Chronic Pain

Descartes’ pain pathway: “Particles of heat“ (A) activate a spot of skin (B) attached by a fine thread (cc) to a valve in the brain (de) where this activity opens the valve, allowing the animal spirits to flow from a cavity (F) into the muscles causing them to flinch from the stimulus, turn the head and eyes toward the affected body part, and move the hand and turn the body protectively. Illustration of the pain pathway in Rene Descartes’ Traite de l’homme (Treatise of Man) 1664. The long fiber running from the foot to the cavity in the head is pulled by the heat and releases a fluid that makes the muscles contract. Graphic credit: Rene Descartes – Copied from a 345 year old book, Traite de l’homme, Public Domain; Wikipedia Commons

 

Pain has accompanied human beings since the moment this species appeared on Earth. From that moment on, and throughout his long history mankind has tried not only to look for the causes of pain but also to find remedies to relieve pain. The concept of pain has remained a topic of long debate since its emergence in ancient times. The initial ideas of pain were formulated in both the East and the West before 1800. Since 1800, due to the development of experimental sciences, different theories of pain have emerged and become central topics of debate. However, the existing theories of pain may be appropriate for the interpretation of some aspects of pain, but are not yet comprehensive. The history of pain problems is as long as that of human beings; however, the understanding of pain mechanisms is still far from sufficient. Thus, intensive research is required. This historical review mainly focuses on the development of pain theories and the fundamental discoveries in this field. Other historical events associated with pain therapies and remedies are beyond the scope of this review. As long as humans have experienced pain, they have given explanations for its existence and sought soothing agents to dull or cease the painful sensation. Archaeologists have uncovered clay tablets dating back as far as 5,000 BCE which reference the cultivation and use of the opium poppy to bring joy and cease pain. In 800 BCE, the Greek writer Homer wrote in his epic, The Odyssey, of Telemachus, a man who used opium to soothe his pain and forget his worries. While some cultures researched analgesics and allowed or encouraged their use, others perceived pain to be a necessary, integral sensation. Physicians of the 19th century used pain as a diagnostic tool, theorizing that a greater amount of personally perceived pain was correlated to a greater internal vitality, and as a treatment in and of itself, inflicting pain on their patients to rid the patient of evil and unbalanced humors. This article focuses both on the history of how pain has been perceived across time and culture, but also how malleable an individual’s perception of pain can be due to factors like situation, their visual perception of the pain, and previous history with pain.

 

Because of the only relatively recent discovery of neurons and how they conduct and interpret signals, including sensations such as pain, within the body, various theories have been proposed as to the causes of pain and its role or function. Even within seemingly limited groups, such as the ancient Greeks, there were competing theories as to the root cause of pain. Aristotle did not include a sense of pain when he enumerated the five senses; he, like Plato before him, saw pain and pleasure not as sensations but as emotions (“passions of the soul“). Alternatively, Hippocrates believed that pain was caused by an imbalance in the vital fluids of a human. At this time, neither Aristotle nor Hippocrates believed that the brain had any role to play in pain processing but rather implicated the heart as the central organ for the sensation of pain. In the 11th century, Avicenna theorized that there were a number of feeling senses including touch, pain and titillation.

 

Portrait of Rene Descartes: Portrait credit: By After Frans Hals – Andre Hatala [[e.a.] (1997) De eeuw van Rembrandt, Bruxelles: Credit communal de Belgique, ISBN 2-908388-32-4., Public Domain, Wikipedia Commons

 

Even just prior to the scientific Renaissance in Europe, pain was not well understood and it was theorized that pain existed outside of the body, perhaps as a punishment from God, with the only management treatment being prayer. Again, even within the confined group of religious, practicing Christians, more than one theory arose. Alternatively, pain was also theorized to exist as a test or trial on a person. In this case, pain was inflicted by god onto person to reaffirm their faith, or in the example of Jesus, to lend legitimacy and purpose to a trial through suffering. In his 1664 Treatise of Man, Rene Descartes theorized that the body was more similar to a machine, and that pain was a disturbance that passed down along nerve fibers until the disturbance reached the brain. This theory transformed the perception of pain from a spiritual, mystical experience to a physical, mechanical sensation meaning that a cure for such pain could be found by researching and locating pain fibers within the bodies rather than searching for an appeasement for god. This also moved the center of pain sensation and perception from the heart to the brain. Descartes proposed his theory by presenting an image of a man’s hand being struck by a hammer. In between the hand and the brain, Descartes described a hollow tube with a cord beginning at the hand and ending at a bell located in the brain. The blow of the hammer would induce pain in the hand, which would pull the cord in the hand and cause the bell located in the brain to ring, indicating that the brain had received the painful message. Researchers began to pursue physical treatments such as cutting specific pain fibers to prevent the painful signal from cascading to the brain.

 

 

Scottish anatomist Charles Bell proposed in 1811 that there exist different kinds of sensory receptors, each adapted to respond to only one stimulus type. In 1839 Johannes Muller, having established that a single stimulus type (e.g., a blow, electric current) can produce different sensations depending on the type of nerve stimulated, hypothesized that there is a specific energy, peculiar to each of five nerve types that serve Aristotle’s five senses, and that it is the type of energy that determines the type of sensation each nerve produces. He considered feelings such as itching, pleasure, pain, heat, cold and touch to be varieties of the single sense he called “feeling and touch.“ Muller’s doctrine killed off the ancient idea that nerves carry actual properties or incorporeal copies of the perceived object, marking the beginning of the modern era of sensory psychology, and prompted others to ask, do the nerves that evoke the different qualities of touch and feeling have specific characteristics?

 

Filippo Pacini had isolated receptors in the nervous system which detect pressure and vibrations in 1831. Georg Meissner and Rudolf Wagner described receptors sensitive to light touch in 1852; and Wilhelm Krause found a receptor that responds to gentle vibration in 1860. Moritz Schiff was first to definitively formulate the specificity theory of pain when, in 1858, he demonstrated that touch and pain sensations traveled to the brain along separate spinal cord pathways. In 1882 Magnus Blix reported that specific spots on the skin elicit sensations of either cold or heat when stimulated, and proposed that “the different sensations of cool and warm are caused by stimulation of different, specific receptors in the skin.“ Max von Frey found and described these heat and cold receptors and, in 1896, reported finding “pain spots“ on the skin of human subjects. Von Frey proposed there are low threshold cutaneous spots that elicit the feeling of touch, and high threshold spots that elicit pain, and that pain is a distinct cutaneous sensation, independent of touch, heat and cold, and associated with free nerve endings.

 

In the first volume of his 1794 Zoonomia; or the Laws of Organic Life, Erasmus Darwin supported the idea advanced in Plato’s Timaeus, that pain is not a unique sensory modality, but an emotional state produced by stronger than normal stimuli such as intense light, pressure or temperature. Wilhelm Erb, in 1874, also argued that pain can be generated by any sensory stimulus, provided it is intense enough, and his formulation of the hypothesis became known as the intensive theory. Alfred Goldscheider (1884) confirmed the existence of distinct heat and cold sensors, by evoking heat and cold sensations using a fine needle to penetrate to and electrically stimulate different nerve trunks, bypassing their receptors. Though he failed to find specific pain sensitive spots on the skin, Goldscheider concluded in 1895 that the available evidence supported pain specificity, and held the view until a series of experiments were conducted in 1889 by Bernhard Naunyn. Naunyn had rapidly (60-600 times/second) prodded the skin of tabes dorsalis patients, below their touch threshold (e.g., with a hair), and in 6-20 seconds produced unbearable pain. He obtained similar results using other stimuli including electricity to produce rapid, sub-threshold stimulation, and concluded pain is the product of summation. In 1894 Goldscheider extended the intensive theory, proposing that each tactile nerve fiber can evoke three distinct qualities of sensation – tickle, touch and pain – the quality depending on the intensity of stimulation; and extended Naunyn’s summation idea, proposing that, over time, activity from peripheral fibers may accumulate in the dorsal horn of the spinal cord, and “spill over“ from the peripheral fiber to a pain-signaling spinal cord fiber once a threshold of activity has been crossed. The British psychologist, Edward Titchener, pronounced in his 1896 textbook, “excessive stimulation of any sense organ or direct injury to any sensory nerve occasions the common sensation of pain.“

 

By the mid-1890s, specificity was mainly backed by physiologists (prominently by von Frey) and clinicians; and the intensive theory received most support from psychologists. But after Henry Head in England published a series of clinical observations between 1893 and 1896, and von Frey’s experiments between 1894 and 1897, the psychologists migrated to specificity almost en masse, and by century’s end, most textbooks on physiology and psychology were presenting pain specificity as fact, with Titchener in 1898 now placing “the sensation of pain“ alongside that of pressure, heat and cold. Though the intensive theory no longer featured prominently in textbooks, Goldscheider’s elaboration of it nevertheless stood its ground in opposition to von Frey’s specificity at the frontiers of research, and was supported by some influential theorists well into the mid-twentieth century. William Kenneth Livingston advanced a summation theory in 1943, proposing that high intensity signals, arriving at the spinal cord from damage to nerve or tissue, set up a reverberating, self-exciting loop of activity in a pool of interneurons, and once a threshold of activity is crossed, these interneurons then activate “transmission“ cells which carry the signal to the brain’s pain mechanism.  The reverberating interneuron activity also spreads to other spinal cord cells that trigger a sympathetic nervous system and somatic motor system response; and these responses, as well as fear and other emotions elicited by pain, feed into and perpetuate the reverberating interneuron activity. A similar proposal was made by RW Gerard in 1951, who proposed also that intense peripheral nerve signaling may cause temporary failure of inhibition in spinal cord neurons, allowing them to fire as synchronized pools, with signal volleys strong enough to activate the pain mechanism. Building on John Paul Nafe’s 1934 suggestion that different cutaneous qualities are the product of different temporal and spatial patterns of stimulation, and ignoring a large body of strong evidence for receptor fiber specificity, DC Sinclair and G Weddell’s 1955 “peripheral pattern theory“ proposed that all skin fiber endings (with the exception of those innervating hair cells) are identical, and that pain is produced by intense stimulation of these fibers. In 1953, Willem Noordenbos had observed that a signal carried from the area of injury along large diameter “touch, pressure or vibration“ fibers may inhibit the signal carried by the thinner “pain“ fibers – the ratio of large fiber signal to thin fiber signal determining pain intensity; hence, we rub a smack. This was taken as a demonstration that pattern of stimulation (of large and thin fibers in this instance) modulates pain intensity.

 

Ronald Melzack and Patrick Wall introduced their “gate control“ theory of pain in the 1965 Science article “Pain Mechanisms: A New Theory“. The authors proposed that both thin (pain) and large diameter (touch, pressure, vibration) nerve fibers carry information from the site of injury to two destinations in the dorsal horn of the spinal cord: transmission cells that carry the pain signal up to the brain, and inhibitory interneurons that impede transmission cell activity. Activity in both thin and large diameter fibers excites transmission cells. Thin fiber activity impedes the inhibitory cells (tending to allow the transmission cell to fire) and large diameter fiber activity excites the inhibitory cells (tending to inhibit transmission cell activity). So, the large fiber (touch, pressure, vibration) activity relative to thin fiber activity at the inhibitory cell, the less pain is felt. The authors had drawn a neural “circuit diagram“ to explain why we rub a smack. They pictured not only a signal traveling from the site of injury to the inhibitory and transmission cells and up the spinal cord to the brain, but also a signal traveling from the site of injury directly up the cord to the brain (bypassing the inhibitory and transmission cells) where, depending on the state of the brain, it may trigger a signal back down the spinal cord to modulate inhibitory cell activity (and so pain intensity). The theory offered a physiological explanation for the previously observed effect of psychology on pain perception. In 1975, well after the time of Descartes, the International Association for the Study of Pain sought a consensus definition for pain, finalizing “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage“ as the final definition. It is clear from this definition that while it is understood that pain is a physical phenomenon, the emotional state of a person, as well as the context or situation associated with the pain also impacts the perception of the nociceptive or noxious event. For example, if a human experiences a painful event associated with any form of trauma (an accident, disease, etc.), a reoccurrence of similar physical pain will not only inflict physical trauma but also the emotional and mental trauma first associated with the painful event. Research has shown that should a similar injury occur to two people, one person who associates large emotional consequence to the pain and the other person who does not, the person who associates a large consequence on the pain event will feel a more intense physical pain that the person who does not associate a large emotional consequence with the pain.

 

Modern research has gathered considerable amounts of evidence that support the theory that pain is not only a physical phenomenon but rather a biopsychosocial phenomenon, encompassing culture, nociceptive stimuli, and the environment in the experience and perception of pain. For example, the Sun Dance is a ritual performed by traditional groups of Native Americans. In this ritual, cuts are made into the chest of a young man. Strips of leather are slipped through the cuts, and poles are tied to the leather. This ritual lasts for hours and undoubtedly generates large amounts of nociceptive signaling, however the pain may not be perceived as noxious or even perceived at all. The ritual is designed around overcoming and transcending the effects of pain, where pain is either welcomed or simply not perceived. Additional research has shown that the experience of pain is shaped by a plethora of contextual factors, including vision. Researchers have found that when a subject views the area of their body that is being stimulated, the subject will report a lowered amount of perceived pain. For example, one research study used a heat stimulation on their subjects’ hands. When the subject was directed to look at their hand when the painful heat stimulus was applied, the subject experienced an analgesic effect and reported a higher temperature pain threshold. Additionally, when the view of their hand was increased, the analgesic effect also increased and vice versa. This research demonstrated how the perception of pain relies on visual input. The use of fMRI to study brain activity confirms the link between visual perception and pain perception. It has been found that the brain regions that convey the perception of pain are the same regions that encode the size of visual inputs. One specific area, the magnitude-related insula of the insular cortex, functions to perceive the size of a visual stimulation and integrate the concept of that size across various sensory systems, including the perception of pain. This area also overlaps with the nociceptive-specific insula, part of the insula that selectively processes nociception, leading to the conclusion that there is an interaction and interface between the two areas. This interaction tells the individual how much relative pain they are experiencing, leading to the subjective perception of pain based on the current visual stimulus.

 

Humans have always sought to understand why they experience pain and how that pain comes about. While pain was previously thought to be the work of evil spirits, it is now understood to be a neurological signal. However, the perception of pain is not absolute and can be impacted by various factors in including the context surrounding the painful stimulus, the visual perception of the stimulus, and an individual’s personal history with pain.

Jan Evangelista Purkyne, Medical Researcher, Cell Biologist (1787-1869)

1856: Jan Evangelista Purkyne

 

Jan Evangelista Purkyne (Czech: also written Johann Evangelist Purkinje) (1787-1869) was a Czech anatomist and physiologist. He was one of the best known scientists of his time. In 1839, he coined the term ?protoplasm’ for the fluid substance of a cell. His son was the painter Karel Purkyne. Such was his fame that when people from outside Europe wrote letters to him, all that they needed to put as the address was “Purkyne, Europe”. He is buried in the Czech National Cemetery in Vysehrad, Prague, modern-day Czech Republic.

 

Jan Evangelista Purkyne was born on December 17, 1787, in Libochovice, in what was then the Czech territory in the Austro-Hungarian monarchy. His father was an estate manager. After his father’s death when Jan was 6, he was encouraged to become a priest. These plans along with his own poverty led to a situation in which, from the age of 10, he was driven from one Piarist monastery school to another, learning German and Latin along the way. He was sent to the Piarist Philosophical Institute in Litomysl, and later, the Philosophical Institute in Prague. As a recent graduate of Prague’s Institute, he earned money as a tutor of rich children. In 1813, he took up medical studies at the University of Prague and in 1818, he graduated from the medical faculty. He then obtained a doctorate in 1819, following a thesis on subjective visual phenomena. By way of self-examination, he established that the visual sensations are caused by brain activity and the brain’s connection to the eye, such that they might not be triggered by external stimulation. Purkyne became a prosector, a  person with the special task of preparing a dissection for demonstration, and an assistant in the Physiology Institute at the University of Prague, but he had no opportunities to carry out his own experiments. He conducted research on vertigo phenomena, still relying on the method of self-examination in a Prague fairground on a carousel. He noticed that the vertigo direction is independent of the direction of rotation, but depends instead on the position of the head in relation to the body. Additionally, he described the phenomena of nystagmus, a vision condition in which the eyes make repetitive, uncontrolled movements, resulting in reduced vision and depth perception and can affect balance and coordination. Purkyne also analyzed the physiological phenomena that occurred after the use of certain drugs, including camphor, opium, digitalis and belladonna. He experimented on himself, sometimes going to dangerous extremes. He noticed that using one drug after another seemed to intensify the effect of the first one. He observed, nearly 30 years before Helmholtz, the interior of the eye in the light reflected into it by concave lenses. He noticed some differences of color detection in dim light, especially in comparison with the detection in daylight – what was then called the “Purkyne phenomenon“. Nowadays, it is explained by differential rod and cone excitation. He also emphasized the significance of fingerprints in crime detection, an idea that was an absolute innovation at that time.

 

Purkyne applied for a teaching position at many universities in the Austrian Empire. However, he was unsuccessful on many occasions. He was a Czech, and university officials preferred to promote German citizens to academic positions. Fortunately, his doctorate thesis was well received, and caught the attention of Goethe, who was interested in the same issue. With strong support shown by Goethe and Aleksander von Humboldt, in 1823, he was offered the position of the Professor of Physiology at the University of Breslau. His candidacy was accepted despite strong opposition from the faculty members. Thus, the most fruitful period of his career began. Purkyne’s successes in Breslau were based on excellent equipment and new techniques for the preparation of research material. He had a very modern and accurate microscope and microtome. He was the first to establish that the whole body is composed of cells. He did this 2 years ahead of T. Schwann. Paradoxically, in the history of science, Schwann is more commonly connected with this discovery. This may have resulted from the fact that Purkyne’s main interest was the inside of the cell, while Schwann described the cell membrane and was the first to use the word “cell“. Undoubtedly, Purkyne was the first to observe and account for the cell nucleus. He also noticed that cells are the structural components of animals and plants. He introduced the terms “protoplasm“ of the cells, and “plasma“ of the blood into the scientific language.

 

The modern techniques of Purkyne’s time allowed him to obtain his neurological results. In 1837, he published a paper about the ganglion cells in the brain, spinal cord, and cerebellum. He was the first to notice the significance of the grey substance of the brain. Before his discovery, scientists thought that only the white substance and nerves had any meaning. He emphasized that those cells are the centers of neurological function and that nerve fibers are like wires that transmit power from the nerves to the whole body. He accurately described the cells in the middle layer of the cerebellum with dendrites branching like a tree. They were then called Purkyne cells. Purkyne’s discoveries were often published in the dissertations of his assistants. He supervised the doctorate of David Rosenthal (1821-1875); they jointly discovered that nerves have fibers inside, and analyzed the number of nerve fibers in spinal and cranial nerves. Purkyne also established that sleep is caused by a decrease of external impulses. He conducted research on the effects of partial destruction of the animal brain by needles, being one of the earliest researchers to use this method. For many years, Purkyne used a special rotating chair and recorded all the optical, motion-associated, and physiological signs accompanying vertigo. He carried out studies in which he directed the galvanic current flow through his own skull, and observed the resulting vertigo and physiological phenomena. He determined the movement of cilia in the genital and respiratory systems, and ultimately, in the ventricles of the brain as well. In 1839, Purkyne discovered the fibrous tissue that transmits electrical impulses from the atrioventricular node to the ventricles of the heart. Today, they are called the Purkyne fibers.

 

In 1839, Purkyne opened the Physiological Institute in Wroclaw, which was the first such institute in the world. He became the dean of the medical faculty, elected to this position four times in a row. In 1850, he became a professor of physiology at the University of Prague. There, he concentrated on encouraging a return to the use of the Czech language instead of German in the university’s operations. He discovered the Purkinje effect, the human eye’s much reduced sensitivity. to dim red light compared to dim blue light. He published two volumes, Observations and Experiments Investigating the Physiology of Senses and New Subjective Reports about Vision, which contributed to the emergence of the science of experimental psychology. He created the world’s first Department of Physiology at the University of Breslau in Prussia (now Wroclaw, Poland) in 1839 and the world’s first official physiology laboratory in 1842. Here he was a founder of the Literary-Slav Society.

 

Personal Sigil 1837

 

Purkinje effect: simulated appearance of a red geranium and foliage in normal bright-light (photopic) vision, dusk (mesopic) vision, and night (scotopic) vision

 

Purkinje is best known for his 1837 discovery of Purkinje cells, large neurons with many branching dendrites found in the cerebellum. He is also known for his discovery in 1839 of Purkinje fibers, the fibrous tissue that conducts electrical impulses from the atrioventricular node to all parts of the ventricles of the heart. Other discoveries include Purkinje images, reflections of objects from structures of the eye, and the Purkinje shift, the change in the brightness of red and blue colors as light intensity decreases gradually at dusk. Purkyne was the first to use a microtome to make wafer thin slices of tissue for microscopic examination and was among the first to use an improved version of the compound microscope. He described the effects of camphor, opium, belladonna and turpentine on humans in 1829. He also experimented with nutmeg that same year, when he “washed down three ground nutmegs with a glass of wine and experienced headaches, nausea, euphoria, and hallucinations that lasted several days”, which remain a good description of today’s average nutmeg binge. Purkyne also discovered sweat glands in 1833 and published a thesis that recognized 9 principal configuration groups of fingerprints in 1823. Purkyne was also the first to describe and illustrate in 1838 the intracytoplasmic pigment neuromelanin in the substantia nigra. Purkyne also recognized the importance of the work of Eadweard Muybridge and constructed his own version of a stroboscope which he called forolyt. He put nine photos of him shot from various sides to the disc and entertained his grandchildren by showing them how he, an old and famous professor, is turning around at great speed.

 

In 1827, Purkyne married Julie Rudolphi, the daughter of a professor of physiology from Berlin. They had four children, two of whom were girls that died in early childhood. After 7 years of marriage, Julie died, leaving Purkyne with two young sons and in deep despair. Purkyne died on July 28, 1869, in Prague. He was buried in the cemetery for distinguished citizens near the Czech Royal Castle on Wyszehrad. Czechoslovakia issued two stamps in 1937 to commemorate the 150th anniversary of the birth of Purkinje (spelt Purkyne in Czech). The Masaryk University in Brno, Czech Republic, bore his name from 1960 to 1990, as did the standalone military medical academy in Hradec Kralove (1994-2004.) Today, a university in Ust? nad Labem bears his name: Jan Evangelista Purkyne University in Ust? nad Labem (Univerzita Jana Evangelisty Purkyne v Usti nad Labem.)

 

The crater Purkyne on the Moon is named after him, as is the asteroid 3701 Purkyne.

 

Sources: nih.gov; Wikipedia

 

Benjamin Franklin’s Contributions to Health and Medicine

Benjamin Franklin Drawing Electricity from the Sky c. 1816 at the Philadelphia Museum of Artby Benjamin West; Google Cultural Institute; Public Domain; Wikipedia Commons

 

Benjamin Franklin took a great interest in health-related topics. In his day, many beliefs about health and disease were based on superstition. Franklin applied Enlightenment reasoning to his study of various afflictions and came up with some astonishingly accurate hypotheses. Here are just a few of Franklin’s theories and accomplishments in the fields of health, physical fitness, and medicine.

Common cold: In the 18th century, most people believed that wet clothing and dampness in the air caused the common cold. However, Franklin observed that sailors, who were constantly wearing wet clothing, remained healthy. After considering the matter on and off for several years, he eventually concluded: “People often catch cold from one another when shut up together in small close rooms, coaches, &c. and when sitting near and conversing so as to breathe in each other’s transpiration.“ Before the knowledge of viruses and germs, Franklin had determined that the common cold was passed between people through the air. Franklin’s views on the cause of the common cold indicate that he was sympathetic to the view that it could result from some causative agent or agents transmitted from one person to another. In writing to Benjamin Rush, the eminent Philadelphia physician best known for his strong advocacy of blood-letting, Franklin commented thus.

 

[I] am glad to hear that [Dr. Cullen] speaks of Catarrhs or Colds by contagion. I have long been satisfy’d from Observation, that besides the general Colds now termed Influenza’s, which may possibly be spread by Contagion as well as by a particular Quality of the Air, People often catch Cold from one another when shut up together in small close Rooms, Coaches, &c. and when sitting near and conversing so as to breathe in each others Transpiration, the Disorder being in a certain State. As to Dr. Cullen’s Cold or Catarrh a frigore, I question whether such an one ever existed. (Franklin 1773a; 1773b).

 

Lead poisoning: Franklin learned first-hand from the printing business that working with warm lead type caused his hands to become exceptionally stiff and sore. He discovered that some typesetters who warmed their type sometimes lost the complete use of their hands. Franklin decided to work with cold type from that point on. Years later, he visited a hospital in France that treated patients suffering from what was then called the “dry gripes“ or “dry belly ache.“ In analyzing the list of patients, Franklin deduced that all of them were in professions where they were exposed to large quantities of lead. He corresponded with others interested in this health issue, exchanging observations and insights about the illness. Franklin concluded: “I have long been of the opinion that that distemper [dry gripes] proceeds always from a metallic cause only, observing that it affects among tradesmen those that use lead, however different their trades, as glazers, type-founders, plumbers, potters, white lead-makers and painters.“ Franklin’s observations were among the earliest to link health problems with exposure to lead.

 

Pennsylvania Hospital: A friend of Franklin, Dr. Thomas Bond, came up with the idea of establishing a public hospital. Bond was unable to raise the money, so he turned to Franklin, who mounted a public relations and information campaign in support of a hospital. The colonial government finally agreed and the hospital was founded in 1751. The hospital’s mission was to serve the mentally ill, along with providing medical care to poor citizens who could not afford a private physician. The Pennsylvania Hospital is considered to be the first public hospital in the United States. While raising money for the hospital, Franklin came up with a new idea for combining public (government) money with private donations, which created the first matching grant.

 

Electricity and paralysis: Franklin experimented with giving electrical shocks to individuals who had paralysis in their limbs due to a stroke or other cause. He wired the patients to Leyden jars and sent electrical shocks to the paralyzed limbs. Franklin observed improvement in many of the patients, but reported that most relapsed after several days. Although he was initially excited about the possibilities, he wrote that he “never knew any advantage from electricity in palsies that was permanent.“ Modern medical doctors stimulate immobile muscles with electrical impulses to help prevent atrophy.

 

Exercise: As an avid swimmer in his youth, Franklin learned the joys of exercise. He was one of the earliest supporters of regular exercise as a way of maintaining one’s health. He especially believed in outdoor exercise with lots of fresh air. In a letter to his son William, Franklin outlined a complete program of vigorous exercise, which Franklin contended would help prevent disease. Franklin rightly believed that the more strenuous the exercise, the higher the degree of body warmth. He commented that when he exercised vigorously with dumbbells that both his heart rate and temperature rose. Today we know that regular cardiovascular exercise can prevent a variety of ailments.

 

Swimming: Franklin grew up near the ocean in Boston and began swimming at a young age. On his first trip to London in 1724, he often swam in the Thames River and entertained observers with the “ornamental“ maneuvers he performed in the water. While in London, Franklin considered taking a job as a full-time swimming instructor. For his early encouragement of the sport of swimming, Franklin was posthumously inducted into the International Swimming Hall of Fame. In a 1747 letter to his parents, Benjamin Franklin noted:

 

“I apprehend I am too busy in prescribing, and meddling in the Dr’s sphere, when any of you complain of ails in your letters: but as I always employ a physician myself when any disorder arises in my family and submit implicitly to his orders in everything, so I hope you consider my advice, when I give any, only as a mark of my good will, and put no more of it in practice that happens to agree with what your Dr. directs.“

 

After giving this assurance that he did not mean to play the physician, Franklin continued with advice about remedies for bladder stone and gravel. In fact, throughout his life he dispensed such advice and wrote knowledgeably on a number of health-related issues. Franklin played many roles during his long life: printer and publisher, civic activist, revolutionary and statesman, scientist and philosopher, diplomat, and sage. Given the significance of his political and civic activities and his experimentation with electricity, it is little wonder that Franklin’s medical interests have attracted less attention. Nonetheless, despite his lack of formal training, medicine was prominent among Franklin’s interests. His writings ranged over a number of topics, from treatment of the common cold to promotion of exercise and a moderate diet. With his connections to prominent physicians on both sides of the Atlantic and with his published works widely read, Franklin’s thoughts on health and medicine found a broad contemporary audience. He was also a medical activist and inventor, championing smallpox inoculation, taking a leading role in founding Pennsylvania Hospital (the first such institution in the British North American colonies), and inventing devices like bifocal glasses.

 

Born in Boston in 1706, Benjamin Franklin was the youngest son of 17 children. He came to Philadelphia in 1723, after leaving an apprenticeship with his brother, a printer. By the 1730s, Franklin was owner of his own printing house, publishing a popular newspaper and almanac, and a civic activist. He retired from printing in 1748 to pursue other interests and later gained international fame for his experiments with electricity. Franklin spent the latter portion of his life in politics and diplomacy. He served in the Pennsylvania Assembly and spent 15 years in London as a colonial agent. He was also a member of the legislative bodies crucial to the founding of the United States, serving as a delegate to the Continental Congress and, later, the oldest participant in the Constitutional Convention. Franklin signed both the Declaration of Independence and the Constitution, and was sent to France as the first diplomat from the USA. Such diverse interests and activities were not unusual for the time. Many educated men were active or interested in politics, civic or social improvement, and scientific exploration. These pursuits rose out of a social consciousness born of the Enlightenment. This movement valued reason and observation as the means to knowledge and improved social organization. An Enlightenment temperament, such as that shown by Franklin, had a high regard for rationality, valued self-discipline and social consciousness, and desired to generate progress by increase of learning. In his roles as scientist and purveyor of information, Franklin was an active citizen in the eighteenth-century medical world. His contemporaries sought healthcare and medical advice from a wide variety of sources and most medical care was provided in the home from family members or – for the wealthy – servants. Sources of counsel about health, disease and medicine included popular health manuals, almanacs, newspapers and cookbooks. The adages and poetry in Poor Richard’s Almanac, the entire contents of which were authored by Franklin, served to instruct the masses at the same time they entertained. Through his almanac and other writings, Benjamin Franklin exerted his greatest influence on the medical sphere. With numerous well-informed correspondents – including physicians and scientists on two continents – and, as a skilled writer, he was capable of writing letters, articles, collections of sayings and other works filled with medical commentary. These covered a wide range of subjects including electrical treatments for paralysis.

 

Medical uses of electricity were much discussed during Franklin’s lifetime. It was known, from early in the eighteenth century, that an electrical shock could cause involuntarily twitching and contraction of muscles. Many people thus hoped that ?electrical fire’ would provide a cure for paralysis. They believed that sending a charge through the affected limbs might increase blood flow, regenerate muscle and restore movement or physical control. Franklin was doubtful about the usefulness of electrical treatment for palsy and paralysis and never promoted himself as an electrical therapist. Nonetheless, because of his reputation as an electrical innovator, he was from time to time contacted by people seeking electrical therapy. Using an electrostatic generator (in which electrical charge was created by rubbing material against a mounted glass ball or cylinder turned by a crank) and a Leyden jar (which stored the electrical energy), Franklin obliged those patients who came to him desiring electrical therapies. He described these treatments in a letter to Sir John Pringle, dated 21 December 1757.

 

“Some years since.a number of paralytics were brought to me from different parts of Pennsylvania and the neighboring provinces, to be electris’d, which I did for them, at their request. My method was, to place the patient first in a chair on an electric stool, and draw a number of large strong sparks from all parts of the affected limb or side. Then I fully charg’d two 6 gallon glass jars, each of which had about 3 square feet of surface coated and I sent the united shock of these thro’ the affected limb or limbs, repeating the stroke commonly three times each day.

 

The first thing observed was an immediate greater sensible warmth in the lame limbs that receiv’d the stroke than in the others. The limbs too were found more capable of voluntary motion and seem’d to receive strength. These appearances gave great spirits to the patients, and made them hope a perfect cure; but I do not remember that I ever saw any amendment after the fifth day: Which the patients perceiving, and finding the shocks pretty severe, they became discourag’d, went home and in a short time relapsed; so that I never knew any advantage from electricity in palsies that was permanent.’

 

Although Franklin’s patients found no permanent cure for their paralysis, he continued to receive requests for aid – one even from Pringle himself, who requested Franklin’s presence in 1767 at the treatments administered to the daughter of a nobleman. Franklin also concerned himself with medical problems more removed from his own scientific expertise. He wrote about lead poisoning on several occasions, in particular about a disease known as the dry-gripes (or dry-bellyache) that had plagued Europe and the colonies for years. Franklin had not yet left Boston when, in 1723 the Massachusetts colonial legislature passed a bill outlawing the use of lead in the coils and heads of stills. Observance of this law led to vastly decreased incidence of the dry-gripes, as the population drank less and less lead-contaminated rum. In a letter to his friend, Philadelphia physician Cadwalader Evans, Franklin wrote that he was certain that the symptoms known as dry-bellyache were always the result of lead exposure, whether in food or drink or from exposure through trades that used lead. In his correspondence with Dr George Baker, Franklin advanced this idea and thus helped Baker discover the aetiology of the Devonshire Colic, a condition the symptoms of which included weakened muscles, loss of weight and pallor. It was widespread in Baker’s native Devonshire; Baker suspected lead-contaminated cider was the cause, and his discussions with Franklin helped confirm his hypothesis. Baker eventually found that millwheels that were used to crush the apples were bound together with poured molten lead. He credited Franklin with his assistance in this discovery on several occasions.

 

Franklin’s scientific activities and medical acumen was respected on both sides of the Atlantic by physicians, scientists and, in one case, royalty. During Franklin’s time in Paris, he participated in the discrediting of the medical cult surrounding Mesmerism. Franz Anton Mesmer arrived in Paris in 1778, promoting his new principle of healing known as animal magnetism. His treatments attracted many followers, but also the scepticism of French physicians, who regarded Mesmer as a fraud. In March 1784, Louis XVI appointed a commission to investigate Mesmer’s claims. Four physicians and five eminent scientists were on the commission, including Franklin, who was chosen to preside over their investigation. The Commission observed one of Mesmer’s disciples, a Dr D’Eslon, at Franklin’s home in Passy, outside Paris. D’Eslon attempted to magnetize several patients chosen by the Commission, as well as members of Franklin’s own household, and the subjects reported feeling no change. In the Commission’s report, written by Franklin, Mesmer was declared a fraud, as no reasonable proof of animal magnetism could be determined. Franklin felt that any cures made were a product of imagination, and the report he authored led to Mesmer’s disgrace.

 

Throughout his lifetime, Franklin produced many lighter writings on health related topics as well. His advice in Poor Richard’s Almanac includes Franklin’s most famous advice on health, including such maxims as:

 

Early to bed and early to rise, makes a man healthy, wealthy and wise

Be not sick too late, nor well too soon

Time is an herb that cures all diseases

Eat to live and not live to eat.

 

Franklin promoted a moderate diet, exercise, and self-control in all things, and sometimes even followed his own advice. In his youth, Franklin was influenced to try vegetarianism after reading Thomas Tryon’s Way to Health and Happiness; he later returned to eating meat. He exercised frequently, favoring swimming and endorsing it not only as good exercise but also as a method to open pores, hydrate the body and maintain cleanliness. In his old age, Franklin continued to exercise, lifting and swinging weights when his health no longer allowed him to swim or walk. Many of Franklin’s medical writings showed the same spirit of public activism that characterized his civic and national projects. He repeatedly used his skills with pen and press in support of innovations that could make a difference in the public health. Most significant, perhaps, was his lifelong endorsement of smallpox inoculation. Inoculation spread rapidly in North America and Europe after its introduction into western medicine in the 1720s. The practice involved exposing healthy individuals to the disease by abrading the skin and introducing a small amount of morbid matter. Typically the patient would contract a similarly mild instance of the disease and, once recovered, would have permanent immunity. Cases contracted the natural way would often leave victims disfigured and had a significant mortality rate. Franklin wrote articles promoting inoculation and its safety as early as 1731. His support of inoculation grew after the heartbreaking loss of his 6-year-old son, Francis Folger Franklin, to smallpox in 1736. Franklin had planned to inoculate the boy at the time of an outbreak, but was unable to do so because the child was in a weakened state from another illness. Critics of inoculation suggested that Franklin’s son had been a victim of the procedure, and Franklin was forced to publish an article in his paper, The Pennsylvania Gazette, insisting that his son had contracted a natural case of the disease. Throughout his life, Franklin monitored the success of inoculation in several colonial cities, and shared information with his correspondents about the procedure’s extremely low mortality rates and the decreased smallpox incidence that resulted. The statistics he compiled were useful for Some Account of the Success of Inoculation for the Small-pox in England and America, a pamphlet he wrote with physician William Heberden. While in London, Franklin encouraged Heberden to write briefly on the value of inoculation and to include instructions by which any educated layman could inoculate his own family. Franklin wrote the preface and had 1500 copies printed and sent to the colonies for free distribution.

 

Franklin did more than just write about medical matters. Most of his inventions provided practical solutions to everyday problems, and Franklin brought that same inventive spirit into the medical realm. His medical creations were uncomplicated and made to be immediately useful, like the flexible catheter he designed for his brother John, who suffered from bladder stone and urinary retention. Franklin designed a device in 1757, had it made by a local silversmith, and sent it to John in Boston, with a letter detailing its design and use. The catheter was made from silver wire, coiled with joints to allow flexibility, and covered with gut. Most famous among his contributions to medical care were Franklin’s ?double spectacles’, better known as bifocals. He himself was probably wearing these spectacles as early as the 1750s, during his time in London. In several letters to London philanthropist, George Whatley, Franklin stated that he had created bifocals to avoid awkward shifting between his regular and reading glasses. Cutting his other glasses and having half of each lens placed in the same frame, Franklin believed, make my eyes as useful to me as ever they were. The first written record of his bifocals design, is a letter to George Whatley:

 

“I had formerly two Pair of Spectacles, which I shifted occasionally, as in travelling I sometimes read, and often wanted to regard the Prospects. Finding this Change troublesome, and not always sufficiently ready, I had the Glasses cut, and half of each kind associated in the same Circle. By this means, as I wear my spectacles constantly, I have only to move my Eyes up or down, as I want to see distinctly far or near, the proper Glasses being always ready.“ (Franklin 1785).

 

Franklin also served the Philadelphia medical scene with his skills as an organizer and philanthropist. In 1751 Franklin’s friend, Dr Thomas Bond, began a campaign to raise money for what would be the first voluntary hospital in the colonies. Bond had little success raising money and turned to Franklin for assistance. Franklin supported the idea completely and agreed to become a subscriber. His involvement had the desired effect, and once he was involved in the project funds were raised easily. He then petitioned the Pennsylvania Assembly for support and convinced the legislators to match the voluntary funds if he and Bond could solicit ?2000 from citizens of the colony. The founders used the Assembly’s promise of matching funds to encourage private donors, and the necessary sum was soon raised. Pennsylvania Hospital received its charter in May 1751 and, in 1756, the first patients were admitted to the hospital’s building at Eighth and Pine Streets. Franklin served on the hospital’s board for a number of years, and sought support from abroad for the institution during his time in London. Franklin enjoyed good health. While most images of Franklin show him in prosperous middle age or as an elderly statesman, he was a strong and active youth. As a young man, Franklin’s most serious afflictions were respiratory illnesses. He was thus very interested in the common cold and its causes. He dismissed the popular notion that changes in temperature, particularly exposure to cold air, made people apt to catch cold. He suggested instead that putrid matter in the air was responsible. Because of this belief, Franklin championed proper ventilation as essential to good health, noting that:

 

?I am persuaded that no common Air from without, is so unwholesome as the Air within a close Room, that has been often breath’d and not changed.’

 

Franklin advocated as much exposure to fresh air as possible and frequently slept with an open window. He enjoyed a daily air bath to cleanse his skin. This involved sitting naked in his chambers with the windows open. Other than frequent respiratory problems, Franklin suffered two common eighteenth-century complaints: gout and pain from bladder stones. These were largely nuisance diseases in Franklin’s middle years, and he was fortunate to enter his seventies still active and mentally focused. His gout attacks began in his forties and continued intermittently for the rest of his life – with occasional attacks in his knees, feet and hands so severe as to render him bedridden. He often returned to a simple diet when dealing with this problem and he believed that exposing his afflicted limbs to fresh air was also helpful. As late as 1783, at the age of 76, Franklin faced gout attacks philosophically, noting:

 

?I have been lately ill with a Fit of the Gout, if that may indeed be called a Disease; I rather suspect it to be a Remedy; since I always find my Health and Vigor of Mind improv’d after the Fit is over.’

 

As he advanced into his eighties, Franklin’s health increasingly failed. His bladder stone grew, causing him pain in movement and curtailing the active life he had enjoyed before then. The stone was probably sizable by the time it began to cause Franklin difficulty, and it only grew larger. Late in his life, he noted that he could actually feel the weight of the stone moving in his body when he rolled over in bed or shifted position. Franklin’s stone was too large for surgery by the time it caused him the greatest suffering. With the high risks of any procedure where cutting was involved, and his advanced age making the operation even more dangerous, Franklin chose to manage the stone as best he could with diet and gentle exercise. In a 1787 letter to the Comte de Buffon, a friend and fellow sufferer, Franklin noted that he had ?tried all the noted Prescriptions for diminishing the Stone, without procuring any good Effect. But observing Temperance in Eating, avoiding wine and Cyder, and using daily the Dumb Bell, which exercises the upper Part of the Body without much moving the Parts in contact with the Stone, I think I have prevented its Increase’.

 

In his final years, Franklin took opium to combat the severe pain resulting from the stone and he was often bedridden. He died 17 April 1790, after suffering a bout of pneumonia and pleurisy.

 

With the breadth of his commentary, and the useful products of his inventiveness, Franklin’s medical legacy continues to the present. His wit and wisdom on diet, health care and moderate living, as written in Poor Richard’s Almanac, is still part of the public consciousness. Almost immediately after his death, authors began quoting and reprinting Franklin’s advice to give their own works legitimacy and to boost sales. We may now be able to quantify the calories burned during exercise or the nutritional content in our diet, but Franklin’s advice, made long before such activities were possible or even understood, still rings true in its simplicity. In a larger sense, Franklin’s medical legacy is similar to the legacy of the Enlightenment world in which he lived – a legacy of public health initiatives and ideas about improvement through moderation and human enterprise. Franklin’s thoughts and inventions fit squarely into this heritage, from his campaign against smallpox that paved the way for acceptance of vaccination (announced by Edward Jenner within a decade of Franklin’s death) to his invention of spectacles that could serve two purposes simultaneously. Because his thoughts on health and medicine depended so much upon people taking an active role in remaining healthy and improving society, the medical world of Benjamin Franklin will continue to have relevance and influence for years to come.

 

Lisa Gensel; The Royal Society of Medicine; pbs.org/benfranklin/l3l; http://www.jameslindlibrary.org/articles/benjamin-franklins-1706-1790-place-in-the-history-of-medicine/; Twin Cities Public Television, Inc.Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1299336/

 

History of Cell Biology 101

Structure of a typical animal cell; Graphic credit: Royroydeb – Own work, CC BY-SA 4.0; Wikipedia Commons

 

Structure of a typical plant cell; Graphic credit: LadyofHats – Self-made using Adobe Illustrator. (The original edited was also made by me, LadyofHats), Public Domain, Wikipedia Commons

 

Graphic credit: National Center for Biotechnology Information; Vectorized by Mortadelo2005. – Public Domain, Wikipedia Commons

 

 

Editor’s note: The evolution of the cell is one of Science’s most awesome areas of study, leading to the origins of life itself. It is beyond our comprehension, why anyone able to contribute to the funding of research, inquiring into the mystery of life, and its pathologies, which cell biology does, why anyone would not be eager to do so. Perhaps Americans should vote to require that all politicians have an education high enough to enable them to understand the worlds of science, math, technology, engineering, and all the arts (which remind us of our humanity).

 

Stromatolites are left behind by cyanobacteria, also called blue-green algae. They are the oldest known fossils of life on Earth. This one-billion-year-old fossil is from Glacier National Park in the United States. Photo credit: P. Carrara, NPS – National Park Service – http://www.nature.nps.gov/geology/cfprojects/photodb/Photo_Detail.cfm?PhotoID=204; Public Domain, Wikimedia Commons

 

 

There are several theories about the origin of small molecules that led to life on the early Earth. They may have been carried to Earth on meteorites (see Murchison meteorite), created at deep-sea vents, or synthesized by lightning in a reducing atmosphere (see Miller-Urey experiment). There is little experimental data defining what the first self-replicating forms were. RNA is thought to be the earliest self-replicating molecule, as it is capable of both storing genetic information and catalyzing chemical reactions (see RNA world hypothesis), but some other entity with the potential to self-replicate could have preceded RNA, such as clay or peptide nucleic acid.

 

Cells emerged at least 3.5 billion years ago. The current belief is that these cells were heterotrophs. The early cell membranes were probably more simple and permeable than modern ones, with only a single fatty acid chain per lipid. Lipids are known to spontaneously form bilayered vesicles in water, and could have preceded RNA, but the first cell membranes could also have been produced by catalytic RNA, or even have required structural proteins before they could form. The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearing organelles like the mitochondria and the chloroplasts are descended from ancient symbiotic oxygen-breathing proteobacteria and cyanobacteria, respectively, which were endosymbiosed by an ancestral archaean prokaryote. There is still considerable debate about whether organelles like the hydrogenosome predated the origin of mitochondria, or vice versa: see the hydrogen hypothesis for the origin of eukaryotic cells.

 

The cell (from Latin cella, meaning “small room“ is the basic structural, functional, and biological unit of all known living organisms. A cell is the smallest unit of life that can replicate independently, and cells are often called the “building blocks of life“. The study of cells is called cell biology. Cells consist of cytoplasm enclosed within a membrane, which contains many biomolecules such as proteins and nucleic acids. Organisms can be classified as unicellular (consisting of a single cell; including bacteria) or multicellular (including plants and animals). While the number of cells in plants and animals varies from species to species, humans contain more than 10 trillion cells. Most plant and animal cells are visible only under a microscope, with dimensions between 1 and 100 micrometers.

 

The cell was discovered by Robert Hooke in 1665, who named the biological unit for its resemblance to cells inhabited by Christian monks in a monastery. Cell theory, first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed of one or more cells, that cells are the fundamental unit of structure and function in all living organisms, that all cells come from preexisting cells, and that all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells. Cells are of two types, eukaryotic, which contain a nucleus, and prokaryotic, which do not. Prokaryotes are single-celled organisms, while eukaryotes can be either single-celled or multicellular. Prokaryotic cells were the first form of life on Earth, characterized by having vital biological processes including cell signaling and being self-sustaining. They are simpler and smaller than eukaryotic cells, and lack membrane-bound organelles such as the nucleus. Prokaryotes include two of the domains of life, bacteria and archaea.

 

Three co-founders of cell theory:

 

Matthias Jakob Schleiden (1804-1881) was a German botanist and co-founder of cell theory, along with Theodor Schwann and Rudolf Virchow. Born in Hamburg, Schleiden was educated at University of Jena, then practiced law in Heidelberg, but soon developed his love for botany into a full-time pursuit. Schleiden preferred to study plant structure under the microscope. While a professor of botany at the University of Jena, he wrote Contributions to our knowledge of phytogenesis (1838), in which he stated that all parts of the plant organism are composed of cells. Thus, Schleiden and Schwann became the first to formulate what was then an informal belief as a principle of biology equal in importance to the atomic theory of chemistry. He also recognized the importance of the cell nucleus, discovered in 1831 by the Scottish botanist Robert Brown, and sensed its connection with cell division. Schleiden was one of the first German biologists to accept Charles Darwin’s theory of evolution. He became professor of botany at the University of Dorpat in 1863. He concluded that all plant parts are made of cells and that an embryonic plant organism arises from the one cell. He died in Frankfurt am Main on 23 June 1881. It was during the four years spent under the influence of Muller in Berlin, that Schwann’s most valuable work was done. Muller was at this time preparing his great book on physiology, and Schwann assisted him in the experimental work required. Schwann observed animal cells under the microscope, noting their different properties. Schwann found particular interest in the nervous and muscular tissues. He discovered the cells that envelope the nerve fibers, now called Schwann cells in his honor. Schwann discovered the striated muscle in the upper esophagus and initiated research into muscle contraction, since expanded upon greatly by Emil du Bois-Reymond and others. Muller directed Schwann’s attention to the process of digestion, and in 1837 Schwann isolated an enzyme essential to digestion, which he called pepsin. Schwann became chair of anatomy at the Belgian Catholic University of Leuven in 1839. Here he produced little new scientific work, the exception being a paper establishing the importance of bile in digestion. He nonetheless proved to be a dedicated and conscientious professor. In 1848, his compatriot Antoine Frederic Spring convinced him to transfer to the University of Liege, also in Belgium. At Liege, he continued to follow the latest advances in anatomy and physiology without himself contributing. He became something of an inventor, working on numerous projects including a human respirator for environments where the surroundings are not breathable. In his later years, Schwann found growing interest in theological issues. Three years after retiring, Schwann died in Cologne on 11 January 1882. There is a bronze statue of Theodor Schwann at the entrance of the Institute of Zoology, University of Liege, Belgium.

 

Cell theory

 

In 1837, Matthias Jakob Schleiden viewed and stated that new plant cells formed from the nuclei of old plant cells. While dining that year with Schwann, the conversation turned on the nuclei of plant and animal cells. Schwann remembered seeing similar structures in the cells of the notochord (as had been shown by Muller) and instantly realized the importance of connecting the two phenomena. The resemblance was confirmed without delay by both observers, and the results soon appeared in Schwann’s famous Microscopical Researches into the Accordance in the Structure and Growth of Animals and Plants, in which he declared that “All living things are composed of cells and cell products“. This became cell theory or cell doctrine. In the 19th century, physiological knowledge began to accumulate at a rapid rate, in particular with the 1838 appearance of the Cell theory of Matthias Schleiden and Theodor Schwann. It dramatically stated that organisms are made up of units called cells. At this time, cell theory was considered a radical idea. In the course of his verification of cell theory, Schwann proved the cellular origin and development of the most highly differentiated tissues including nails, feathers, and tooth enamel. Schwann established a basic principle of embryology by observing that the ovum is a single cell that eventually develops into a complete organism.

 

In 1857, pathologist Rudolf Virchow posed the maxim Omnis cellula e cellula – that every cell arises from another cell. By the 1860s, cell doctrine became the conventional view of the elementary anatomical composition of plants and animals. Schwann’s theory and observations became the foundation of modern histology.

 

Timeline: History of Cell Biology

 

– 1632-1723: Antonie van Leeuwenhoek teaches himself to make lenses, constructs basic optical microscopes and draws protozoa, such as Vorticella from rain water, and bacteria from his own mouth.

– 1665: Robert Hooke discovers cells in cork, then in living plant tissue using an early compound microscope. He coins the term cell (from Latin cella, meaning “small room“) in his book Micrographia (1665).

– 1839: Theodor Schwann and Matthias Jakob Schleiden elucidate the principle that plants and animals are made of cells, concluding that cells are a common unit of structure and development, and thus founding the cell theory.

– 1855: Rudolf Virchow states that new cells come from pre-existing cells by cell division (omnis cellula ex cellula).

– 1859: Louis Pasteur (1822-1895) contradicts the belief that life forms can occur spontaneously (generatio spontanea) (although Francesco Redi had performed an experiment in 1668 that suggested the same conclusion).

– 1931: Ernst Ruska builds the first transmission electron microscope (TEM) at the University of Berlin. By 1935, he has built an EM with twice the resolution of a light microscope, revealing previously unresolvable organelles.

– 1953: Watson and Crick made their first announcement on the double helix structure of DNA on February 28.

– 1981: Lynn Margulis published Symbiosis in Cell Evolution detailing the endosymbiotic theory

 

Fuller Albright MD (1900-1969): Founder of Modern Endocrinology

(A) A photo of Fuller Albright as a young physician outside of Massachusetts General Hospital. (B) A photo probably from the late 1940s showing Albright with advanced Parkinson’s disease. Source: Clinical Journal of the American Society of Nephrology

 

 

Fuller Albright’s remarkable book Parathyroid Glands and Metabolic Bone Disease, a landmark publication in 1948, summarized Albright’s many contributions to mineral metabolism during the previous two decades.

 

Fuller Albright was born in Buffalo, New York, on January 12, 1900. His father was a wealthy industrialist and philanthropist. The major art museum in Buffalo is known today as the Albright-Knox Art Gallery. Albright attended the Nichols School in Buffalo, which was founded by his father. He not only excelled academically, but also was captain of the football team. During his childhood, the Albright family made frequent visits to Wilmurt Lake in the Adirondacks, where he became an avid fly fisherman and developed woodsman’s skills. During his academic years in Boston, Albright would spend summer vacations at Wilmurt Lake with his family. It was at Wilmurt Lake where he directed that his ashes be scattered after his death.

 

Fuller Albright attended Harvard College, but after only 18 months, he falsified his age and enlisted in the Army after America’s entry into World War I. It was also the time of the great influenza pandemic, which has been postulated to be a cause of Parkinson’s disease many years after recovery from influenza. Albright was to develop Parkinson’s disease in his mid-30s, and it was to progress relentlessly during the next two decades of his life. In 1921, Albright entered Harvard Medical School, where he excelled and was elected to Alpha Omega Alpha. On graduation, he did an internship and residency in Medicine at Massachusetts General Hospital. There he met Read Ellsworth, who became a close friend and collaborator. Both initially were mentored by Dr. Joseph Aub, a clinical scientist in endocrinology and metabolism. Albright and Ellsworth continued their research collaboration in mineral metabolism until the latter’s premature death from tuberculosis in 1937. Perhaps the most critical year in Albright’s training was that of 1928-1929, when he went to Vienna to study with Dr. Jacob Erdheim, a brilliant pathologist who in 1906 had established the relation between the parathyroid glands and calcium metabolism by showing that calcium is not deposited into growing teeth in the absence of parathyroid glands. Also, it was Erdheim who had first described compensatory hyperplasia of the parathyroid gland associated with osteomalacia. Albright often would later say of Erdheim that quite simply he knew more about human disease than any other living man and referred to him as the greatest of living pathologists.

 

Albright returned to Massachusetts General Hospital in 1929. There he would begin his long, productive career in clinical research, much of which emanated from the then recently established Ward 4, which was a 10-bed research unit where patients and healthy subjects could be intensively studied. On Ward 4, special diets could be prepared, biochemical measurements could be performed, and meticulous collections of urinary and fecal output could be obtained. The latter, when combined with measurement of dietary intake, constituted the balance study that became a major investigative tool for Albright. Albright married Claire Birge in 1932, and they had two sons. She became a major source of support for him as his Parkinson’s disease progressed. By the early 1940s, Albright could no longer write, and by the mid-1940s his speech had become difficult to understand. In an article written in 1946 for the twenty-fifth anniversary of his medical school class enrollment, Albright wrote, I have had the interesting experience of observing the course of Parkinson’s syndrome on myself. It disturbs every movement and gives a certain rigidity that makes small talk look strained. The condition does have its compensations: one is not taken away from interesting work to be sent to Burma, one avoids all forms of deadly committee meetings, etc.

 

The patients for Albright’s studies came from his three weekly clinics: the Ovarian Dysfunction Clinic on Tuesdays, the Stone Clinic on Wednesdays (also known as the Quarry), and the general Endocrine Clinic on Saturdays. Even when not involved in a study, every patient would return to the respective clinic at least once per year. If a patient failed to return, a visiting nurse would be sent to find the patient. In 1939, Anne Forbes became his physician administrative chief and collaborator. She assumed much of the administrative and organizational burden for his studies. In 1942, Albright became an Associate Professor of Medicine at Harvard, but not wanting any administrative burden, he refused to become a full professor. In the 1950s, the medical student taking an elective with Albright would be given the family’s second car with the assigned task of transporting Albright to the hospital and looking after him at work. These students included such future well-known investigators as Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher, and Stan Franklin. By the early 1950s, Anne Forbes has said that Albright was convinced that the Parkinson’s disease was affecting his intellect. In 1952, a noted New York neurosurgeon, Dr. Irving Cooper, had reported that Parkinson’s patients could be improved by a surgical procedure, chemopallidectomy, in which small amounts of alcohol were injected into the areas of the brain responsible for the tremor and rigidity. Despite expert advice to the contrary from his Harvard colleagues and even from Dr. Cooper, Albright was determined to undergo the procedure because of his inability to speak comprehensively and a severely impaired capacity to dress, eat, and write. The surgery was performed in June 1956. After the intervention on the right side, a marked improvement in symptoms was observed. However, the operation on the left side was followed by a major cerebral hemorrhage, from which Albright would never recover. For the next 13 years, he lived in a vegetative state. In a ceremony in 1961, Fuller Albright was officially retired from the Faculty of Medicine at Harvard as Professor, Emeritus. Fuller Albright died on December 8, 1969.

 

Albright, the Clinical Investigator Par Excellence

Mineral Metabolism

 

Albright’s work on serum calcium and phosphorus regulation, primary hyperparathyroidism, and the renal excretion of calcium and phosphorus became the foundation of our understanding of mineral metabolism. His description and study of vitamin D resistant rickets became the basis for the study of renal phosphate transport. Starting in the late 1920s and continuing through the mid-1930s, Albright’s primary focus was studying how differences in dietary calcium and phosphate affected calcium and phosphate balance in healthy subjects and in patients with primary hyperparathyroidism and with hypoparathyroidism. Healthy subjects and patients with hypoparathyroidism were studied with the newly available parathyroid extract (PTE). Because the balance studies were remarkably consistent, only a small number of subjects needed to be studied to provide the results, which remain true today. Albright was the first to provide a comprehensive framework for understanding the regulation of calcium and phosphate in normal subjects and in patients with parathyroid disorders. The report of the seventeen patients operated on for primary hyperparathyroidism published by Albright in 1934 was the largest series until then. The number of patients in that series diagnosed with primary hyperparathyroidism had been greatly expanded when Albright had the insight to measure serum calcium values in patients with kidney stones. At diagnosis, primary hyperparathyroidism was a much more severe disease than now. The average preoperative serum calcium value was 13.9 mg/dl and the average weight of the removed parathyroid adenoma was >11 g. Parathyroidectomy was an entirely new operation for surgeons and required intensive training with autopsy material. Two remarkable findings characterized the first 17 parathyroidectomies. Two patients had ectopic locations of their parathyroid adenoma, one of whom was the famous Captain Martell, who required seven operations before the ectopic gland was discovered. Cases 15 through 17 had parathyroid hyperplasia and not an adenoma as the cause of the hyperparathyroidism.

 

In a discussion of a case of renal osteitis fibrosa cystica in 1937, Albright suggested that the reason for parathyroid hyperplasia was the phosphate retention in renal failure. He added that in the absence of parathyroid hyperplasia, there would be greater phosphate retention and a further lowering of the blood calcium. Also in 1937, Albright described a patient with rickets that was resistant to treatment with vitamin D. This patient was intensively studied and clearly differentiated from patients with rickets from vitamin D deficiency. The name given to the disorder by Albright, vitamin D resistant rickets, was in use for many years until it was renamed X-linked hypophosphatemic rickets. This disorder also became the basis for the study of abnormal renal phosphate transport. Finally, in 1937, Albright reported five cases of another unusual bone disorder, polyostotic fibrous dysplasia, which was associated with hyperpigmented lesions of the skin and endocrine dysfunction. Today the disorder is called the McCune-Albright syndrome. In 1941 at a clinicopathological conference, Albright asked why a patient presenting with a destructive bone lesion in the right ilium from renal cell carcinoma should have hypercalcemia and hypophosphatemia. A neck exploration for presumed hyperparathyroidism was performed, but no abnormality was found. Albright questioned whether the tumor might be responsible for ectopic production of parathyroid hormone. In the same year, Albright described a case of hypercalcemia in a 14 year old boy who fractured his femur through a bone cyst in an athletic accident. After casting and bed rest, the patient developed severe hypercalcemia. Because of the hypercalcemia and the presence of a bone cyst, a parathyroid exploration was performed but no abnormalities were seen. Albright was the first to recognize that immobilization could cause hypercalcemia. A similar report of hypercalcemia following immobilization in Paget’s disease was published in 1944. In 1942 Albright described pseudohypoparathyroidism. In this disorder, the important concept of end-organ resistance to a hormone (PTH) was first shown. Albright chose the name, Seabright-Bantam, because this male fowl has feathers similar to the female despite having normal functioning testes. Other highlights of Albright’s investigation into disorders of calcium and phosphorus included his publication in 1946 of osteomalacia, rickets, and nephrocalcinosis in association with renal tubular acidosis. In 1948, Albright reported the occurrence of band keratopathy of the cornea in 19 patients with diverse causes of hypercalcemia. In 1949, Albright reported several patients with the chronic form of the milk alkali syndrome. These patients had chronic renal failure, hypercalcemia, soft tissue calcium deposits, band keratopathy, and nephrocalcinosis from the chronic ingestion of calcium- containing antacids. In 1953, Albright reported 35 patients with idiopathic hypercalciuria associated with kidney stones, hypophosphatemia, and normal serum calcium values.

 

Pituitary, Adrenal and Gonadal Axis

 

While much of Albright’s first decade as a clinical investigator was devoted to studies of mineral metabolism and the diagnosis and treatment of primary hyperparathyroidism, studies of adrenal and gonadal disorders assumed greater importance in the 1940s. His elegant studies of the Cushing syndrome were highlighted in three papers published in 1941. These studies were previously reviewed in detail by Schwartz, but will be summarized here. In the first paper, Albright showed that glucose intolerance and resistance to insulin were characteristic findings of the Cushing syndrome. In the second paper, Albright showed that besides cortisol excess, the Cushing syndrome was also characterized by androgen excess. The 24 h urine excretion of 17-ketosteroids was used as a measure of androgens. Because urinary excretion of 17-ketosteroids was greater in men than in women (14 versus 9 mg), Albright reasoned that 9 mg was the daily androgen output from the adrenals. His hypothesis was confirmed by studying patients with Addison’s disease in whom the excretion of 17-ketosteroids was 5 mg in men and absent in women. Albright also showed that adrenal excess was the cause of all forms of the Cushing syndrome whether of primary adrenal origin or due to a pituitary adenoma. In the third paper, Albright treated patients with the Cushing syndrome with testosterone, asking the question whether such treatment would counteract the catabolic effects seen in this syndrome. The testosterone treatment resulted in a strikingly positive nitrogen balance, a gain in weight and strength, thickening of the skin, and a reduction in abdominal protuberance. However, because of the availability of adrenal surgery, the use of testosterone treatment never gained widespread use. Albright also performed several studies that helped elucidate the etiology of congenital adrenal hyperplasia, which was called the adrenogenital syndrome by Albright. The paper in which Klinefelter’s syndrome was first described was published in 1942. The story is that the syndrome was discovered because the Draft Board in Boston sent recruits with prominent breasts to Albright’s clinic where small testes were noted and biopsied, and follicle stimulating hormone (FSH) levels were measured and found to be increased. Also in 1942, Albright further defined Turner’s syndrome by showing it was not of pituitary origin, but rather due to primary ovarian failure in which elevated FSH values were present. Finally, it has been stated that Albright first described or contributed to the description of 14 major clinical syndromes.

 

Albright, Through the Eyes of Coworkers and his Presidential Address

 

Fuller Albright’s 1944 presidential address to the annual meeting of the American Society for Clinical Investigation, Some of the Do’s and Do-Not’s in Clinical Investigation, is important because in it he provides his personal road map for performing clinical and laboratory investigation. In his introduction, Albright states that the clinical investigator must avoid the danger that he or she, as the clinician, be swamped with patients and the equal danger that he or she, as an investigator, be segregated entirely from the bedside. Even though his advice to the investigator is shown as a road map leading to the Castle Of Success (Figure 1), Albright refuses to define success, except to say that it is more than academic recognition and self-satisfaction. The reader is strongly encouraged to read this remarkable address in which Albright provides the investigator with the gift of his wisdom. It is readily available in the archives of the Journal of Clinical Investigation.

 

Figure 1.: A schematic diagram of the Do’s and Do Not’s Leading to the Castle of Success. The diagram is from Albright’s presidential address to the 36thAnnual Meeting of the American Society for Clinical Investigation in 1944 in which advice was given to the clinical investigator.

 

The following colleagues’ appreciations from several physicians who worked with Albright, are cited: William Parson worked with Albright during the late 1930s and early 1940s and later became Chairman of Medicine at the University of Virginia. In 1995, Parson wrote of Albright’s creative genius and his engaging personal qualities of unpretentiousness, good humor and wit. He went on to say that Albright was the first to conceptualize two important concepts in Endocrinology, end-organ unresponsiveness to a hormone (pseudohypoparathyroidism) and hormone or hormone-like production by nonendocrine tissue (ectopic production). Parson continued, Albright never had an interest in bench work. He felt that he could always get someone to make the measurements. The trick was to know what to measure and how to interpret the results. It was fun and exciting to work with a genius whose talent was to see relationships between facts universally considered to be unrelated. During the study of the first patient with pseudohypoparathyroidism, Parson relates that Albright was intrigued by her unusual appearance and the failure of a good batch of parathyroid extract to work. Albright refused to move on, even though others wanted to substitute dihydrotachysterol treatment and drop the project. Frederic Bartter worked with Albright in the 1940s and later became Chief of Clinical Endocrinology at the NIH. After Albright’s death in 1969, Bartter wrote a homage to Albright in which he said of Albright that clinical experiments of nature were the substrate for almost all of the inspired and systematic investigation that constituted his enormous contribution. He continued that Albright’s real delight was in formulating a theory to explain the unknown elements that remained, and Albright had no use for the “learned tradition. Rather, Albright believed that progress could only be made by formulation of a precise theory and challenge of that theory. Finally, Gilbert Gordan, who did a fellowship with Albright in the late 1940s and later became Professor of Medicine at the University of California at San Francisco, wrote in 1981 that “when Albright was working on a problem he virtually lived it every day, and he would discuss his ideas with anyone who was interested. Albright was completely self-assured and never concerned that someone less gifted would steal his ideas. Gordan continued, For every problem there were what Albright called ?measuring sticks’ – either chemical or bioassay, or the weight of axillary hair, or displacement of water by acromegalic hands and feet, or measurement of height to determine the growth rate, etc. One of his ?Do’s’ was – do measure something. In his presidential address in 1944, Albright stated that Oliver Wendell Holmes divides intellects into one-story, two-story, and three-story. The latter idealize, imagine, predict; their best illumination comes from above through the skylight. His coworkers and peers appreciated that Albright received illumination through the skylight. Albright also had the capacity to refute accepted dogma and to formulate a working hypothesis of clinical disorders, which he would continuously challenge. Finally, as in the recognition of hormone failure in pseudohypoparathyroidism, Albright understood that when all other possible explanations are eliminated, the remaining explanation no matter how improbable must be true.

 

Gabe Mirkin MD, who specializes in sports medicine, did an internship at Massachusetts General when Fuller Albright occupied a private room, where he lay in a coma. Mirkin saw Albright at this time and like many physicians held Albright in the highest respect; a role model for all physicians. Mirkin and Fuller Albright’s son, Birge Fuller, were in the same class at Harvard. The following was written by Gabe Mirkin MD:

 

Fuller Albright discovered more new diseases and their causes than any other person in the history of medicine. He was the founder of modern endocrinology, the study of how glands work in your body. In his time, many chairmen of the departments of endocrinology in North American medical schools were men who had studied under him. He was one of the most brilliant and innovative doctors who ever lived. He was also an outstanding athlete who captained his high school football team and was one of the better senior tennis players in New England even though he spent most of his time in his lab at the Mass General Hospital. His life of accomplishment ended with an experimental treatment for Parkinson’s disease that left him in a coma for his last thirteen years.

 

Albright left Harvard after 18 months to enlist in the Army to fight in World War I. During the 1918 pandemic, he was infected with influenza which can cause Parkinson’s disease many years later. In 1921, he went to Harvard Medical School and finished at the top of his class. He took his internship and residency at the Massachusetts General Hospital. In 1928, he went to Vienna to study with Dr. Jacob Erdheim. In 1929, Albright returned to the Massachusetts General Hospital and established the world-famous Ward 4, a 10-bed research unit where over the next 15 years, he described many new diseases and was one of the most loved and followed teachers at Harvard Medical School. His students remember this wonderful teacher always dressed in an old tweed jacket, baggy trousers, and a bright-colored bow tie. Married to Claire Birge in 1932, they had two sons. One of his sons, Birge Albright was named after his wife’s maiden name, just as his father had named him Fuller after his mother’s maiden name. Birge was a classmate of mine (of Gabe Mirkin) at Harvard.

 

List of Firsts

Try to imagine how one person could make so many breakthroughs in our understanding of how the human body functions. Fuller Albright was the first person to:

–        describe the functions of the parathyroid gland,

–        associate an overactive parathyroid gland with kidney stones,

–        explain the modern diagnosis and treatment of kidney stones,

–        develop a method for measuring sex hormones in the urine,

–        explain what causes women to have irregular periods or even stop menstruating,

–        describe various male sex hormone deficiencies,

–        show how certain types of diarrhea cause vitamin deficiencies,

–        describe renal tubular acidosis and its treatment,

–        show how menopause weakens bones,

–        use estrogen to prevent a woman from releasing an egg, setting the stage for the first birth control pills,

–        show that progesterone can prevent uterine cancer in women who lack that hormone,

–        demonstrate the cause of overactive adrenal glands (Cushing’s syndrome),

–        warn how dangerous adrenal steroids can be.

–        He was the first to describe or characterize the following syndromes, tests and treatments:

Forbes-Albright syndrome (breast milk and absence of periods caused by a brain tumor)

Jaffe-Lichtenstein syndrome (painful, swollen deformity in one bone that fractures easily)

Klinefelter’s syndrome (a genetic disorder that causes males to be tall and have small testes with low testosterone, delayed puberty, breast enlargement, reduced facial and body hair, and infertility)

Lightwood-Albright syndrome (acidic blood caused by a kidney defect)

Martin-Albright syndrome (inability to respond to the parathyroid hormone, short stature, short fingers, round face, and mental retardation)

McCune-Albright syndrome (a genetic disease characterized by deformed, easily broken bones, premature sexual maturity, enlargement of the adrenal glands and the overproduction of cortisol)

Morgagni-Turner-Albright syndrome (partial or complete absence of one X-chromosome, ovaries fail to respond to pituitary hormones so they do not produce adequate estrogen, short stature, absence of secondary sexual characteristics, webbing of the neck and inconsistent heart problems)

Ahumada-del Castillo syndrome (women with breast milk not associated with nursing and the absence of menstrual periods due to not releasing an egg each month)

Albright’s anemia (anemia in advanced overactive parathyroidism)

Albright’s prophecy (in 1945 Albright wrote that preventing ovulation prevents pregnancy and explored the possibility of birth control by hormone therapy)

Albright’s syndrome II (Albright hereditary osteodystrophy in which a person has normal levels of parathyroid hormone, but cannot respond to that hormone)

Albright’s test (a kidney function test to see how much acid kidneys can clear)

Albright-Butler-Bloomberg disease (a metabolic syndrome marked by dwarfism and other severe developmental anomalies)

Albright-Hadorn syndrome (softening and bending of bones associated with abnormally low concentrations of blood potassium levels)

Chiari-Frommel syndrome (over-production of breast milk and absence of periods for more than six months after giving birth.)

 

Progression of Parkinson’s Disease

 

In 1937, at age 37, when he was one of the most productive, respected and well known physicians in the world, Albright noticed that his hands started to shake and would become even more shaky when he used them. For example, when he raised a glass of water to his mouth to drink, the shaking would increase as the glass came closer to his mouth. He noticed a progressive slurring of his words as he talked. This former athlete had to walk more slowly because the faster he walked, the more he would lose control of his legs and start to fall. These symptoms progressed very slowly over the next 20 years. He appeared to accept the challenges and did everything he could to overcome his increasing disability. He forced himself to work even harder and discovered many new syndromes and basic mechanisms of how hormones work during this period.

 

By his early forties, he could not write, and by his mid-forties, he could no longer speak clearly. In his fifties he could not drive a car, so the medical students assigned to him were given the family’s second car to drive him to and from the hospital. They also wrote notes for him at work. Many of these students became famous researchers themselves: Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher and Stan Franklin.

 

Experimental Treatment Disaster

 

In 1952 Irving Cooper, a New York University neurosurgeon, reported that he could reduce the symptoms of Parkinson’s disease by injecting small amounts of alcohol into a part of the brain called the globus pallidus. Because Albright knew that he was losing his ability to reason in addition to losing his ability to eat, dress, write or speak, he went ahead and had the treatment in June 1956. Virtually all of his Harvard colleagues and even Dr. Cooper himself had discouraged him from having the procedure done. After his right side was injected, he noticed less rigidity and better control. He was able to walk comfortably and use his left hand more effectively. He was so encouraged that he had his left side injected, but this procedure resulted in extensive bleeding into his brain. He never recovered and was unable ever to speak again. He spent the next 13 years in a coma, living in a private room at the Massachusetts General Hospital. He was unable to respond to anyone. He died on December 8, 1969.

 

What is Parkinson’s Disease?

 

When you decide to move a muscle, your brain sends electrical messages between nerves and muscle fibers. When an electrical message reaches the end of a nerve, it releases chemicals called neurotransmitters that travel to the next nerve or muscle fiber to continue the message. Your fine muscle movements are controlled by a neurotransmitter called dopamine that sends messages by passing primarily between two brain areas called the substantia nigra and the corpus striatum.

 

Most of the movement-related symptoms of Parkinson’s disease are caused by a lack of dopamine due to loss of dopamine-producing cells in the substantia nigra. The lower the level of dopamine, the less control you have of your muscles.

 

We do not know the cause of the loss of dopamine-producing cells. A small percentage of Parkinson patients have other members of their family with the same disease. However, more than 90 percent of people with Parkinson’s disease do not have any family history of that disease. Thus most cases of Parkinson’s disease appear to be caused by something in the environment, not by a genetic condition.

 

Risk factors for Parkinson’s disease include:

 

–        Toxins: Exposure to manganese, carbon monoxide, cyanide and other chemicals. Some pesticides and herbicides inhibit dopamine production. Farmers are at increased risk for Parkinson’s disease.

–        Declining estrogen levels: Post-menopausal women and women who have had their ovaries removed are at increased risk.

–        Viruses: For example, people who survived exposure to influenza in the 1918 flu pandemic were at increased risk for Parkinson’s disease many years later.

–        Structural problems: Strokes and fluid buildup in the brain may increase risk of Parkinson’s disease.

–        Low levels of folic acid: A few studies suggest that folic acid deficiency may cause some cases of Parkinson’s disease.

–        Head trauma: Any damage to the head, neck, or upper spine increases risk. Boxer Muhammad Ali developed Parkinson’s disease very early in life, in his forties.

–        Advancing age: Parkinson’s disease affects one percent of people over 60 years of age. Risk increases with age.

–        Gender: Men are more likely to suffer from Parkinson’s than women, possibly because they have greater exposure to other risk factors such as toxins or head trauma.

–        Genetic factors: A Mayo-Clinic-led international study revealed that the gene alpha-synuclein may play a role in the likelihood of developing the disease. Studies showed that individuals with a more active gene had a 1.5 times greater risk of developing Parkinson’s. These findings support the development of alpha-synuclein suppressing therapies, which may in the long run slow or even halt the disease.

Sources: http://cjasn.asnjournals.org; Gabe Mirkin MD; nih.gov; Wikipedia

Arvid Carlsson MD (1923 to Present) and Still Going Strong at 94!

Editor’s note: Short background

 

Kathleen Montagu (died 28 March 1966) was the first researcher to identify dopamine in human brains. Working in Hans Weil-Malherbe’s laboratory at the Runwell Hospital outside London, the presence of dopamine was identified by paper chromatography in the brain of several species, including a human brain. Her research was published in August 1957, followed and confirmed by Hans Weil-Malherbe in November 1957.

 

Nobel Prize-rewarded Arvid Carlsson to be the first researcher to identify that dopamine is a neurotransmitter. His research was published in November 1957, along with colleagues Margit Linsqvist and Tor Magnusson.

 

Arvid Carlsson (born 25 January 1923) is a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson’s disease. For his work on dopamine, Carlsson was awarded the Nobel Prize in Physiology or Medicine in 2000, along with American co-recipients Eric Kandel at Columbia University and Paul Greengard at Rockefeller. Carlsson was born in Uppsala, Sweden, son of Gottfrid Carlsson, historian and later professor of history at the Lund University, where he began his medical education in 1941. In 1944 he was participating in the task of examining prisoners of Nazi concentration camps, whom Folke Bernadotte, a member of the royal Swedish family, had managed to bring to Sweden. Although Sweden was neutral during World War II, Carlsson’s education was interrupted by several years of service in the Swedish Armed Forces. In 1951, he received his M.L. degree and his M.D. He then became a professor at the University of Lund. In 1959 he became a professor at the University of Gothenburg.

 

In 1957 Kathleen Montagu succeeded in demonstrating the presence of dopamine in the human brain; later that same year Carlsson also demonstrated that dopamine was a neurotransmitter in the brain and not just a precursor for norepinephrine. Carlsson went on to developed a method for measuring the amount of dopamine in brain tissues. He found that dopamine levels in the basal ganglia, a brain area important for movement, were particularly high. He then showed that giving animals the drug reserpine caused a decrease in dopamine levels and a loss of movement control. These effects were similar to the symptoms of Parkinson’s disease. By administering to these animals L-Dopa, which is the precursor of dopamine, he could alleviate the symptoms. These findings led other doctors to try using L-Dopa on patients with Parkinson’s disease, and found it to alleviate some of the symptoms in the early stages of the disease. L-Dopa is still the basis for most commonly used means of treating Parkinson’s disease.

 

While working at Astra AB, Carlsson and his colleagues were able to derive the first marketed selective serotonin reuptake inhibitor, zimelidine, from brompheniramine. Zimelidine preceded both Fluoxetine (Prozac) and Fluvoxamine as the first SSRI, but was later withdrawn from the market due to rare cases of Guillain-Barre syndrome.

 

Still an active researcher and speaker at over 90 years of age, Carlsson, together with his daughter Maria, is working on OSU6162, a dopamine stabilizer alleviating symptoms of post-stroke fatigue.

 

Stephen L. Hauser MD (1949 to Present)

Photo credit: UCSF Medical Center, https://commons.wikimedia.org/w/index.php?curid=15734615

 

Stephen L. Hauser is the Robert A. Fishman Distinguished Professor and Chair of the Department of Neurology at the University of California, San Francisco (UCSF), where his work has focused on immune mechanisms and multiple sclerosis (MS). Hauser is a principal investigator of a large multinational effort to identify genetic effects on MS, and part of the team that identified that humoral immune mechanisms are important in the pathogenesis of MS lesions, leading to the development of B-cell based therapies for MS. He has contributed to the establishment of nationwide and international genetics consortia that have identified more than 50 gene variants that contribute to MS risk.

 

Using comparative genomics between African-American and Caucasian MS populations, Hauser’s group was able to identify HLA-DRB1 as the primary MS signal in the MHC, and also fine map other secondary loci in this region.

 

In 2007, as a senior organizer of the International Multiple Sclerosis Genetics Consortium (IMSGC), Dr. Hauser helped identify the first two non-HLA genes involved in MS susceptibility, IL-2R (CD25) and IL-7R (CD127). In 2010, his laboratory published the complete genome sequences and the epigenome of identical twins discordant for MS. By mid-2011 more than fifty MS associated risk alleles were identified, and by now nearly the entire array of common variants associated with MS susceptibility have now been mapped. Hauser also has focused on the role of the B cell and immunoglobulin in the pathogenesis of the disease. He developed and characterized an MS disease model that replicated the core feature of vesicular demyelination previously observed in MS, and demonstrated that this pathology resulted from the synergistic effects of autoreactive T-cells and pathogenic autoantibodies.

 

In 1999, Hauser published work identifying specific myelin reactivity of these autoantibodies deposited in areas of myelin damage in MS brains. Hauser translated this finding into a new potential therapy for MS. He led a large-scale clinical trial with rituximab, a chimeric monoclonal antibody that depletes CD20+ B cells, and demonstrated robust efficacy in relapsing remitting MS. A second trial in primary progressive MS reported in 2009 that rituximab may similarly be effective in patients with primary progressive MS who also have evidence of ongoing inflammatory CNS disease. More recently, a third clinical trial with a fully humanized anti-CD20 monoclonal antibody, ocrelizumab, replicated the results of the rituximab trial in relapsing remitting MS. With the MS Bioscreen project, Hauser has pioneered precision medicine for complex diseases like MS, creating an “actionable digital growth-chart for complex traits”

 

Hauser is a graduate of MIT (Phi Beta Kappa) and Harvard Medical School (Magna Cum Laude). In 2010 Hauser was appointed to the Presidential Commission for the Study of Bioethical Issues. He is a co-editor of the textbook Harrison’s Principles of Internal Medicine and past editor-in-chief of the Annals of Neurology. Hauser trained in internal medicine at the New York Hospital-Cornell Medical Center, in neurology at the Massachusetts General Hospital (MGH), and in immunology at Harvard Medical School and the Institute Pasteur in Paris, France, and was a faculty member at Harvard Medical School before moving to UCSF. Hauser received the 2013 Charcot Award from the Multiple Sclerosis International Federation, the Jacob Javits Neuroscience Investigator Award, and the John Dystel Prize for Multiple Sclerosis Research. In 2011 he delivered the Robert Wartenberg Lecture at the American Academy of Neurology, an honor given for excellence in clinically relevant research. Hauser is also the chair of the Committee on Gulf War and Health Outcomes for the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences and the Association of American Physicians.
In addition to the research of Dr. Hauser, there is a long history of studying MS called by some: the Viking Gene.

 

Detail of Robert Carswell’s drawing of MS lesions in the brain stem and spinal cord (1838). Credit: Wikipedia

 

Robert Carswell (1793-1857), a British professor of pathology, and Jean Cruveilhier (1791-1873), a French professor of pathologic anatomy, described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease. Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”. Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836-1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels. The French neurologist Jean-Martin Charcot (1825-1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the “Charcot Triad”, consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech) Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”. Diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that “signs and symptoms cannot be explained better by another disease process”. Both requirements were later inherited by Poser criteria and McDonald criteria, whose 2010 version is currently in use. During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.
Historical cases

Photographic study of locomotion of an MS female patient with walking difficulties created in 1887 by Muybridge. Photo credit: Wikipedia
There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot. A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380-1433), a Dutch nun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs, and vision loss – symptoms typical of MS. Both cases have led to the proposal of a “Viking gene” hypothesis for the dissemination of the disease. Augustus Frederick d’Este (1794-1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly had MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life. Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889-1919), who maintained a detailed log of his diagnosis and struggle. His diary was published in 1919 as The Journal of a Disappointed Man.

Gerontology

The hand of an older man. Source: Wikipedia Commons

 

Gerontology, from the Greek, geron, “old man” and -logia, “study of”; coined by Ilya Ilyich Mechnikov (in 1903) is the study of the social, cultural, psychological, cognitive, and biological aspects of aging. It is distinguished from geriatrics, which is the branch of medicine that specializes in the treatment of existing disease in older adults. Gerontologists include researchers and practitioners in the fields of biology, nursing, medicine, criminology, dentistry, social work, physical and occupational therapy, psychology, psychiatry, sociology, economics, political science, architecture, geography, pharmacy, public health, housing, and anthropology.

 

Gerontology encompasses the following:

 

  1. studying physical, mental, and social changes in people as they age
  2. investigating the biological aging process itself including aging’s causes, effects and mechanisms (biogerontology)
  3. investigating the social and psycho-social impacts of aging (sociogerontology)
  4. investigating the psychological effects on aging (psychogerontology)
  5. investigating the interface of biological aging with aging-related diseases (geroscience)
  6. investigating the effects of an ageing population on society (demography)
  7. exploring the relationship between the aging and their environment (environmental gerontology)
  8. applying this knowledge to policies and programs, including the macroscopic (for example, government planning) and microscopic (for example, running a nursing home) perspectives.

 

The multidisciplinary nature of gerontology means that there are a number of sub-fields, as well as associated fields such as physiology, anthropology, social work, public health, psychology and sociology that overlap with gerontology. One of the world’s oldest drugs which was first mentioned by Hippocrates in the 5th Century BCE could help restore memory in Alzheimer’s patients, scientists hope. Salsalate, which comes from the same family as aspirin, was typically used to treat inflammatory conditions like rheumatoid arthritis. But a new study suggests that it can prevent the build-up of toxic proteins in the brain and even reverse damage already done, unblocking pathways and restoring memory.

 

In the medieval world, several physicians wrote on issues related to Gerontology. Avicenna’s The Canon of Medicine (1025) offered instruction for the care of the aged, including diet and remedies for problems including constipation. He also wrote on the aches and conditions of the elderly. His scholarly work covers sleep disorders, forgetfulness, how to strengthen memory, and causes of mortality. Ishaq ibn Hunayn (died 910) wrote works on the treatments for forgetfulness (U.S. National Library of Medicine, 1994).

 

While the number of aged humans, and life expectancy, tended to increase in every century since the 14th, society tended to consider caring for an elderly relative as a family issue. It was not until the coming of the Industrial Revolution that ideas shifted in favor of a societal care-system. Some early pioneers, such as Michel Eugene Chevreul, who himself lived to be 102, believed that aging itself should be a science to be studied. Elie Metchnikoff coined the term “gerontology” c. 1903. However, it was not until the 1940s that pioneers like James Birren began organizing gerontology into its own field. Recognizing that there were experts in many fields all dealing with the older population, it became apparent that a group like the Gerontological Society of America (founded in 1945) was needed. Two decades later, James Birren was appointed as the founding director of the first academic research center devoted exclusively to the study of aging, the Ethel Percy Andrus Gerontology Center. The Baltimore Longitudinal Studies of Aging began in 1958 in order to study physiological changes in healthy middle-aged and older men living in the community by testing them every two years on numerous physiological parameters. In 1967, the University of South Florida and the University of North Texas (formerly North Texas State University) received Older Americans Act training grants from the U.S. Administration on Aging to launch the nation’s first degree programs in gerontology, at the master’s level. In 1975, the University of Southern California’s Leonard Davis School of Gerontology, became the country’s first school of gerontology within a university and, later, offered the first PhD in Gerontology degree. Gerontological Education has flourished in the United States since 1967 and degrees at all academic levels are now offered by a number of colleges and universities. One of the pioneering gerontologists, Robert Neil Butler, pushed for care and respect of the elderly. Several university-based centers on aging have been founded such as the Duke University Center on Aging, the University of Georgia Institute of Gerontology, the Center of Aging at the University of Chicago, and the Stanford Center on Longevity. Currently, PhD programs in gerontology are available at Miami University, the University of Kansas, University of Kentucky, University of Maryland Baltimore, University of Massachusetts Boston,[19] and the University of Southern California.

 

The world is forecast to undergo rapid population aging in the next several decades. In 1900, there were 3.1 million people aged 65 years and older living in the United States. However, this population continued to grow throughout the 20th century and reached 31.2, 35, and 40.3 million people in 1990, 2000, and 2010, respectively. Notably, in the United States and across the world, the “baby boomer” generation began to turn 65 in 2011. Recently, the population aged 65 years and older has grown at a faster rate than the total population in the United States. The total population increased by 9.7%, from 281.4 million to 308.7 million, between 2000 and 2010. However, the population aged 65 years and older increased by 15.1% during the same period. It has been estimated that 25% of the population in the United States and Canada will be aged 65 years and older by 2025. Moreover, by 2050, it is predicted that, for the first time in United States history, the number of individuals aged 60 years and older will be greater than the number of children aged 0 to 14 years. Those aged 85 years and older (oldest-old) are projected to increase from 5.3 million to 21 million by 2050. Adults aged 85–89 years constituted the greatest segment of the oldest-old in 1990, 2000, and 2010. However, the largest percentage point increase among the oldest-old occurred in the 90- to 94-year-old age group, which increased from 25.0% in 1990 to 26.4% in 2010. With the rapid growth of the aging population, social work education and training specialized in older adults and practitioners interested in working with older adults are increasingly in demand.

 

Genetic theories of aging propose that aging is programmed within each individual’s genes. According to this theory, genes dictate cellular longevity. Programmed cell death, or apoptosis, is determined by a “biological clock” via genetic information in the nucleus of the cell. Genes responsible for apoptosis provide an explanation for cell death, but are less applicable to death of an entire organism. An increase in cellular apoptosis may correlate to aging, but is not a ‘cause of death’. Environmental factors and genetic mutations can influence gene expression and accelerate aging. More recently epigenetics have been explored as a contributing factor. The epigenetic clock, which objectively measures the biological age of cells and tissues, may become useful for testing different biological aging theories. General imbalance theories of aging suggest that body systems, such as the endocrine, nervous, and immune systems, gradually decline and ultimately fail to function. The rate of failure varies system by system. Accumulation theories of aging suggest that aging is bodily decline that results from an accumulation of elements. Elements can be foreign and introduced to the body from the environment. Other elements can be the natural result of cell metabolism. An example of an accumulation theory is the Free Radical Theory of Aging. According to this theory, byproducts of regular cell metabolism called free radicals interact with cellular components such as the cell membrane and DNA and cause irreversible damage.

The idea that free radicals are toxic agents was first proposed by Rebeca Gerschman and colleagues. In 1956, Denham Harman proposed the free-radical theory of aging and even demonstrated that free radical reactions contribute to the degradation of biological systems. Oxidative damage of many types accumulate with age, such as oxidative stress that oxygen-free radicals, because the free radical theory of aging argues that aging results from the damage generated by reactive oxygen species (ROS). ROS are small, highly reactive, oxygen-containing molecules that can damage a complex of cellular components such as fat, proteins, or from DNA, they are naturally generated in small amounts during the body’s metabolic reactions. These conditions become more common as we age, including diseases related to aging, such as dementia, cancer and heart disease.

DNA damage has been one of the many causes in diseases related to aging. The stability of the genome is defined by the cells machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. One hypothesis proposed by Gioacchino Failla in 1958 is that damage accumulation to the DNA causes aging. The hypothesis was developed soon by physicist Leo Szilard. This theory has changed over the years as new research has discovered new types of DNA damage and mutations, and several theories of aging argue that DNA damage with or without mutations causes aging.

 

To demonstrate how far the interest in longevity goes, Google has a separate division called Calico to study this aspect of aging.


What is Alphabet? Alphabet is mostly a collection of companies. The largest of which, of course, is Google. This newer Google is a bit slimmed down, with the companies that are pretty far afield of our main internet products contained in Alphabet instead. What do we mean by far afield? Good examples are our health efforts: Life Sciences (that works on the glucose-sensing contact lens), and Calico focused on longevity. Fundamentally, we believe this allows us more management scale, as we can run things independently that aren’t very related. What could be better? No wonder we are excited to get to work with everyone in the Alphabet family. Don’t worry, we’re still getting used to the name too!

 

Kfar Shaul Mental Health Center in Jerusalem

Psychiatric hospital Kfar Shaul In Jerusalem – Source: Wikipedia, Public Domain, Creative Commons

 

Kfar Shaul Mental Health Center, established in 1951, is an Israeli public psychiatric hospital located between Givat Shaul and Har Nof, Jerusalem. It is affiliated with the Hadassah Medical Center and the Hebrew University of Jerusalem. The hospital is Jerusalem’s designated psychiatric hospital for tourists who display mental health disturbances, and is widely known for its research on Jerusalem Syndrome.

 

The Givat Shaul mental health center opened in 1951, utilizing the houses and school building of Deir Yassin, which had been left untouched. It was originally a therapeutic community of 300 patients who spent most of the day working outdoors. It was called the Kfar Shaul Government Work Village for Mental Patients. In its early years, the majority of the patients were Holocaust survivors.

 

The hospital is equipped with Snoezelen rooms, a Dutch therapy technique which uses controlled stimulation of the five senses to benefit the mentally and physically disabled. The hospital is known in particular for its association with Jerusalem Syndrome, a condition in which the sufferer is gripped by religious delusions. The hospital sees some 50 patients a year who are diagnosed with the condition Israel psychologist Gregory Katz has said many of the patients are Pentecostals from rural parts of the United States and Scandinavia. The syndrome was first diagnosed in 1993 by Yair Bar-El, a former director of the hospital. In 2000, archaeologists unearthed the remains of a winepress dated to the Byzantine or Roman era on the grounds of the hospital.

 

The Shaare Zedek Medical Center, which means: “Gates of Justice,” is a major hospital in JerusalemIsrael established in 1902. Source: Wikipedia, Public Domain, Creative Commons

 

Original, 1902 Shaare Zedek hospital building on Jaffa Road, now headquarters of the Israel Broadcasting Authority. Source: Wikipedia, Creative Commons

 

 

Shaare Zedek was the first large hospital to be located in the Western portion of Jerusalem and is today the city’s fastest growing hospital and the only major medical facility in the city’s center. After the Ottoman Turks gave permission in the 1890s, and with funding from European donors, the hospital was built on Jaffa Road, two miles (3 km) outside the Old City. Its opening ceremony took place on January 27, 1902. Dr. Moshe Wallach was the director from then until 1947. Schwester Selma lived in the hospital and cared for abandoned children. The building in Bayit Vegan was inaugurated in 1980. In December 2012, Shaare Zedek assumed operational control over Bikur Cholim Hospital and merged many of its activities. The hospital treats over 600,000 patients per year in more than 30 inpatient departments and over 70 outpatient units and maintains a very active academic service as a leading research and teaching institution. Shaare Zedek is classified as a public/private hospital, serving as a non-profit institution and dependent on donor support for capital development, while committed to offering advanced medical care for the wider Jerusalem-area community.

Stephan Wolfram (1959 to Present)

Stephen Wolfram at home. Source: Wikipedia

 

Target Health Inc. is an eCRO, that creates software for clinical trials and is interested in how Big Data is sorted through, especially for application to medical research, and clinical trials.

 

Wolfram Alpha (also: WolframAlpha and Wolfram|Alpha) is a computational knowledge engine or answer engine developed by Wolfram Research, which was founded by Stephen Wolfram. Stephen Wolfram is a brilliant computer scientist/physicist who thinks about the world and its issues, in a very Big way. Wolfram Research is an online service that answers factual queries directly by computing the answer from externally sourced “curated data“, rather than providing a list of documents or web pages that might contain the answer as a search engine might. Wolfram Alpha, which was released on May 18, 2009, is based on Wolfram’s earlier flagship product Wolfram Mathematica, a computational platform or toolkit that encompasses computer algebra, symbolic and numerical computation, visualization, and statistics capabilities. Additional data is gathered from both academic and commercial websites such as the CIA’s The World Factbook, the United States Geological Survey, a Cornell University Library publication called All About Birds, Chambers Biographical Dictionary, Dow Jones, the Catalogue of Life, CrunchBase, Best Buy,the FAA and optionally a user’s Facebook account.

 

Stephen Wolfram (born 29 August 1959) is a British-American computer scientist, physicist, and businessman. He is known for his work in computer science, mathematics, and in theoretical physics. He is the author of the book A New Kind of Science. In 2012 he was named an inaugural fellow of the American Mathematical Society. His recent work has been on knowledge-based programming, expanding and refining the programming language of Mathematica into what is now called the Wolfram Language. His book An Elementary Introduction to the Wolfram Language appeared in 2015 and Idea Makers appeared in 2016.

 

Stephen Wolfram was born in London in 1959 to Hugo and Sybil Wolfram. Wolfram’s father, Hugo Wolfram (1925-2015), a textile manufacturer born in Bochum, Germany, served as managing director of the Lurex Company, makers of the fabric Lurex, and was the author of three novels. He emigrated to England in 1933. When World War II broke out, young Hugo left school at 15 and subsequently found it hard to get a job since he was regarded as an “enemy alien.“ As an adult, he took correspondence courses in philosophy and psychology. Wolfram’s mother, Sybil Wolfram (1931-1993) was a Fellow and Tutor in philosophy at Lady Margaret Hall at University of Oxford from 1964 to 1993. She published two books, Philosophical Logic: An Introduction (1989) and In-laws and Outlaws: Kinship and Marriage in England (1987). She was the daughter of criminologist and psychoanalyst Kate Friedlander (1902-1949), an expert on the subject of juvenile delinquency, and the physician Walter Misch (1889-1943) who, together, wrote Die vegetative Genese der neurotischen Angst und ihre medikament?se Beseitigung. After the Reichstag fire in 1933, she emigrated from Berlin, Germany to England with her parents and Jewish psychoanalyst, Paula Heimann (1899-1982).

 

As a young child, Wolfram initially struggled in school and had difficulties learning arithmetic. At the age of 12, he wrote a dictionary on physics. By 13 or 14, he had written three books on particle physics. They were not published. Wolfram was a wunderkind. By age 15, he began research in applied quantum field theory and particle physics and published scientific papers. Topics included matter creation and annihilation, the fundamental interactions, elementary particles and their currents, hadronic and leptonic physics, and the parton model, published in professional peer-reviewed scientific journals including Nuclear Physics B, Australian Journal of Physics, Nuovo Cimento, and Physical Review D. Working independently, Wolfram published a widely cited paper on heavy quark production at age 18 and nine other papers. He continued to do research and to publish on particle physics into his early twenties. Wolfram’s work with Geoffrey C. Fox on the theory of the strong interaction is still used in experimental particle physics.

 

He was educated at Eton College, but left prematurely in 1976. He entered St. John’s College, Oxford at age 17 but found lectures “awful“, and left in 1978 without graduating to attend the California Institute of Technology, the following year, where he received a PhD in particle physics on November 19, 1979 at age 20. Wolfram’s thesis committee was composed of Richard Feynman, Peter Goldreich, Frank J. Sciulli and Steven Frautschi, and chaired by Richard D. Field. A 1981 letter from Feynman to Gerald Freund giving reference for Wolfram for the MacArthur grant appears in Feynman’s collective letters, Perfectly Reasonable Deviations from the Beaten Track. Following his PhD, Wolfram joined the faculty at Caltech and became the youngest recipient of the MacArthur Fellowships in 1981, at age 21. In 1983, Wolfram left for the School of Natural Sciences of the Institute for Advanced Study in Princeton, where he conducted research into cellular automata, mainly with computer simulations. He produced a series of papers systematically investigating the class of elementary cellular automata, conceiving the Wolfram code, a naming system for one-dimensional cellular automata, and a classification scheme for the complexity of their behavior. He conjectured that the Rule 110 cellular automaton might be Turing complete.

 

A 1985 letter, from Feynman to Wolfram, also appears in Feynman’s letters. In it, in response to Wolfram writing to him that he was thinking about creating some kind of institute where he might study complex systems, Feynman tells Wolfram, “You do not understand ordinary people,“ and advises him “find a way to do your research with as little contact with non-technical people as possible.“ In the mid-1980s, Wolfram worked on simulations of physical processes (such as turbulent fluid flow) with cellular automata on the Connection Machine alongside Richard Feynman and helped initiate the field of complex systems, founding the first institute devoted to this subject, The Center for Complex Systems Research (CCSR) at the University of Illinois at Urbana-Champaign and the journal Complex Systems in 1987. Wolfram led the development of the computer algebra system SMP (Symbolic Manipulation Program) in the Caltech physics department during 1979-1981. A dispute with the administration over the intellectual property rights regarding SMP – patents, copyright, and faculty involvement in commercial ventures – eventually caused him to resign from Caltech. SMP was further developed and marketed commercially by Inference Corp. of Los Angeles during 1983-1988. In 1986 Wolfram left the Institute for Advanced Study for the University of Illinois at Urbana-Champaign where he founded their Center for Complex Systems Research and started to develop the computer algebra system Mathematica, which was first released in 1988, when he left academia. From 1992 to 2002, Wolfram worked on his controversial book A New Kind of Science,which presents an empirical study of very simple computational systems. Additionally, it argues that for fundamental reasons these types of systems, rather than traditional mathematics, are needed to model and understand complexity in nature. Wolfram’s conclusion is that the universe is digital in its nature, and runs on fundamental laws which can be described as simple programs. He predicts that a realization of this within the scientific communities will have a major and revolutionary influence on physics, chemistry and biology and the majority of the scientific areas in general, which is the reason for the book’s title. Since the release of the book in 2002, Wolfram has split his time between developing Mathematica and encouraging people to get involved with the subject matter of A New Kind of Science by giving talks, holding conferences, and starting a summer school devoted to the topic.

 

In March 2009, Wolfram announced Wolfram|Alpha, an answer engine. Wolfram|Alpha later launched in May 2009, and a paid-for version with extra features launched on February 2012. The engine is based on natural language processing and a large library of algorithms, and answers queries using the approach described in A New Kind of Science. The application programming interface allows other applications to extend and enhance Alpha. Wolfram believes that as Wolfram Alpha comes into common use, “It will raise the level of scientific things that the average person can do.“ Wolfram|Alpha is one of the answer engines behind Microsoft’s Bing and Apple’s Siri answering factual questions. In June 2014, Wolfram officially announced the Wolfram Language as a new general multi-paradigm programming language. The documentation for the language was pre-released in October 2013 to coincide with the bundling of Mathematica and the Wolfram Language on every Raspberry Pi computer. While the Wolfram Language has existed for over 25 years as the primary programming language used in Mathematica, it was not officially named until 2014. Wolfram’s son, Christopher Wolfram, appeared on the program of SXSW giving a live-coding demonstration using Wolfram Language and has blogged about Wolfram Language for Wolfram Research. On 8 December 2015, Wolfram published the book “An Elementary Introduction to the Wolfram Language“ to introduce people with no knowledge of programming to the Wolfram Language and the kind of computational thinking it allows. Both Stephen Wolfram and Christopher Wolfram were involved in helping create the alien language for the film Arrival, for which they used the Wolfram Language. The significance that data has on the products Stephen creates transfers into his own life. He has an extensive log of personal analytics, including emails received and sent, key strokes made, meetings and events attended, phone calls, even physical movement dating back to the 1980s. He has stated “[personal analytics] can give us a whole new dimension to experiencing our lives“.

Sources: Wikipedia; Edge.org

 

Click here to read a short piece by Stephan Wolfram, written beautifully with great clarity, about his vision of artificial intelligence and how humans should deal with it, through a shared language, through personal analytics and more. To know more about shared language, all humans should read, the recently published: An Elementary Introduction to the Wolfram Language. If you saw the Academy Award nominee, Arrival, you would have heard a version of this shared language, which a human linguist, is finally able to understand.

 

Beauty is truth, truth beauty, – that is all

Ye know on earth, and all ye need to know.’

John Keats

 

TED talk by Stephan Wolfram Computing a Theory of Everything

 

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