Gunter Blobel MD, PhD (1936 – 2018) Redefined Cell Biology

Gunter Blobel: Died a few days ago, on 18 February 2018 (aged 81): From Wikimedia Commons, the free media repository

 

Gunter Blobel (May 21, 1936 – February 18, 2018 was a Silesian German and American biologist and 1999 Nobel Prize laureate in Physiology for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell. Blobel was born in Waltersdorf in the Prussian Province of Lower Silesia, now a part of Poland. In January 1945 his family fled from native Silesia from the advancing Red Army. After the war Blobel grew up and attended gymnasium in the Saxon town of Freiberg. He graduated at the University of Tubingen in 1960 with MD and received his Ph.D. from the University of Wisconsin-Madison in 1967. Blobel joined the Rockefeller University faculty 51 years ago where he was the John D. Rockefeller Jr. Professor. He was also a Howard Hughes Medical Institute Investigator since 1986.

 

Blobel was awarded the 1999 Nobel Prize in Physiology or Medicine for the discovery of signal peptides. Signal peptides form an integral part of protein targeting, a mechanism for cells to direct newly synthesized protein molecules to their proper location by means of an “address tag“ (i.e. a signal peptide) within the molecule. Proteins that are manufactured within cells must be transported to the sites where they are needed. Blobel discovered a system of intrinsic signals that explain how cells are able to accurately distribute billions of such proteins within a cell each day. Along with his colleagues, Blobel learned that sequences in proteins were responsible for directing traffic, matching up these “zip codes“ with transport machinery in the cell that facilitate targeting to the proper cellular membranes. This connection results in the proteins either passing through the membranes or becoming embedded within them. His observations were central to uniting the fields of molecular biology, which deals primarily with proteins and nucleic acids, and cell biology, which is focused on the structures inside cells, called organelles. In addition, he found that the same system plays a role across all eukaryotes, ranging from yeast to humans.

 

Blobel became well known for his direct and active support for the rebuilding of Dresden in Germany, becoming, in 1994, the founder and president of the nonprofit “Friends of Dresden, Inc.“ He donated all of the Nobel award money to the restoration of Dresden, in particular for the rebuilding of the Frauenkirche (completed in 2005) and the building of a new synagogue. In Leipzig he pursued a rebuilding of the Paulinerkirche, the university church of the University of Leipzig, which had been blown up by the communist regime of East Germany in 1968, arguing “this is a shrine of German cultural history, connected to the most important names in German cultural history.“ In addition to his research at the Rockefeller University in New York City from 1968 to 2018, Blobel lived in Manhattan’s Upper East Side with his wife, Laura Maioglio (owner of Barbetta Restaurant in Manhattan). He was on the board of directors for Nestle and the Board of Scientific Governors at The Scripps Research Institute. Furthermore, he was Co-Founder and Chairman of the Scientific Advisory Board for Chromocell Corporation. He sat on the Selection Committee for Life Science and Medicine which chooses winners of the Shaw Prize.

 

Excellent video about the work of Dr. Gunter Blobel

 

CRISPR

Please open up this video so that this serves as the graphic for the article

 

The discovery of clustered DNA repeats began independently in three parts of the world. One of the first discoveries was in 1987 at Osaka University in Japan. Researcher Yoshizumi Ishino and colleagues published their findings on the sequence of a gene called “iap“ and its relation to E. coli. Technological advances in the 1990s allowed them to continue their research and speed up their sequencing with a technique called metagenomics. They were able to collect seawater or soil samples and sequence the DNA in the sample. The first description of what would later be called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), occurred in 1987 when Yoshizumi Ishino accidentally cloned part of a CRISPR together with the iap gene, the target of interest. The organization of the repeats was unusual because repeated sequences are typically arranged consecutively along DNA. The function of the interrupted clustered repeats was not known at the time.

 

Ishino received his BS, MS and PhD degree in 1981, 1983 and 1986, respectively, from Osaka University. From 1987 to 1989, he was a post-doctoral fellow at Yale University (Dieter Soll’s laboratory). In 2002, he became a professor at Kyushu University. Since October 2013, he is also a member of the NASA Astrobiology Institute, University of Illinois at Urbana-Champaign.

 

In 1993 researchers of Mycobacterium tuberculosis in the Netherlands published two articles about a cluster of interrupted direct repeats (DR) in this bacterium. These researchers recognized the diversity of the DR-intervening sequences among different strains of M. tuberculosis and used this property to design a typing method that was named spoligotyping, which is still in use today. At the same time, repeats were observed in the archaeal organisms of Haloferax and Haloarcula species, and their function was studied by Francisco Mojica at the University of Alicante in Spain. Although his hypothesis turned out to be wrong, Mojica surmised at the time that the clustered repeats had a role in correctly segregating replicated DNA into daughter cells during cell division because plasmids and chromosomes with identical repeat arrays could not coexist in Haloferax volcanii. Transcription of the interrupted repeats was also noted for the first time. Transcription of the interrupted repeats was also noted for the first time. In 2017 Mojica was a winner of the Albany Medical Center Prize.

 

The three articles below, are well written and informative regarding this new and exciting technology.

 

https://www.wired.com/2015/07/crispr-dna-editing-2/

https://www.the-scientist.com/?articles.view/articleNo/44919/title/Credit-for-CRISPR–A-Conversation-with-George-Church/

https://genotopia.scienceblog.com/573/a-whig-history-of-crispr/

 

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

 

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