: Untersuchungen mit der Golgi-cajal’schen Chromsilbermethode und der ehrlich’schen Methylenblauf?rbung (Retina of vertebrates) (in German). Bergmann.

Ramon y Cajal, Santiago; L. Azoulay (1894). Les nouvelles idees sur la structure du systeme nerveux chez l’homme et chez les vertebres’ (‘New ideas on the fine anatomy of the nerve centres) (in French). C. Reinwald.

Ramon y Cajal, Santiago; Johannes Bresler; E. Mendel (1896). Beitrag zum Studium der Medulla Oblongata: Des Kleinhirns und des Ursprungs der Gehirnnerven (in German). Verlag von Johann Ambrosius Barth.

Ramon y Cajal, Santiago (1898). “Estructura del quiasma optico y teoria general de los entrecruzamientos de las vias nerviosas. (Structure of the Chiasma opticum and general theory of the crossing of nerve tracks)“ [Die Structur des Chiasma opticum nebst einer allgemeine Theorie der Kreuzung der Nervenbahnen (German, 1899, Verlag Joh. A. Barth)]. Rev. Trim. Micrografica (in Spanish). 3: 15-65.

Ramon y Cajal, Santiago (1899). Comparative study of the sensory areas of the human cortex. p. 85. Archived from the original on 10 September 2009.

Ramon y Cajal, Santiago (1899-1904). Textura del sistema nervioso del hombre y los vertebrados (in Spanish). Madrid.

Histologie du systeme nerveux de l’homme & des vertebres (in French) – via Internet Archive.

Texture of the Nervous System of Man and the Vertebrates.

Ramon y Cajal, Santiago (1906). Studien uber die Hirnrinde des Menschen v.5 (Studies about the meninges of man) (in German). Johann Ambrosius Barth.

Ramon y Cajal, Santiago (1999) [1897]. Advice for a Young Investigator. Translated by Neely Swanson and Larry W. Swanson. Cambridge: MIT Press. ISBN 0-262-68150-1.

Ramon y Cajal, Santiago (1937). Recuerdos de mi Vida (in Spanish). Cambridge: MIT Press. ISBN 84-206-2290-7.

 

Other accomplishments and honors:

 

In 1905, he published five science-fiction stories called “Vacation Stories“ under the pen name “Dr. Bacteria“.

The asteroid 117413 Ramonycajal has been named in his honor.

 

In the 21st Century:

In 2014, the National Institutes of Health exhibited original Ramon y Cajal drawings in its Neuroscience Research Center.

 

This year 2018:

An exhibition called The Beautiful Brain: The Drawings of Santiago Ramon y Cajal travelled through the US beginning 2017 at the Weisman Art Museum in Minneapolis ending April 2019 at the Ackland Art Museum in Chapel Hill, North Carolina.

 

A short documentary by REDES is available on YouTube. Spanish public television filmed a biopic series to commemorate his life

 

Take a look at the beauty of the drawings by the great neuroscientist, Santiago Ramon-y-Cajal

 

Review of Cajal’s work

Life of the genius at work

Short biography

NIH discusses the great drawings

Discussion of 21 drawings, with a short pause between each discussion

Charles M. Lieber PhD (1959 to present)

Charles M. Lieber (Photo Credit: Wikipedia)

 

Charles M. Lieber (born 1959) is an American chemist and pioneer in the field of nanoscience and nanotechnology. In 2011, Lieber was recognized by Thomson Reuters as the leading chemist in the world for the decade 2000-2010 based on the impact of his scientific publications. Lieber has also published over 390 papers in peer-reviewed scientific journals and has edited and contributed to many books on nanoscience. He is the principal inventor on over fifty issued US patents and applications, and founded the nanotechnology company Nanosys in 2001 and Vista Therapeutics in 2007. He is known for his contributions to the synthesis, assembly and characterization of nanoscale materials and nanodevices, the application of nanoelectronic devices in biology, and as a mentor to numerous leaders in nanoscience.

 

Lieber “spent much of his childhood building – and breaking – stereos, cars and model airplanes.“ He obtained a B.A. in Chemistry from Franklin & Marshall College, graduating with honors in 1981. He went on to earn his doctorate at Stanford University in Chemistry, carrying out research on surface chemistry in the lab of Nathan Lewis, followed by a two year postdoc at Caltech in the lab of Harry Gray on long-distance electron transfer in metalloproteins. Studying the effects of dimensionality and anisotropy on the properties of quasi-2D planar structures and quasi-1D structures in his early career at Columbia and Harvard led him to become interested in the question of how one could make a one-dimensional wire, and to the epiphany that if a technology were to emerge from nascent work on nanoscale materials “it would require interconnections – exceedingly small, wire-like structures to move information around, move electrons around, and connect devices together. “Lieber was an early proponent of using the fundamental physical advantages of the very small to meld the worlds of optics and electronics and create interfaces between nanoscale materials and biological structures, and “to develop entirely new technologies, technologies we cannot even predict today.”

 

Lieber joined the Columbia University Department of Chemistry in 1987, where he was Assistant Professor (1987-1990) and Associate Professor (1990-1991) before moving to Harvard as Full Professor (1992). He now holds a joint appointment at Harvard University in the Department of Chemistry and Chemical Biology and the Harvard Paulson School of Engineering and Applied Sciences, as the Joshua and Beth Friedman University Professor. In 2015 he became Chair of the Department of Chemistry and Chemical Biology.

 

Lieber’s contributions to the rational growth, characterization, and applications of a range of functional nanoscale materials and heterostructures have provided concepts central to the bottom-up paradigm of nanoscience. These include rational synthesis of functional nanowire building blocks, characterization of these materials, and demonstration of their application in areas ranging from electronics, computing, photonics, and energy science to biology and medicine.

 

Nanomaterials synthesis: In his early work, Lieber articulated the motivation for pursuing designed growth of nanometer-diameter wires in which composition, size, structure and morphology could be controlled over a wide range, and outlined a general method for the first controlled synthesis of free-standing single-crystal semiconductor nanowires, providing the groundwork for predictable growth of nanowires of virtually any elements and compounds in the periodic table. He proposed and demonstrated a general concept for the growth of nanoscale axial heterostructures and the growth of nanowire superlattices with new photonic and electronic properties, the basis of intensive efforts today in nanowire photonics and electronics. In parallel, he proposed and demonstrated the heterojunction concept of radial core-shell nanowire structures and single-crystalline multi-quantum well structures. Lieber also demonstrated a synthetic methodology to introduce controlled stereocenters – kinks – into nanowires, introducing the possibility of increasingly complex and functional nanostructures for three-dimensional nanodevices.

 

Nanostructure characterization: Lieber developed applications of scanning probe microscopies that could provide direct experimental measurement of the electrical and mechanical properties of individual carbon nanotubes and nanowires. This work showed that semiconductor nanowires with controlled electrical properties can be synthesized, providing electronically tunable functional nanoscale building blocks for device assembly. Additionally, Lieber invented chemical force microscopy to characterize the chemical properties of materials surfaces with nanometer resolution.

 

Nanoelectronics and nanophotonics: Lieber has used quantum-confined core/shell nanowire heterostructures to demonstrate ballistic transport, the superconducting proximity effect, and quantum transport. Other examples of functional nanoscale electronic and optoelectronic devices include nanoscale electrically driven lasers using single nanowires as active nanoscale cavities, carbon nanotube nano-tweezers, nanotube-based ultrahigh-density electromechanical memory, an all-inorganic fully integrated nanoscale photovoltaic cell and functional logic devices and simple computational circuits using assembled semiconductor nanowires. These concepts led to the integration of nanowires on the Intel roadmap, and their current top-down implementation of these structures.

 

Nanostructure assembly and computing: Lieber has originated a number of approaches for parallel and scalable of assembly of nanowire and nanotube building blocks. The development of fluidic-directed assembly and subsequent large-scale assembly of electrically addressable parallel and crossed nanowire arrays was cited as one of the Breakthroughs of 2001 by Science. He also developed a lithography-free approach to bridging the macro-to-nano scale gap using modulation-doped semiconductor nanowires. Lieber recently introduced the assembly concept ?nanocombing,’ which can be used to align nanoscale wires in a deterministic manner independent of material. He used this concept to create a programable nanowire logic tile and the first stand-alone nanocomputer.

 

Nanoelectronics for biology and medicine: Lieber demonstrated the first direct electrical detection of proteins, selective electrical sensing of individual viruses and multiplexed detection of cancer marker proteins and tumor enzyme activity. His approach uses electrical signals for high-sensitivity, label-free detection, for use in wireless/remote medical applications. More recently, Lieber demonstrated a general approach to overcome the Debye screening that makes these measurements challenging in physiological conditions, overcoming the limitations of sensing with silicon nanowire field-effect devices and opening the way to their use in diagnostic healthcare applications. Lieber has also developed nanoelectronic devices for cell/tissue electrophysiology, showing that electrical activity and action potential propagation can be recorded from cultured cardiac cells with high resolution. Most recently, Lieber realized 3D nanoscale transistors in which the active transistor is separated from the connections to the outside world. His nanotechnology-enabled 3D cellular probes have shown point-like resolution in detection of single-molecules, intracellular function and even photons.

 

Nanoelectronics and brain science: The development of nanoelectronics-enabled cellular tools underpins Lieber’s views on transforming electrical recording and modulation of neuronal activity in brain science. Examples of this work include the integration of arrays of nanowire transistors with neurons at the scale that the brain is wired biologically, mapping functional activity in acute brain slices with high spatiotemporal resolution and a 3D structure capable of interfacing with complex neural networks. He developed macroporous 3D sensor arrays and synthetic tissue scaffold to mimic the structure of natural tissue, and for the first time generated synthetic tissues that can be innervated in 3D, showing that it is possible to produce interpenetrating 3D electronic-neural networks following cell culture.

 

Lieber’s current work focuses on integrating electronics in a minimally/non-invasive manner within the central nervous system. Most recently, he has demonstrated that this macroporous electronics can be injected by syringe to position devices in a chosen region of the brain. Chronic histology and multiplexed recording studies demonstrate minimal immune response and noninvasive integration of the injectable electronics with neuronal circuitry. Reduced scarring may explain the mesh electronics’ (also referred to as neural lace) demonstrated recording stability on time scales of up to a year. This concept of electronics integration with the brain as a nanotechnological tool potentially capable of treating neurological and neurodegenerative diseases, stroke and traumatic injury has drawn attention from a number of media sources. Scientific American named injectable electronics one of 2015’s top ten world changing ideas. Chemical & Engineering News called it “the most notable chemistry research advance of 2015.“

 

Lieber is an elected member of the National Academy of Sciences, the American Academy of Arts and Sciences, the National Academy of Medicine, the National Academy of Inventors, and an elected Foreign Member of the Chinese Academy of Sciences (2015). He is an elected Fellow of the Materials Research Society, American Chemical Society (Inaugural Class), Institute of Physics, International Union of Pure and Applied Chemistry (IUPAC), American Association for the Advancement of Science, and World Technology Network, and Honorary Fellow of the Chinese Chemical Society. In addition he belongs to the American Physical Society, Institute of Electrical and Electronics Engineers, International Society for Optical Engineering, Optical Society of America, Biophysical Society and Society for Neuroscience. Lieber is Co-editor of the journal Nano Letters, and serves on the editorial and advisory boards of a number of science and technology journals.

 

Other Interests: Since 2007 Lieber has grown giant pumpkins in his back yard in Lexington, MA. In 2010 he won the annual weigh-off at Frerich’s Farm in Rhode Island with a 1,610-lb pumpkin, and returned in 2012 with a 1,770-lb pumpkin that won 2nd place in that year’s weigh-off but set a Massachusetts record. His 1,870-lb pumpkin in 2014 was named the largest pumpkin in Massachusetts and ranked 17th largest in the world that year. The discrepancy between the size scales of his day job and hobby has been noted: “on the one hand, Lieber’s chemistry” has had a defining influence on the field of nanoscience and nanotechnology, “according to his CV. On the other, his pumpkin could probably fill an entire Trader Joe’s with pumpkin specialty products for the fall season.”

Sources: Wikipedia, Harvard.edu and NIH.gov

 

Thomas Bayes (1701-1761)

Graphic credit: Unknown, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14532025

 

The randomized clinical trial is widely viewed to be the gold standard for evaluation of treatments, diagnostic procedures, or disease screening. The proper design and analysis of a clinical trial requires careful consideration of the study objectives (e.g., whether to demonstrate treatment superiority or non-inferiority) and the nature of the primary end point. Different statistical methods apply when the end point variable is discrete (counts), continuous (measurements), or time to event (survival analysis). Other complicating factors include patient noncompliance, loss to follow-up, missing data, and multiple comparisons when more than 2 treatments are evaluated in the same study.  The best known statistical method used today, in clinical trials is the Bayesian method, named after 18thCentury Thomas Bayes.

 

Thomas Bayes (1701 – 1761) was an English statistician, philosopher and Presbyterian minister who is known for having formulated a specific case of the theorem that bears his name: Bayes’ theorem. Bayes never published what would eventually become his most famous accomplishment; his notes were edited and published after his death by Richard Price. Bayes was the son of London Presbyterian minister Joshua Bayes, and was possibly born in Hertfordshire. He came from a prominent nonconformist family from Sheffield. In 1719, he enrolled at the University of Edinburgh to study logic and theology. On his return around 1722, he assisted his father at the latter’s chapel in London before moving to Tunbridge Wells, Kent, around 1734. There he was minister of the Mount Sion chapel, until 1752.

 

Bayes is known to have published two works in his lifetime, one theological and one mathematical:

 

1. Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731)

 

2. An Introduction to the Doctrine of Fluxions, and a Defence of the Mathematicians Against the Objections of the Author of The Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newton’s calculus (“fluxions”) against the criticism of George Berkeley, author of The Analyst

 

It is speculated that Bayes was elected as a Fellow of the Royal Society in 1742 on the strength of the Introduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime. In his later years, Bayes took a deep interest in probability. Professor Stephen Stigler, historian of statistical science, thinks that Bayes became interested in the subject while reviewing a work written in 1755 by Thomas Simpson, but George Alfred Barnard thinks he learned mathematics and probability from a book by Abraham de Moivre.  Others speculate he was motivated to rebut David Hume’s argument against believing in miracles on the evidence of testimony in An Enquiry Concerning Human Understanding.  His work and findings on probability theory were passed in manuscript form to his friend Richard Price after his death. By 1755 he was ill and by 1761 had died in Tunbridge Wells. He was buried in Bunhill Fields burial ground in Moorgate, London, where many nonconformists lie.

 

Bayes’ solution to a problem of inverse probability was presented in “An Essay towards solving a Problem in the Doctrine of Chances” which was read to the Royal Society in 1763 after Bayes’ death. Richard Price shepherded the work through this presentation and its publication in the Philosophical Transactions of the Royal Society of London the following year. This was an argument for using a uniform prior distribution for a binomial parameter and not merely a general postulate. This essay contains a statement of a special case of Bayes’ theorem. In the first decades of the eighteenth century, many problems concerning the probability of certain events, given specified conditions, were solved. For example: given a specified number of white and black balls in an urn, what is the probability of drawing a black ball? Or the converse: given that one or more balls has been drawn, what can be said about the number of white and black balls in the urn? These are sometimes called “inverse probability” problems. Bayes’ “Essay” contains his solution to a similar problem posed by Abraham de Moivre, author of The Doctrine of Chances (1718). In addition, a paper by Bayes on asymptotic series was published posthumously.

 

Bayesian probability is the name given to several related interpretations of probability as an amount of epistemic confidence – the strength of beliefs, hypotheses etc. -, rather than a frequency. This allows the application of probability to all sorts of propositions rather than just ones that come with a reference class. “Bayesian” has been used in this sense since about 1950. Since its rebirth in the 1950s, advancements in computing technology have allowed scientists from many disciplines to pair traditional Bayesian statistics with random walk techniques. The use of the Bayes theorem has been extended in science and in other fields. Bayes himself might not have embraced the broad interpretation now called Bayesian, which was in fact pioneered and popularized by Pierre-Simon Laplace; it is difficult to assess Bayes’ philosophical views on probability, since his essay does not go into questions of interpretation. There Bayes defines probability of an event as “the ratio between the value at which an expectation depending on the happening of the event ought to be computed, and the value of the thing expected upon its happening”. Within modern utility theory, the same definition would result by rearranging the definition of expected utility (the probability of an event times the payoff received in case of that event – including the special cases of buying risk for small amounts or buying security for big amounts) to solve for the probability. As Stigler points out, this is a subjective definition, and does not require repeated events; however, it does require that the event in question be observable, for otherwise it could never be said to have “happened”. Stigler argues that Bayes intended his results in a more limited way than modern Bayesians. Given Bayes’ definition of probability, his result concerning the parameter of a binomial distribution makes sense only to the extent that one can bet on its observable consequences.

 

Bayes was elected to membership in the Royal Society in 1742; and his nomination letter has been posted with other membership records at the Royal Society website. Those signing that nomination letter were: Philip Stanhope; Martin Folkes; James Burrow; Cromwell Mortimer; John Eames.

 

Click here if you’re interested in reading a short piece about the multi-armed bandits, or slot machines, and how/why statistics are important when it comes to gambling at these machines in Las Vegas.

 

Slot machines in Las Vegas

Photo credit: Wikipedia

 

Antonio Damasio MD, PhD (1944 to present)

Antonio Damasio giving a talk at the Universidade de Sao Paulo, in Brazil in 2013.

Photo credit: Fronteiras do Pensamento – This file has been extracted from another file: Antonio Damasio no Fronteiras do Pensamento Porto Alegre 2013 original file, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=50130700

 

 

Antonio Damasio is a Portuguese-American neuroscientist who is currently the David Dornsife Professor of Neuroscience, Psychology and Philosophy at the University of Southern California, and an adjunct professor at the Salk Institute. Damasio heads the Brain and Creativity Institute, and has authored several books including, Self Comes to Mind: Constructing the Conscious Brain (2010), which explores the relationship between the brain and consciousness. His most recent book, about to be released in February 2018 is The Strange Order of Things: Life, Feeling, and the Making of Cultures. Damasio’s research in neuroscience has shown that emotions play a central role in social cognition and decision-making. Damasio continues his quest for a theory of human consciousness, in his latest book he links feelings and culture with homeostasis and evolution. His ideas are exciting, his explanations tend to be abstract, as might be expected when describing consciousness. He writes that “the constructions that inhabit our minds can well be imagined as ephemeral musical performances, played by several hidden orchestras.“ Attempting to explain “the biological underpinnings of the human cultural mind,“ Damasio begins with the Cambrian unicellular organism and shows how the mapping of internal and external images led to the development of nervous systems, which in turn laid the groundwork for verbal language, consciousness, subjectivity, and feeling. Damasio posits that feelings in humans “arose from a series of gradual, body-related processes accumulated and maintained over evolution.“ He then explores the biological roots of culture, particularly the role homeostasis played in generating behavioral strategies. Damasio extends his thinking on homeostasis to the shaping of moral codes and the emergence of religious and political systems, and even to the internet and what he dubs “the current crisis of the human condition.“ Wide in scope, Damasio’s book contains moments of genius but feels like a work in progress. As expected from a scientist whose life has been dedicated to a constant search for difficult solutions.

 

Damasio studied medicine at the University of Lisbon Medical School, where he also did his neurological residency and completed his doctorate. For part of his studies, he researched behavioral neurology under the supervision of Norman Geschwind of the Aphasia Research Center in Boston. Damasio’s main field is neurobiology, especially the neural systems which underlie emotion, decision-making, memory, language and consciousness. Damasio believes that emotions play a critical role in high-level cognition – an idea counter to dominant views in psychology, neuroscience and philosophy. Damasio formulated the somatic marker hypothesis, a theory about how emotions and their biological underpinnings are involved in decision-making (both positively and negatively, and often non-consciously). Emotions provide the scaffolding for the construction of social cognition and are required for the self processes which undergird consciousness. “Damasio provides a contemporary scientific validation of the linkage between feelings and the body by highlighting the connection between mind and nerve cells, this personalized embodiment of mind.“

 

The somatic marker hypothesis has inspired many neuroscience experiments carried out in laboratories in the U.S. and Europe, and has had a major impact in contemporary science and philosophy. Damasio has been named by the Institute for Scientific Information as one of the most highly cited researchers in the past decade. Current work on the biology of moral decisions, neuro-economics, social communication, and drug-addiction, has been strongly influenced by Damasio’s hypothesis. An article published in the Archives of Scientific Psychology in 2014 named Damasio one of the 100 most eminent psychologist of the modern era. (Diener et al. Archives of Scientific Psychology, 2014, 2, 20-32). The June-July issue of Sciences Humaines included Damasio in its list of 50 key thinkers in the human sciences of the past two centuries.

 

Damasio also proposed that emotions are part of homeostatic regulation and are rooted in reward/punishment mechanisms. He recovered William James’ perspective on feelings as a read-out of body states, but expanded it with an “as-if-body-loop“ device which allows for the substrate of feelings to be simulated rather than actual (foreshadowing the simulation process later uncovered by mirror neurons). He demonstrated experimentally that the insular cortex is a critical platform for feelings, a finding that has been widely replicated, and he uncovered cortical and subcortical induction sites for human emotions, e.g. in ventromedial prefrontal cortex and amygdala. He also demonstrated that while the insular cortex plays a major role in feelings, it is not necessary for feelings to occur, suggesting that brain stem structures play a basic role in the feeling process. He has continued to investigate the neural basis of feelings and demonstrated that although the insular cortex is a major substrate for this process it is not exclusive, suggesting that brain stem nuclei are critical platforms as well. He regards feelings as the necessary foundation of sentience.

 

In another development, Damasio proposed that the cortical architecture on which learning and recall depend involves multiple, hierarchically organized loops of axonal projections that converge on certain nodes out of which projections diverge to the points of origin of convergence (the convergence-divergence zones). This architecture is applicable to the understanding of memory processes and of aspects of consciousness related to the access of mental contents. In The Feeling of What Happens, Damasio laid the foundations of the “enchainment of precedences“: “the nonconscious neural signaling of an individual organism begets the proto-self which permits core self and core consciousness, which allow for an autobiographical self, which permits extended consciousness. At the end of the chain, extended consciousness permits conscience.

 

Damasio’s research depended significantly on establishing the modern human lesion method, an enterprise made possible by Hanna Damasio’s structural neuroimaging/neuroanatomy work complemented by experimental neuroanatomy (with Gary Van Hoesen and Josef Parvizi), experimental neuropsychology (with Antoine Bechara, Ralph Adolphs, and Dan Tranel) and functional neuroimaging (with Kaspar Meyer, Jonas Kaplan, and Mary Helen Immordino-Yang). The experimental neuroanatomy work with Van Hoesen and Bradley Hyman led to the discovery of the disconnection of the hippocampus caused by neurofibrillary tangles in the entorhinal cortex of patients with Alzheimer’s disease. Damasio’s books deal with the relationship between emotions and their brain substrates. His 1994 book, Descartes’ Error: Emotion, Reason and the Human Brain, won the Science et Vie prize, was a finalist for the Los Angeles Times Book Award, and is translated in over 30 languages. It is regarded as one of the most influential books of the past two decades. His second book, The Feeling of What Happens: Body and Emotion in the Making of Consciousness, was named as one of the ten best books of 2001 by the New York Times Book Review, a Publishers Weekly Best Book of the Year, a Library Journal Best Book of the Year, and has over 30 foreign editions. Damasio’s Looking for Spinoza: Joy, Sorrow, and the Feeling Brain, was published in 2003. In it, Damasio suggested that Spinoza’s thinking foreshadowed discoveries in biology and neuroscience views on the mind-body problem and that Spinoza was a proto-biologist. In Damasio’s book, Self Comes to Mind: Constructing the Conscious Brain. Damasio suggests that the self is the key to conscious minds and that feelings, from the kind he designates as primordial to the well-known feelings of emotion, are the basic elements in the construction of the proto-self and core self. The book received the Corinne International Book Prize.

 

Damasio is a member of the American Academy of Arts and Sciences, the National Academy of Medicine, the European Academy of Sciences and Arts. He is the recipient of several prizes, amongst them the Grawemeyer Award, the Honda Prize, the Prince of Asturias Award in Science and Technology and the Beaumont Medal from the American Medical Association, as well as honorary degrees from, most recently, the Sorbonne (Universit? Paris Descartes), shared with his wife Hanna Damasio. He has also received doctorates from the Universities of Aachen, Copenhagen, Leiden, Barcelona, Coimbra, Leuven and numerous others. In 2013, the Escola Secundaria Antonio Damasio was dedicated in Lisbon. He says he writes in the belief that “scientific knowledge can be a pillar to help humans endure and prevail.“ Damasio additionally serves on the board of directors of the Berggruen Institute, and sits on the jury for the Berggruen Prize for Philosophy.

 

Great Ormond Street Hospital (London) for Children

The above photo shows part of Great Ormond Street Hospital in London, United Kingdom, which was the first pediatric hospital in the English-speaking world.

Photo credit: Nigel Cox, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=5364709

 

Great Ormond Street Hospital (informally GOSH or Great Ormond Street, formerly the Hospital for Sick Children) is a children’s hospital located in the Bloomsbury area of the London Borough of Camden, and a part of Great Ormond Street Hospital for Children NHS Foundation Trust. The hospital, founded in 1852, is the largest center for child heart surgery in the UK and one of the largest centers for heart transplantation in the world. In 1962, almost one hundred years after its founding, they developed the first heart and lung bypass machine for children. With children’s book author Roald Dahl, they developed an improved shunt valve for children with water on the brain (hydrocephalus), and non-invasive (percutaneous) heart valve replacements. They did the first UK clinical trials of the rubella vaccine, and the first bone marrow transplant and gene therapy for severe combined immunodeficiency. This children’s hospital is closely associated with University College London (UCL) and in partnership with the UCL Great Ormond Street Institute of Child Health, which is adjacent to it, is the largest center for research and postgraduate teaching in children’s health in Europe.

 

After a long campaign by Dr. Charles West, the Hospital for Sick Children was founded on 14 February 1852 and was the first hospital providing in-patient beds specifically for children in England. Despite opening with just 10 beds, it grew into one of the world’s leading children’s hospitals through the patronage of Queen Victoria, counting Charles Dickens, a personal friend of Dr. West, the Chief Physician, as one of its first fundraisers.

 

Audrey Callaghan, wife of James Callaghan (prime minister of the United Kingdom from 1976 to 1979), served the hospital as Chairman of the Board of Governors from 1968 to 1972 and then as Chairman of the Special Trustees from 1983 until her final retirement in 1990. Diana, Princess of Wales, served as president of the Hospital from 1989 until her death. A plaque at the entrance of the hospital commemorates her services, as well as a bust in the lobby of the hospital chapel. The Charles West School of Nursing transferred from Great Ormond Street to London South Bank University in 1995. In 2002 Great Ormond Street Hospital commenced a redevelopment program which is budgeted at ?343 million and the next phase of which was scheduled to be complete by the end of 2016. The redevelopment was needed to expand capacity, deliver treatment in a more comfortable and modern way, and to reduce unnecessary inpatient admissions. In July 2012, Great Ormond Street Hospital was featured in the opening ceremony of the London Summer Olympics and in 2017 Great Ormond Street Hospital was subject to international attention regarding the Charlie Gard treatment controversy. The hospital’s archives are available for research under the terms of the Public Records Act 1958 and a catalogue is available on request. Admission records from 1852 to 1914 have been made available online on the Historic Hospital Admission Records Project.

 

St Christopher’s Chapel, in Great Ormond Street Hospital, is a chapel decorated in the Byzantine style and a Grade II listed building located in the Variety Club Building of the hospital. Designed by Edward Middleton Barry (son of the architect Sir Charles Barry who designed the Houses of Parliament) and built in 1875, it is dedicated to the memory of Caroline Barry, wife of William Henry Barry (eldest son of Sir Charles Barry) who provided the money required to build the Chapel and a stipend for the chaplain. It was built in “elaborate Franco-Italianate style.“ As the chapel exists to provide pastoral care to ill children and their families, many of its details refer to childhood. The stained glass depicts the Nativity, the childhood of Christ and biblical scenes related to children. The dome depicts a pelican pecking at her breast in order to feed her young with drops of her own blood, a traditional symbol of Christ’s sacrifice for humanity. When the old hospital was being demolished in the late 1980s, the chapel was moved to its present location via a ‘concrete raft’ to prevent any damage. The stained glass and furniture were temporarily removed for restoration and repair. It was reopened along with the new Variety Club Building on 14 February 1994 by Diana, Princess of Wales, then president of the hospital.

 

In April 1929 the hospital was the recipient of playwright J. M. Barrie’s copyright to the Peter Pan works, with the provision that the income from this source not be disclosed. This gave the institution control of the rights to these works, and entitled it to royalties from any performance or publication of the play and derivative works. Four theatrical feature films were produced, innumerable performances of the play have been presented, and numerous editions of the novel were published under license from the hospital. Its trustees commissioned a sequel novel, Peter Pan in Scarlet, which was published in 2006 and received mixed reviews, with a film adaptation planned. When the copyright first expired at the end of 1987 in the UK, 50 years after Barrie’s death, the UK government’s Copyright, Designs and Patents Act of 1988 granted the hospital a perpetual right to collect royalties for public performances, commercial publication, or other communications to the public, of the work, but this does not constitute a true copyright. When copyright term itself was subsequently extended to the author’s life plus 70 years by a European Union directive in 1996 standardizing terms throughout the EU, GOSH revived its copyright of Peter Pan which then expired in 2007. The terms of the Copyright, Designs and Patents Act now prevail in the UK.

 

GOSH has been in legal disputes in the United States, where the copyright term is based on date of publication, putting the 1911 novel in the public domain, although the Hospital asserts that the 1928 version of the play is still under copyright in the US. Legal opinion as to whether or not permission is required for new works based on the story and characters is divided and open to interpretation and so far, there has been no legal precedent to prove one view or the other.

 

The hospital has relied on charitable support since it first opened. One of the main sources for this support is Great Ormond Street Hospital Children’s Charity. While the NHS meets the day-to-day running costs of the hospital, the fundraising income allows Great Ormond Street Hospital to remain at the forefront of child healthcare. The charity aims to raise over 50 million pounds every year to complete the next two phases of redevelopment, as well as provide substantially more fundraising directly for research. The charity also purchases up-to-date equipment, and provides accommodation for families and staff. The charity’s teardrop logo was designed for the Wishing Well Appeal in 1987 by the firm Collett Dickenson Pearce. Great Ormond Street Hospital Children’s Charity was one of the charities that benefited from the national Jeans for Genes campaign, which encourages people across the UK to wear their jeans and make a donation to help children affected by genetic disorders. All Great Ormond Street Hospital Charity’s proceeds from the campaign went to its research partner, the UCL Institute of Child Health.

 

On 6 August 2009, Arsenal F.C. confirmed that Great Ormond Street Hospital Children’s Charity was to be their ‘charity of the season’ for the 2009-10 season. They raised over 800,000 pounds for a new lung function unit at the hospital, having raised 532,816 pounds for Teenage Cancer Trust in the previous season. Two charity singles have been released in aid of the hospital. In 1987, “The Wishing Well”, recorded by an ensemble line-up including Boy George, Peter Cox and Dollar among others, and became a top 30 hit. In 2009, The X Factor finalists covered Michael Jackson’s “You Are Not Alone” in aid of the charity, reaching No.1 in the UK Charts. Also, the winner’s singles of James Arthur and Sam Bailey have been released in aid of the charity. On 30 March 2010, Channel 4 staged the first Channel 4’s Comedy Gala at the O2 Arena in London, in aid of the charity. The event has been repeated every year since, raising money for Great Ormond Street Hospital Children’s Charity each time. In 2011, Daniel Boys recorded a charity single called ‘The World is Something You Can Imagine’. It was also released as with proceeds going to the Disney Appeal at Great Ormond Street Hospital. Source: Wikipedia

 

Hans Gerhard Creutzfeldt MD

Hans Gerhard Creutzfeldt (June 2, 1885 – December 30, 1964) was a German neuropathologist, who first described the Creutzfeldt-Jakob disease. He was born in Harburg upon Elbe and died in Munich.

Photo credit: Unknown – http://www.sammlungen.hu-berlin.de/dokumente/11727/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4008658

 

 

Hans Gerhard Creutzfeldt was born into a medical family in Harburg, which was incorporated into Hamburg in 1937. In 1903, at the age of 18, Creutzfeldt was drafted into the German army and spent his service stationed in Kiel. Afterwards, he attended the School of Medicine of the Universities of University of Jena and University of Rostock, receiving his doctorate at the latter in 1909. Part of his practical training was undertaken at St. Georg – Hospital in Hamburg. After qualification he sought adventure as a ship’s surgeon, voyaging the Pacific Ocean, taking the opportunity to study local crafts, linguistics, and tropical plants. After returning to Germany, Creutzfeldt worked at the Neurological Institute in Frankfurt am Main, at the psychiatric-neurological clinics in Breslau, Kiel and Berlin, and at the Deutsche Forschungsanstalt fur Psychiatrie in Munich. Creutzfeldt was habilitated at Kiel in 1920, and in 1925 became Extraordinarius of psychiatry and neurology. In 1938 he was appointed professor and director of the university psychiatric and neurological division in Kiel. Later, Creutzfeldt helped to recognize a neurodegenerative disease, with Alfons Maria Jakob, now known as Creutzfeldt-Jakob disease, in which the brain tissue develops holes and takes on a sponge-like texture. It is now known that this disease is due to a type of infectious protein called a prion. Prions are misfolded proteins which replicate by converting their properly folded counterparts.

 

In the Third Reich, Creutzfeldt became a Patron Member of Heinrich Himmler’s SS. However, when Creutzfeldt was 54 years old and WW2 broke out, he was unmoved by the Nazi regime and was able to save some people from death in concentration camps. He also managed to rescue almost all of his patients from being murdered under the Nazi Action T4 euthanasia program, an unusual event since most mental patients identified by T4 personnel were gassed or poisoned at separate euthanasia clinics such as Hadamar Euthanasia Centre. During the war, bombing raids destroyed his home and clinic. After the war he was director of the University of Kiel for six months, before being dismissed by the British occupation forces. His efforts to rebuild the university caused a series of conflicts with the British because he wanted to allow more former army officers to study there. In 1953 he moved on to Munich to work on scientific research commissioned by the Max Planck Society.

 

Creutzfeldt was married to Clara Sombart, a daughter of Werner Sombart. They had five children, among them Otto Detlev Creutzfeldt and Werner Creutzfeldt (1924-2006), a renowned German Internist. Hans Gerhard Creutzfeldt died in 1964 in Munich.

 

As mentioned above, Creutzfeldt-Jakob disease, is a subacute spongiform encephalopathy caused from prions involving the cerebral cortex, the basal ganglia and the spinal cord. Some of the clinical findings described in the Creutzfeldt and Jakob first papers do not match current criteria for Creutzfeldt-Jakob disease. It has been speculated that at least two of the patients in initial studies were suffering from a different ailment. A study published in 1997 counted more than 100 cases worldwide of transmissible CJD and new cases continued to appear at the time. The first report of suspected iatrogenic CJD was published in 1974. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways. A second case of CJD associated with a corneal transplant was reported without details. In 1977, CJD transmission caused by silver electrodes previously used in the brain of a person with CJD was first reported. Transmission occurred despite decontamination of the electrodes with ethanol and formaldehyde. Retrospective studies identified four other cases likely of similar cause. The rate of transmission from a single contaminated instrument is unknown, although it is not 100%. In some cases, the exposure occurred weeks after the instruments were used on a person with CJD.

 

A review article published in 1979 indicated that 25 dura mater cases had occurred by that date in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States.

By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans. In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person. In 2004, a report published by Edinburgh doctors in the Lancet medical journal demonstrated that vCJD was transmitted by blood transfusion.

 

Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 “for his discovery of Prions – a new biological principle of infection“. However, Yale University neuropathologist Laura Manuelidis has challenged the prion protein (PrP) explanation for the disease. In January 2007, she and her colleagues reported that they had found a virus-like particle in naturally and experimentally infected animals. “The high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid-protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions.“ Four Australians had been reported with CJD following transfusion as of 1997. There have been ten cases of healthcare-acquired CJD in Australia. They consist of five deaths following treatment with pituitary extract hormone for either infertility or short stature, with no further cases since 1991. The five other deaths were caused by dura grafting during brain surgery, where the covering of the brain was repaired. There have been no other known healthcare-acquired CJD deaths in Australia. A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt-Jakob disease (CJD) in 2012.

 

Researchers believe one in 2,000 people in the UK is a carrier of the disease linked to eating contaminated beef (vCJD). The survey provides the most robust prevalence measure to date – and identifies abnormal prion protein across a wider age group than found previously and in all genotypes, indicating “infection“ may be relatively common. This new study examined over 32,000 anonymous appendix samples. Of these, 16 samples were positive for abnormal prion protein, indicating an overall prevalence of 493 per million population, or one in 2,000 people are likely to be carriers. No difference was seen in different birth cohorts (1941-60 and 1961-85), in both genders, and there was no apparent difference in abnormal prion prevalence in three broad geographical areas. Genetic testing of the 16 positive samples revealed a higher proportion of valine homozygous (VV) genotype on the codon 129 of the gene encoding the prion protein (PRNP) compared with the general UK population. This also differs from the 177 patients with vCJD, all of whom to date have been methionine homozygous (MM) genotype. The concern is that individuals with this VV genotype may be susceptible to developing the condition over longer incubation periods.

 

In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire in the United States. Massachusetts General Hospital believed the patient acquired the disease from a surgical instrument at a podiatrist’s office. In September 2013, another patient in Manchester, New Hampshire was posthumously determined to have died of the disease. The patient had undergone brain surgery at Catholic Medical Center three months before his death, and a surgical probe used in the procedure was subsequently reused in other operations. Public health officials identified thirteen patients at three hospitals who may have been exposed to the disease through the contaminated probe, but said the risk of anyone’s contracting CJD is “extremely low.“ In January 2015, the former speaker of the Utah House of Representatives, Rebecca D. Lockhart, died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016.

 

An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003. The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient’s lateral ventricle within the brain. PPS does not seem to stop the disease from progressing, and both brain function and tissue continue to be lost. However, the treatment is alleged to slow the progression of the otherwise untreatable disease, and may have contributed to the longer than expected survival of the seven patients studied. Simms died in 2011. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 patients with PPS finds no proof of efficacy because of the lack of accepted objective criteria. Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years. Both amphotericin B and doxorubicin have been investigated as potentially effective against CJD, but as yet there is no strong evidence that either drug is effective in stopping the disease. Further study has been taken with other medical drugs, but none are effective. However, anticonvulsants and anxiolytic agents, such as valproate or a benzodiazepine, may be administered to relieve associated symptoms.

 

Scientists from the University of California, San Francisco are currently running a treatment trial for sporadic CJD using quinacrine, a medicine originally created for malaria. Pilot studies showed quinacrine permanently cleared abnormal prion proteins from cell cultures, but results have not yet been published on their clinical study. The efficacy of quinacrine was also assessed in a rigorous clinical trial in the UK and the results were published in Lancet Neurology, and concluded that quinacrine had no measurable effect on the clinical course of CJD. In a 2013 paper published in the Proceedings of the National Academy of Sciences, scientists from The Scripps Research Institute reported that Astemizole, a medication approved for human use, has been found to have anti-prion activity and may lead to a treatment for Creutzfeldt-Jakob disease.

 

A Short History of Pills

An old Cadmach rotary tablet press

Photo credit: Slashme at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21895660

 

 

Pills date back to roughly 1500 BCE. They were presumably invented so that measured amounts of a medicinal substance could be delivered to a patient. A long time ago, around 4,000 years or so, medicines were generally liquid preparations. An inscription on an Assyrian clay tablet instructs the user to pulverize various seeds, plant resins and leaves together–then dissolve them in beer. Pills are first referenced in ancient Egyptian. One famous set of papyruses is filled with medical remedies, including pills made from bread dough, honey or grease. Medicinal plants would be reduced to powders, and other active ingredients, and would then be mixed with these substances–then little balls, or pills, would be formed with the fingers. Early ingredients of pills included saffron, myrrh, cinnamon, tree resins and many other botanicals. Pills came in various sizes as well as flat and round, and other assorted shapes. As far back as 500 BCE, some were even trademarked with special indentations in the pills.

 

Hippocrates, knew about the curative powers of willow bark. And in ancient Greece, the round balls or other shapes were called katapotia (meaning “something to be swallowed“). It was the Roman scholar Pliny (23-79 CE–who first coined the word “pilula.“

 

Some early pills still exist in museums, such as a famous one dating from 500 BCE. that was known as Terra Sigillata–consisting of clay from a particular island that was mixed with goat’s blood then shaped into pills. Terra Sigillata was supposedly good for practically every ailment, including dysentery, ulcers and gonorrhea. A pill was originally defined as a small, round, solid pharmaceutical oral dosage form of medication. The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes, and were found aboard a Roman ship Relitto del Pozzino which wrecked in 140 BCE. Today, pills include tablets, capsules, and variants thereof like caplets ? essentially any solid form of medication, colloquially falls into the pill category. There are pieces of ancient Roman pill-making equipment, such as a carved stone in the British Museum. The stone has long flat grooves into which the pill maker would press clay or other substances to make long, snaky strings. Then the pill maker would pry the strings out and cut them into discs to form pills–much the way one cuts dough for cookies.

 

During the Middle medieval times, people would coat their pills with slimy plant substances and other materials so they were easier to swallow and tasted less bitter. Some pills were rolled in spices, and later pills began to be coated with gold and silver. Silver, unfortunately, rendered the pills pretty inert, since they’d pass right through the digestive tract without releasing any of their medicinal compounds. Gilding of pills, continued well into the 19th century. Medicines in pill form were popular in 17th century England and thereafter. Pill manufacturers were granted special patent rights from the king for their top-secret formulas. One famous patented product from the 18th century: “Hooper’s Female Pills,“ which were guaranteed to contain “the best purging and anti-hysterik ingredients.“ And pills, of course, made their way over to the still-new United States–which had its own set of patent-protected preparations, courtesy of the U.S. Patent office–including Chase’s Kidney-Liver Pills, Cheeseman’s Female Regulating Pills and Williams’ Pink Pills for Pale People.

 

The old-fashioned, roll-and-cut kinds of pills had a drawback: Their preparation required moisture. Early researchers, (doctors) were learning that this moisture could de-activate the drugs contained. In the 1800s, innovators began sugar-coating and gelatin-coating pills. At this time gelatin capsules were invented, as well as the ability to compress tablets. In 1843, English scientist, William Brockedon invented a different pill form. Powder was placed in a tube and then compressed with a mallet, until it solidified. Eventually, this invention became popular. Holloway’s Pills were perhaps the most famous of the patent medicines, and were popular enough to make Thomas Holloway a wealthy man. Testimonials to the value of the pills can be found at this time, in newspapers all over the British Empire, including Indian, Australia and the North American colonies. The range of diseases the pills claimed to cure is astonishing. Along with Holloway’s Ointment, Holloway’s Pills could treat almost anything. Analysis of the pills showed that they contained aloe, myrrh, and saffron. While probably not harmful, these pills would be unlikely to have the claimed affects. The Holloway advertising changed from time to time, listing a variety of dangers that the pills could prevent. An example, for “Children’s Complaints“:

 

“It is not generally known, but such is the fact that children require medicine oftener than their parents. Three-fourths of the children die before they attain the age of eight years. Let their

mothers, then, be wise, and give to their children small doses of these invaluable pills once or twice every week… The gross humors that are constantly floating about in the blood of children, the forerunners of so many complaints, will thus be expelled, and the lives of thousands saved and preserved to their parents.“

 

Pills have always been difficult to swallow and efforts long have been made to make them go down easier. In medieval times, people coated pills with slippery plant substances. Another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. In the 1800s sugar-coating and gelatin-coating was invented, as were gelatin capsules. In 1843, the British painter and inventor William Brockedon was granted a patent for a machine capable of “Shaping Pills, Lozenges and Black Lead by Pressure in Dies“. The device was capable of compressing powder into a tablet without use of an adhesive. In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet. Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).

 

Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants. Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets with special properties, for example, sustained release or fast dissolving formulations. Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the “first pass effect“), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosa, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example, salbutamol, used to treat problems in the respiratory system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action. A proportion of the population have difficulties swallowing tablets either because they just don’t like taking them or because their medical condition makes it difficult for them (dysphagia, vomiting). In such instances it may be better to consider alternative dosage form or administration route.

 

Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems. Tablet diameter and shape are determined by the machine tooling used to produce them – a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don’t break up in the bottle, yet friable enough that they disintegrate in the gastric tract. Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (i) simple failure and erosion tests, and (ii) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.). The hardness of tablets is the principle measure of mechanical strength. Hardness is tested using a tablet hardness tester. The units for hardness have evolved since the 1930s, but are commonly measured in kilograms per square centimeter. Models of tester include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.

 

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.

 

Combined oral contraceptive pills were nicknamed “the pill“ in the 1960s

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https://www.pinterest.com/nanherriman/19th-century-medicine/

 

Frederic Chopin’s Cause of Death

Chopin plays for the Radziwills, 1829 (painting by Henryk Siemiradzki, 1887)

Credit: Henryk Siemiradzki – images.fineartamerica.com, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1086097

 

In 2014, a team of medical experts received permission to remove Polish genius, Frederic Chopin’s preserved heart from the Holy Cross Church in Warsaw, where it had ultimately been interred, and examine it for clues that might shed light on the mysterious ailment that led to Chopin’s death at the age of 39. The diagnosis, published in the American Journal of Medicine this past week, is the latest and most convincing foray into the long-running dispute over the likely cause of Chopin’s slow decline and death in his 30s. This published paper suggests that the composer died of pericarditis, a complication of chronic tuberculosis. Other suggested causes of his debilitation and death have included the inherited disease cystic fibrosis; alpha-1-antitrypsin deficiency, a relatively rare genetic ailment that leaves individuals prone to lung infections; and mitral stenosis, a narrowing of the heart valves. Used for the recent analysis and diagnosis was the great composer’s heart, stored in a jar of cognac for 170 years.

 

An autopsy was performed to try to solve the mysterious cause of the 39-year-old’s death. His heart was removed and later stored in a jar of cognac, then interred in a church pillar in Poland. But when the researchers recently examined the jar containing Chopin’s heart – kept in the crypt of the Holy Cross church in Warsaw – they noted the heart was covered with a fine coating of white fibrous materials. In addition, small lesions were visible, the telltale symptoms of serious complications of tuberculosis, concluded the team. “We didn’t open the jar,“ team leader Professor Michael Witt of the Polish Academy of Sciences told the Observer. “But from the state of the heart we can say, with high probability, that Chopin suffered from tuberculosis while the complication pericarditis was probably the immediate cause of his death.“

 

The new study is the latest chapter in the strange story of Chopin’s heart. After the composer died in October 1849 in Paris the rest of his remains were buried in the city’s Pere Lachaise cemetery, also the last resting place of Marcel Proust, Oscar Wilde and Jim Morrison. However, his status as a Polish national hero ensured that his heart became embroiled in controversy. Chopin’s health began to falter in the late 1830s, ultimately making it difficult for him to continue composing music. Over the years, a number of diseases have been named as the culprit of his physical decline, from cystic fibrosis to alpha-1-antitrypsin deficiency, a rare genetic condition that eventually leads to lung disease. According to a 2014 article by Alex Ross of the New Yorker, Ludwika Jedrzejewicz, Chopin’s eldest sister, smuggled the organ past Austrian and Russian authorities on her way to Poland, hiding the jar that held the heart beneath her cloak. The jar was subsequently encased in a wooden urn and buried beneath a monument at the Holy Cross Church.

 

In the early 20th century, Chopin, as one of Poland’s most famous native sons, became the focus of nationalist fervor in the country. During the WWII-era, Nazi occupiers recognized the symbolic significance of Chopin’s legacy and sought to block the performance of his music. But his heart was removed from the Holy Cross and given to the S.S. officer Heinz Reinefarth, who claimed to admire the composer and kept the heart safe at Nazi headquarters in Poland. The organ was returned to Holy Cross in 1945, where it remained until church officials and medical researchers collaborated to dig it up. The examination of the heart by Professor Witt and colleagues was the first since 1945. “We found it is still perfectly sealed in the jar,“ said Witt. “Some people still want to open it in order to take tissue samples to do DNA tests to support their ideas that Chopin had some kind of genetic condition. That would be absolutely wrong. It could destroy the heart and in any case, I am quite sure we now know what killed Chopin.“ The recent examination of Chopin’s heart is unlikely to quell discussion over the cause of his death. As Nature reports, the organ has never been tested for cystic fibrosis, another proposed cause of Chopin’s demise. And some scholars have cast doubt on whether the heart belonged to Chopin at all. But for now, the (possible) relic of the composer can rest undisturbed. Researchers will not be permitted to examine the heart again for another 50 years.

Sources: The Guardian; The Smithsonian; Wikipedia

Read more: http://www.smithsonianmag.com/smart-news/chopins-preserved-heart-may-offer-clues-about-his-death-180967168/#1mR2vDjK42vsapca.99

 

Chopin on His Deathbed, by Teofil Kwiatkowski, 1849, commissioned by Jane Stirling. Chopin is in the presence of (from left) Aleksander Jelowicki, Chopin’s sister Ludwika, Princess Marcelina Czartoryska, Wojciech Grzymala, Kwiatkowski. Credit: Teofil Kwiatkowski – www.psm.vin.pl, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9613090

 

Funerary monument on a pillar in Holy Cross Church, Warsaw, enclosing Chopin’s heart.

Photo credit: Nihil novi – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2704160

 

Chopin’s grave in Paris

Photo credit: Auguste Clesinger – Marcin L., 26 December 2005, Public Domain, https://commons.wikimedia.org/w/index.php?curid=479220

 

Here are some favorite Chopin masterpieces.

Frederic Chopin – Prelude in E-Minor (op.28 no. 4)

Chopin Nocturne C sharp minor (1830) (Arjen Seinen).

Chopin Ballade in G Minor Scene; Pianist, Wladyslaw Szpilman

Chopin, Nocturne in C sharp Minor (1830); Pianist, Jan Lisiecki

Chopin Nocturne No. 20; Pianist, Wladyslaw Szpilman

Chopin Piano Concerto No 1 in E Minor; Pianist, Land Lang

 

Approximately 65 Years Ago, Eugene Aserinsky Discovered REM Sleep

REM Sleep, outlined in red, above. Below the REM Sleep, are slow EEG waveforms of brain activity during non-REM sleep. – By en:User:MrSandman – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=452350

 

It was Sigmund Freud who stated, “Dreams are the royal road to the unconscious.”

 

Eugene Aserinsky (May 6, 1921 – July 22, 1998), a pioneer in sleep research, was a graduate student at the University of Chicago in 1953 when he discovered REM sleep. Aserinsky the son of a dentist of Russian – Jewish descent, like many great scientists, was of an immigrant family. Aserinsky made his discovery after hours spent studying the eyelids of sleeping subjects. Aserinsky and his PhD adviser, Nathaniel Kleitman, went on to demonstrate that this “rapid-eye movement“ was correlated with dreaming and a general increase in brain activity. Aserinsky and Kleitman pioneered procedures that have now been used with thousands of volunteers using the electroencephalograph. Because of these discoveries, Aserinsky and Kleitman are generally considered the founders of modern sleep research.

 

In 1953, for his Ph.D. in physiology at the University of Chicago, Dr. Aserinsky produced his ground-breaking thesis, ”Eye Movements During Sleep.” His discovery of rapid eye movement, or R.E.M. — the periodic, rapid, jerky movement of the eyeballs under the lids during stages of sleep associated with dreaming — showed that the brain was in a state of some alertness for about 22% of total sleep time. In a long career, he taught at Jefferson Medical College in Philadelphia, Marshall University Medical School and West Virginia University.

 

Eugene Aserinsky, died on July 22, 1998, when his car hit a tree north of San Diego. He was 77 and lived in Escondido, Calif. Nathaniel Kleitman lived to be 104 years old.

 

Editor’s note: All the Eugene Aserinsky sources we searched through, were quite limited – dry facts only. Then we discovered a fascinating write-up in the Smithsonian Magazine, by Chip Brown, that is such a fascinating account of Eugene Aserinsky, we have included the whole article, below. https://www.smithsonianmag.com/science-nature/the-stubborn-scientist-who-unraveled-a-mystery-of-the-night-91514538/

 

Night after night Eugene Aserinsky had been working late. He’d dragged an ancient brain-wave machine, an Offner Dynograph, from the basement to the physiology lab on the second floor of Abbott Hall at the University of Chicago. He had tinkered with it long enough to think it might not be totally unreliable. And now, late one December evening in 1951, his 8-year-old son, Armond, came over to the lab and sat patiently on an Army cot while his father scrubbed his scalp and the skin around his eyes with acetone, taped electrodes to the boy’s head and plugged the leads into a switch box over the bed. From the adjacent room, Aserinsky calibrated the machine, telling Armond to look left, right, up and down. The ink pens jumped in concert with the boy’s eyes. And then it was lights out, the sharp smell of acetone lingering in the darkness. Armond fell asleep; his father tried not to. Sustained by pretzels and coffee, Aserinsky sat at a desk under the hellish red eyes of a gargoyle-shaped lamp. He was 30 years old, a trim, handsome man of medium height, with black hair, a mustache, blue eyes and the mien of a bullfighter. When he was not in his lab coat, he usually wore a bow tie and a dark suit. He was a graduate student in physiology, and his future was riding on this research. He had nothing but a high school degree to fall back on. His wife, Sylvia, was pregnant with their second child. They lived on campus in a converted Army barracks heated by a kerosene stove. Money was so tight Aserinsky would eventually have to accept a small loan from his dissertation advisor, Nathaniel Kleitman, and then be obliged to feign enthusiasm for the distinguished man’s suggestion that he economize by eating chicken necks.

 

The hours crept by in the spooky gray-stone gloom of Abbott Hall. While the long banner of graph paper unfurled, Aserinsky noticed that the pens tracking his son’s eye movements – as well as the pens registering brain activity – were swinging back and forth, suggesting Armond was alert and looking around. Aserinsky went in to check on his son, expecting to find him wide awake. But Armond’s eyes were closed; the boy was fast asleep. What was going on? Yet another problem with the infernal machine? Aserinsky didn’t know what to think, standing in bewildered excitement, on the threshold of a great discovery.

 

The existence of rapid eye movement (REM) and its correlation with dreaming was announced 50 years ago last month in a brief, little-noted report in the journal Science. The two-page paper is a fine example of the maxim that the eye can see only what the mind knows: for thousands of years the physical clues of REM sleep were baldly visible to anyone who ever gazed at the eyelids of a napping child or studied the twitching paws of a sleeping dog. The association of a certain stage of sleep with dreaming might have been described by any number of observant cave men; in fact, if the 17,000-year-old Lascaux cave painting of a presumably dreaming Cro-Magnon hunter with an erect penis is any indication, maybe it was. But scientists had long been blinkered by preconceptions about the sleeping brain. It remains an astonishing anachronism in the history of science that Watson and Crick unraveled the structure of DNA before virtually anything was known about the physiological condition in which people spend one-third of their lives. As Tom Roth, the former editor of the journal Sleep, put it: “It’s analogous to going to Mars with a third of the Earth’s surface still unexplored.“ The REM state is so important that some scientists have designated it a “third state of being“ (after wakefulness and sleep), yet the phenomenon itself remained hidden in plain sight until September 1953, when the experiments conducted in Chicago by Aserinsky were published.

 

His now-classic paper, coauthored by advisor Kleitman, was less important for what it revealed than what it began. REM opened the terra incognita of the sleeping brain to scientific exploration. Before REM, it was assumed that sleep was a passive state; absent stimulation, the brain simply switched off at night like a desk lamp. After REM, scientists saw that the sleeping brain actually cycled between two distinct electrical and biochemical climates – one characterized by deep, slow-wave sleep, which is sometimes called “quiet sleep“ and is now known as non-REM or NREM sleep, and the other characterized by REM sleep, also sometimes called “active“ or “paradoxical“ sleep. The mind in REM sleep teems with vivid dreams; some brain structures consume oxygen and glucose at rates equal to or higher than in waking. The surprising implication is that the brain, which generates and evidently benefits from sleep, seems to be too busy to get any sleep itself.

 

The discovery of REM launched a new branch of medicine, leading to the diagnosis and treatment of sleep disorders that afflict tens of millions of people. It also changed the way we view our dreams and ourselves. It shifted scientists’ focus from the dreaming person to the dreaming brain, and inspired new models in which the chimerical dramas of the night were said to reflect random neural fireworks rather than the hidden intentions of unconscious conflict or the escapades of disembodied souls. By showing that the brain cycles through various neurodynamic phases, the discovery of REM underscored the view that the “self“ is not a fixed state but reflects fluctuating brain chemistry and electrical activity. Many researchers continue to hope that REM may yet provide a link between the physical activity of the brain during a dream and the experience of dreaming itself. It’s hard to overestimate the importance of Aserinsky’s breakthrough, said Bert States, an emeritus professor of dramatic arts at the University of California at Santa Barbara and the author of three books on dreams and dreaming: “The discovery of REM sleep was just about as significant to the study of cognition as the invention of the telescope was to the study of the stars.“

 

In 1950, when Aserinsky knocked on Nathaniel Kleitman’s office door, Kleitman, then 55, was considered the “father of modern sleep research.“ A Russian emigre, he had received a doctorate from the University of Chicago in 1923 and joined the faculty two years later. There he set up the world’s first sleep lab. The cot where research subjects slept was pitched under a metal hood formerly used to suck out noxious lab fumes. At the time, few scientists were interested in the subject. Despite research on the electrical activity of the brain in the late 1920s, the understanding of sleep hadn’t advanced much beyond the ancient Greeks, who viewed Hypnos, the god of sleep, as the brother of Thanatos, the god of death. Sleep was what happened when you turned out the lights and stopped the influx of sensation. Sleep was what the brain lapsed into, not what it actively constructed. On the face of it, dull stuff.

 

Kleitman was intrigued nonetheless, and began to explore the physiology of the body’s basic rest-activity cycle. A painstaking researcher, he once stayed up 180 hours straight to appraise the effects of sleep deprivation on himself. In 1938, he and fellow researcher Bruce Richardson moved into Mammoth Cave in Kentucky for more than a month to study fluctuations in their body temperatures and other darkness-engendered changes in their normal sleep-wake cycle – pioneering work in the now booming field of circadian rhythm research. Kleitman backed his fieldwork with formidable scholarship. When he published his landmark book Sleep and Wakefulness in 1939, he apologized for being unable to read in any language other than Russian, English, German, French and Italian. At the office door, Aserinsky found a man with “a grey head, a grey complexion and a grey smock.“ As the younger scientist wrote years later, “there was no joy in this initial encounter for either of us. For my part I recognized Kleitman as the most distinguished sleep researcher in the world. Unfortunately, sleep was perhaps the least desirable of the scientific areas I wished to pursue.“

 

Aserinsky had grown up in Brooklyn in a Yiddish- and Russian-speaking household. His mother died when he was 12, and he was left in the care of his father, Boris, a dentist who loved to gamble. Boris often had his son sit in on pinochle hands if the table was a player short. Meals were catch as catch can. Aserinsky’s son, Armond, recalled: “Dad once told me he said to his father, ?Pop, I’m hungry,’ and his father said, ?I’m not hungry, how can you be hungry?“ Eugene graduated from public high school at the age of 16 and for the next 12 years knocked about in search of his metier. At Brooklyn College, he took courses in social science, Spanish and premedical studies but never received a degree. He enrolled at the University of Maryland dental school only to discover that he hated teeth. He kept the books for an ice company in Baltimore. He served as a social worker in the Maryland state employment office. Though he was legally blind in his right eye, he did a stint in the U.S. Army as a high explosives handler. By 1949, Aserinsky, married and with a 6-year-old son, was looking to take advantage of the G.I. Bill of Rights to launch a science career. He aced the entrance exams at the University of Chicago and, though he lacked an undergraduate degree, persuaded the admissions office to accept him as a graduate student. “My father was courtly, intelligent and intensely driven,“ says Armond Aserinsky, 60, now a clinical psychologist in North Wales, Pennsylvania. “He could be extremely charming, and he had a fine scientific mind, but he had all kinds of conflicts with authority. He always wore black suits. I once asked him, ?Dad, how come you never wear a sports jacket?’ He looked at me and said, ?I’m not a sport.“

 

Kleitman’s first idea was to have Aserinsky test a recent claim that the rate of blinking could predict the onset of sleep. But after a number of vexing weeks trying to concoct a way to measure blink rates, Aserinsky confessed his lack of progress. Kleitman proposed that Aserinsky observe infants while they slept and study what their eyelids did. So he sat by cribs for hours but found that it was difficult to differentiate eyelid movements from eyeball movements. Once again he knocked on Kleitman’s door, something he was loath to do because of Kleitman’s austere and formal air. (Ten years after their famous paper was published, Kleitman began a letter to his colleague and coauthor, “Dear Aserinsky.“) Aserinsky had the idea of studying all eye movements in sleeping infants, and with Kleitman’s approval embarked on a new line of inquiry – one that, he would later confess, was “about as exciting as warm milk.“ Significantly, he did not at first “see“ REM, which is obvious if you know to look for it. Over months of monotonous observations, he initially discerned a 20-minute period in each infant’s sleep cycle in which there was no eye movement at all, after which the babies usually woke up. He learned to exploit the observation. During such periods, the fatigued researcher was able to nap himself, certain he would not miss any important data. And he was also able to impress mothers hovering near the cribs by telling them when their babies would wake up. “The mothers were invariably amazed at the accuracy of my prediction and equally pleased by my impending departure,“ he once wrote.

 

At home, Aserinsky was under considerable pressure. His daughter, Jill, was born in April 1952. His wife, Sylvia, suffered from bouts of mania and depression. Aserinsky couldn’t even afford the rent on the typewriter he leased to draft his dissertation. “We were so poor my father once stole some potatoes so we would have something to eat,“ recalls Jill Buckley, now 51 and a lawyer in Pismo Beach, California, for the American Society for the Prevention of Cruelty to Animals. “I think he saw himself as a kind of Don Quixote. Ninety percent of what drove him was curiosity – wanting to know. We had a set of Collier’s Encyclopedias, and my father read every volume.“ After studying babies, Aserinsky set out to study sleeping adults. At the time, no scientist had ever made all-night continuous measurements of brain-wave activity. Given the thinking of the era – that sleep was a featureless neurological desert – it was pointless to squander thousands of feet of expensive graph paper making electroencephalogram (EEG) recordings. Aserinsky’s decision to do so, combined with his adapting the balky Offner Dynograph machine to register eye movements during sleep, led to the breakthrough. His son, Armond, liked to hang out at the lab because it meant spending time with his father. “I remember going into the lab for the night,“ Armond says. “I knew the machine was harmless. I knew it didn’t read my mind. The set up took a long time. We had to work out some things. It was a long schlep to the bathroom down the hall, so we kept a bottle by the bed.“ Aserinsky did a second nightlong sleep study of Armond with the same results – again the pens traced sharp jerky lines previously associated only with eye movements during wakefulness. As Aserinsky recruited other subjects, he was growing confident that his machine was not fabricating these phenomena, but could it be picking up activity from the nearby muscles of the inner ear? Was it possible the sleeping subjects were waking up but just not opening their eyes? “In one of the earliest sleep sessions, I went into the sleep chamber and directly observed the eyes through the lids at the time that the sporadic eye movement deflections appeared on the polygraph record,“ he would recall in 1996 in the Journal of the History of the Neurosciences. “The eyes were moving vigorously but the subject did not respond to my vocalization. There was no doubt whatsoever that the subject was asleep despite the EEG that suggested a waking state.“ By the spring of 1952, a “flabbergasted“ Aserinsky was certain he had stumbled onto something new and unknown. “The question was, what was triggering these eye movements. What do they mean?“ he recalled in a 1992 interview with the Journal of NIH Research. In the fall of 1952, he began a series of studies with a more reliable EEG machine, running more than 50 sleep sessions on some two dozen subjects. The charts confirmed his initial findings. He thought of calling the phenomena “jerky eye movements,“ but decided against it. He didn’t want critics to ridicule his findings by playing off the word “jerk.“

 

Aserinsky went on to find that heart rates increased an average of 10% and respiration went up 20% during REM; the phase began a certain amount of time after the onset of sleep; and sleepers could have multiple periods of REM during the night. He linked REM interludes with increased body movement and particular brain waves that appear in waking. Most amazingly, by rousing people from sleep during REM periods, he found that rapid eye movements were correlated with the recall of dreams – with, as he noted in his dissertation, “remarkably vivid visual imagery.“ He later wrote, “The possibility that these eye movements might be associated with dreaming did not arise as a lightning stroke of insight. An association of the eyes with dreaming is deeply ingrained in the unscientific literature and can be categorized as common knowledge. It was Edgar Allan Poe who anthropomorphized the raven, ?and his eyes have all the seeming of a demon’s that is dreaming.’ “

 

Aserinsky had little patience for Freudian dream theory, but he wondered if the eyes moving during sleep were essentially watching dreams unfold. To test that possibility, he persuaded a blind undergraduate to come into the lab for the night. The young man brought his Seeing Eye dog. “As the hours passed I noticed at one point that the eye channels were a little more active than previously and that conceivably he was in a REM state,“ Aserinsky wrote. “It was imperative that I examine his eyes directly while he slept. Very carefully I opened the door to the darkened sleeping chamber so as not to awaken the subject. Suddenly, there was a low menacing growl from near the bed followed by a general commotion which instantaneously reminded me that I had completely forgotten about the dog. By this time the animal took on the proportions of a wolf, and I immediately terminated the session, foreclosing any further exploration along this avenue.“ (Other researchers would later confirm that blind people do indeed experience REM.) In any event, Aserinsky wasn’t much interested in the meaning of dreams, said his daughter Jill, adding: “He was a pure research scientist. It always irritated him when people wanted him to interpret their dreams.“

 

But a future colleague of Aserinsky’s was intrigued. William Dement was a medical student at Chicago, and in the fall of 1952 Kleitman assigned him to help Aserinsky with his overnight sleep studies. Dement recounted his excitement in his 1999 book, The Promise of Sleep. “Aserinsky told me about what he had been seeing in the sleep lab and then threw in the kicker that really hooked me: ?Dr. Kleitman and I think these eye movements might be related to dreaming.’ For a student interested in psychiatry, this offhand comment was more stunning than if he had just offered me a winning lottery ticket. It was as if he told me, ?We found this old map to something called the Fountain of Youth.’ “ By Aserinsky’s account, Dement ran five overnight sessions for him starting in January 1953. With a camera Kleitman had obtained, Dement and Aserinsky took 16-millimeter movie footage of subjects in REM sleep, one of whom was a young medical student named Faylon Brunemeier, today a retired ophthalmologist living in Northern California. They were paying three dollars a night, he recalled, “and that was a lot to an impecunious medical student.“ Kleitman had barred women as sleep study subjects, fearing the possibility of scandal, but Dement wheedled permission to wire up his sweetheart, a student named Pamela Vickers. The only provision was that Aserinsky had to be on hand to “chaperon“ the session. While the sleep-deprived Aserinsky passed out on the lab couch, Dement documented that Vickers, too, experienced REM. Next, Dement says he recruited three other female subjects, including Elaine May, then a student at the University of Chicago. Even if she had not become famous a few years later as part of the comedy team Nichols and May, and had not gone on to write Heaven Can Wait and other movies, she would still have a measure of fame, in the annals of sleep science.

 

From 1955 to 1957, Dement published studies with Kleitman establishing the correlation between REM sleep and dreaming. Dement went on to help organize the first sleep research society and started the world’s first sleep clinic at Stanford in 1970. With a collaborator, Howard Roffwarg, a psychiatrist now at the University of Mississippi Medical Center, Dement showed that even a 7-month-old premature infant experiences REM, suggesting that REM may occur in the womb. Dement’s colony of dogs with narcolepsy – a condition of uncontrollable sleep – shed light on the physiological basis of the disorder, which in people had long been attributed to psychological disturbances. Dement became such an evangelist about the dangers of undiagnosed sleep disorders that he once approached the managers of the rock band R.E.M., seeking to enlist the group for a fundraising concert. The musicians brushed him off with a shaggy story about the acronym standing for retired english majors.

 

When Aserinsky left the University of Chicago, in 1953, he turned his back on sleep research. He went to the University of Washington in Seattle and for a year studied the effects of electrical currents on salmon. Then he landed a faculty position at Jefferson Medical College in Philadelphia, where he explored high-frequency brain waves and studied animal respiration. In 1957, his wife’s depression came to a tragic conclusion; while staying at a mental hospital in Pennsylvania, Sylvia committed suicide. Two years later, Aserinsky married Rita Roseman, a widow, and became stepfather to her young daughter, Iris; the couple remained together until Rita’s death in 1994.

 

In the early 1960s, Armond Aserinsky urged his father, then in his 40s, to return to the field he had helped start. Aserinsky finally wrote to Kleitman, who had retired from the University of Chicago. Kleitman replied, “It was good to learn that you have renewed work on rapid eye movements during sleep. The literature on the subject is quite extensive now. I believe that you have ability and perseverance but have had personal hard knocks to contend with. Let us hope that things will be better for you in the future.“ Kleitman also took the opportunity to remind his former student that he still owed him a hundred dollars. In March 1963, Aserinsky went home to Brooklyn to attend a meeting of sleep researchers. “People were shocked,“ his son recalled. “They looked at him and said, ?My God, you’re Aserinsky! We thought you were dead!’ “

 

Delving into the night again in an unused operating room at the Eastern Pennsylvania Psychiatric Institute in Philadelphia, Aserinsky worked on the physiology of REM and non-REM sleep, but he had prickly encounters with colleagues. He took offense when he did not receive an invitation to a prestigious dinner at a 1972 meeting of sleep researchers. He was often stung when Dement and Kleitman got credit he felt belonged to him. (For his part, Dement said he resented that Aserinsky never acknowledged all the work he did as low man on the lab totem pole. “I was so naive,“ he told me.) In 1976, after more than two decades at Jefferson MedicalCollege, Aserinsky was passed over for the chairmanship of the physiology department. He left, becoming chairman of physiology at Marshall University in Huntington, West Virginia. He retired in 1987. “He could be a deeply suspicious and impolitic person,“ Armond Aserinsky said. Narrating his version of events in the Journal of the History of the Neurosciences, Aserinsky criticized Dement’s contention that the discovery of REM was a “team effort,“ saying, “If anything is characteristic about the REM discovery, it was that there was no teamwork at all. In the first place, Kleitman was reserved, almost reclusive, and had little contact with me. Secondly, I myself am extremely stubborn and have never taken kindly to working with others. This negative virtue carried on throughout my career as evidenced by my resume, which reveals that I was either the sole or senior author in my first thirty publications, encompassing a period of twenty-five years.“ That stubbornness spilled into his family relations as well. Years passed in which he had no contact with Armond. To younger sleep scientists, Aserinsky was only a name on a famous paper, an abstraction from another time. And such he might have remained if not for a license plate and a chance encounter in 1989. Peter Shiromani, then an assistant professor of psychiatry at the University of California at San Diego, had just nosed his Datsun 310 into the parking lot of a Target department store in Encinitas, California. His custom license plates advertised what had been his scientific obsession since his undergraduate days at City College in New York City: REM SLEP. “A woman walked up to me and said, ?I really love your plates! Did you know my father discovered REM sleep?’ “ Shiromani recalled. “I said, ?You must be Eugene Aserinsky’s daughter!’ She was very pleased. I think she felt a lot of pride in her father’s accomplishment, and here was someone who recognized her father’s name. We chatted briefly with much enthusiasm about REM sleep. Fortunately, I had the presence of mind to ask for her father’s address.“ Shiromani passed the address along to Jerry Siegel, a sleep researcher at UCLA and the Sepulveda Veterans Affairs medical center in suburban Los Angeles, who invited Aserinsky to address the June 1995 meeting of the Associated Professional Sleep Societies in Nashville. Siegel was organizing a symposium in honor of Kleitman, who had recently turned 100. “It was very difficult to get Aserinsky to come,“ Siegel recalls. “People who knew him in the early days said, ?Don’t invite him.’ But my dealings with him were very pleasant.“ Despite their rivalry, it was Dement who introduced Aserinsky to the crowd of 2,000 people in the ballroom at the OpryLand Hotel. They gave him a standing ovation. And when he finished a witty, wide-ranging talk on the history of REM, the audience again rose to its feet. “It was one of the high points of his life,“ recalls his daughter Jill, who had accompanied her father to the meeting along with his stepdaughter, Iris Carter. “He wore a name tag, and people would stop and point and say, ?There’s Aserinsky!’ “ says Carter.

 

One July day three years later, Aserinsky, driving down a hill in Carlsbad, California, collided with a tree and was killed. He was 77. An autopsy could not determine the cause of the accident. It’s possible he fell asleep at the wheel.

 

Today it’s well established that normal sleep in human adults includes between four and six REM periods a night. The first starts about 90 minutes after sleep begins; it usually lasts several minutes. Each subsequent REM period is longer. REM sleep is characterized by not only brain-wave activity typical of waking but also a sort of muscle paralysis, which renders one incapable of acting on motor impulses. (Sleepwalking most often occurs during non-REM sleep.) In men and women, blood flow to the genitals is increased. Parts of the brain burn more energy. The heart may beat faster. Adults spend about two hours a night in REM, or 25% of their total sleep. Newborns spend 50 percent of their sleep in REM, upwards of eight hours a day, and they are much more active than adults during REM sleep, sighing and smiling and grimacing. After 50 years, researchers have learned a great deal about what REM isn’t. For example, it was once thought that people prevented from dreaming would become psychotic. That proved not to be the case; patients with injuries to the brainstem, which controls REM, do not go nuts without it. Still, if you deprive a person of REM sleep, they’ll recoup it at the first chance, plunging directly into the REM phase – a phenomenon discovered by Dement and called REM rebound.

 

Studies of animals have yielded insights into REM, sometimes. In the early 1960s, Michel Jouvet, a giant of sleep research and a neurophysiologist at the University Claude Bernard in Lyon, France, mapped the brain structures that generate REM sleep and produce the attendant muscle paralysis. Jouvet, who coined the term “paradoxical sleep“ as a substitute for REM sleep, also discovered that cats with lesions in one part of the brainstem were “disinhibited“ and would act out their dreams, as it were, jumping up and arching their backs. (More recently, University of Minnesota researchers have documented a not-dissimilar condition in people; REM sleep behavior disorder, as it’s called, mainly affects men over 50, who kick, punch and otherwise act out aggressive dream scenarios while they sleep. Researchers believe that REM sleep disorder may be a harbinger of Parkinson’s disease in some people.) Paradoxical sleep has been found in almost all mammals tested so far except for some marine mammals, including dolphins. Many bird species appear to have short bursts of paradoxical sleep, but reptiles, at least the few that have been assessed, do not. Jouvet was especially interested in penguins, because they stay awake for long periods during the brooding season. Hoping to learn more about their physiology, he went to great trouble to implant a costly radio-telemetry chip in an emperor penguin in Antarctica. The prize research subject was released into the sea, only to be promptly gobbled up by a killer whale.

 

In 1975, Harvard’s Allan Hobson and Robert McCarley proposed that many properties of dreams – the vivid imagery, the bizarre events, the difficulty remembering them – could be explained by neurochemical conditions of the brain in REM sleep, including the ebb and flow of the neurotransmitters norepinephrine, serotonin and acetylcholine. Their theory stunned proponents of the idea that dreams were rooted not in neurochemistry but psychology, and it has been a starting point of dream theorizing for the past 25 years. The once-popular description of REM as “dream sleep“ is now considered an oversimplification, and debate rages over questions of what can be properly claimed about the relation of dreaming to the physiology of REM sleep. (In 2000, an entire volume of the journal Behavioral and Brain Sciences was devoted to the debate.) To be sure, you can have REM without dreaming, and you can dream without experiencing REM. But most researchers say that dreaming is probably influenced and may be facilitated by REM. Still, dissenters, some of whom adhere to psychoanalytic theory, say that REM and dreaming have little connection with each other, as suggested by clinical evidence that different brain structures control the two phenomena. In the years to come, new approaches may help clarify these disagreements. In a sort of echo of Aserinsky’s first efforts to probe the sleeping brain with EEG, some researchers have used powerful positron brain-scanning technology to focus on parts of the brain activated during REM.

 

This past June, more than 4,800 people attended the Associated Professional Sleep Societies’ annual meeting in Chicago. The scientists took time out to mark REM’s golden anniversary. With mock solemnity, Dement echoed the Gettysburg Address in his lecture: “Two score and ten years ago Aserinsky and Kleitman brought forth on this continent a new discipline conceived at night and dedicated to the proposition that sleep is equal to waking.“ But to paraphrase the physicist Max Planck, science advances funeral by funeral. Kleitman died in 1999 at the age of 104, and though he was a coauthor of the milestone REM study, he never really accepted that REM was anything other than a phase of especially shallow sleep. “Kleitman died still believing there was only one state of sleep,“ Dement told me. Aserinsky had his own blind spots; he never relinquished his doubts that sleeping infants exhibit REM. To honor the research done in Kleitman’s lab five decades ago, the Sleep Research Society commissioned a 65-pound zinc plaque. It now hangs in the psychiatry department at the University of Chicago Medical Center, adjacent to Abbott Hall. To be sure, the inscription – “Commemorating the 50th Anniversary of the Discovery of REM Sleep by Eugene Aserinsky, Ph.D., and Nathaniel Kleitman, Ph.D., at the University of Chicago“ – doesn’t speak to the poetry of a lyric moment in the history of science, a moment when, as Michel Jouvet once said, humanity came upon “a new continent in the brain.“ If it’s the poetry of REM you want, you need wait only until tonight.

 

Fifty years ago, Eugene Aserinksy discovered rapid eye movement and changed the way we think about sleep and dreaming

 

 

Sources: Smithsonian Magazine, October 2003, By Chip Brown; https://public-media.smithsonianmag.com/filer/rem; NIH.gov; Wikipedia

Read more: http://www.smithsonianmag.com/science-nature/the-stubborn-scientist-who-unraveled-a-mystery-of-the-night-91514538/#SHP3CAzWr84vqbsw.99

 

For your sheer pleasure, British tenor, John Owen-Jones sings, Music of the Night, from Phantom of the Opera.

 

Dr. Peter Dennis Mitchell, British Biochemist

 

The Nobel Prize in Chemistry 1978 was awarded to Peter Mitchell “for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory“.

Peter Dennis Mitchell (29 September 1920-10 April 1992), British biochemist

Sources: Nobel Prize Foundation: MLA style: “The Nobel Prize in Chemistry 1978“. Nobelprize.org. Nobel Media AB 2014. Web. 24 Oct 2017. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1978/; Wikipedia: By Source, Fair use, https://en.wikipedia.org/w/index.php?curid=29893461

 

The Thesis – The rates of synthesis and proportions by weight of the nucleic acid components of a Micrococcus during growth in normal and in penicillin containing media with reference to the bactericidal action of penicillin.

 

Peter Dennis Mitchell was born in Mitcham, Surrey on 29 September 1920. His parents were Christopher Gibbs Mitchell, a civil servant, and Kate Beatrice Dorothy (nee) Taplin. His uncle was Sir Godfrey Way Mitchell, chairman of George Wimpey. He was educated at Queen’s College, Taunton and Jesus College, Cambridge where he studied the Natural Sciences Tripos specializing in Biochemistry. He was appointed a research post in the Department of Biochemistry, Cambridge, in 1942, and was awarded a Ph.D. in early 1951 for work on the mode of action of penicillin.

 

In 1955 Mitchell was invited by Professor Michael Swann to set up a biochemical research unit, called the Chemical Biology Unit, in the Department of Zoology, at the University of Edinburgh, where he was appointed a Senior Lecturer in 1961 and then Reader in 1962. From 1963 to 1965, he supervised the restoration of a Regency-fronted Mansion, known as Glynn House, at Cardinham near Bodmin, Cornwall – adapting a major part of it for use as a research laboratory. He and his former research colleague, Jennifer Moyle founded a charitable company, known as Glynn Research Ltd., to promote fundamental biological research at Glynn House and they embarked on a program of research on chemiosmotic reactions and reaction systems.

 

In the 1960s, ATP was known to be the energy currency of life, but the mechanism by which ATP was created in the mitochondria was assumed to be by substrate-level phosphorylation. Mitchell’s chemiosmotic hypothesis was the basis for understanding the actual process of oxidative phosphorylation. At the time, the biochemical mechanism of ATP synthesis by oxidative phosphorylation was unknown. Mitchell realized that the movement of ions across an electrochemical potential difference could provide the energy needed to produce ATP. His hypothesis was derived from information that was well known in the 1960s. He knew that living cells had a membrane potential; interior negative to the environment. The movement of charged ions across a membrane is thus affected by the electrical forces (the attraction of positive to negative charges). Their movement is also affected by thermodynamic forces, the tendency of substances to diffuse from regions of higher concentration. He went on to show that ATP synthesis was coupled to this electrochemical gradient.

 

His hypothesis was confirmed by the discovery of ATP synthase, a membrane-bound protein that uses the potential energy of the electrochemical gradient to make ATP; and by the discovery by Andre Jagendorf that a pH difference across the thylakoid membrane in the chloroplast results in ATP synthesis. Later, Mitchell also hypothesized some of the complex details of electron transport chains. He conceived of the coupling of proton pumping to quinone-based electron bifurcation, which contributes to the proton motive force and thus, ATP synthesis. In 1978 he was awarded the Nobel Prize in Chemistry “for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory.“ He was elected a Fellow of the Royal Society (FRS) in 1974. Mitchell could not have achieved all that he did, without standing on the shoulders of at least two other great researchers (among many), Dr. Friedrich Miescher and Dr. Richard Altmann.

 

Friedrich Miescher (1844-1895)

Photo credit: copied from http://www.pbs.org/wgbh/nova/photo51/images/befo-miescher.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=789048

 

 

Miescher isolated various phosphate-rich chemicals, which he called nuclein (now nucleic acids), from the nuclei of white blood cells. This took place in 1869 in Felix Hoppe-Seyler’s laboratory at the University of Tubingen, Germany, paving the way for the identification of DNA as the carrier of inheritance. The significance of the discovery, first published in 1871, was not at first apparent, and it was Albrecht Kossel who made the initial inquiries into its chemical structure. Later, Friedrich Miescher raised the idea that the nucleic acids could be involved in heredity.

 

Richard Altmann (12 March 1852 – 8 December 1900) was a German pathologist and histologist from Deutsch Eylau in the Province of Prussia. Altmann studied medicine in Greifswald, Konigsberg, Marburg, and Giessen, obtaining a doctorate at the University of Giessen in 1877. He then worked as a prosector at Leipzig, and in 1887 became an anatomy professor (extraordinary). He died in Hubertusburg in 1900 from a nervous disorder. Altmann improved fixation methods, for instance, his solution of potassium dichromate and osmium tetroxide. Using that along with a new staining technique of applying acid-fuchsin contrasted by picric acid amid delicate heating, he observed filaments in the nearly all cell types, developed from granules. He named the granules “bioblasts“, and explained them as the elementary living units, having metabolic and genetic autonomy, in his 1890 book “Die Elementarorganismen“ (“The Elementary Organism“). His explanation drew much skepticism and harsh criticism. Altmann’s granules are now believed to be mitochondria. He is credited with coining the term “nucleic acid“, replacing Friedrich Miescher’s term “nuclein“ when it was demonstrated that nuclein was acidic.

 

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