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Home , Bernard Katz, Camillo Golgi, Croonian Medal, Dickson Prize, Edgar Adrian, Eric Kandel

NEURO NOBELS Richard J. Barohn, MD Gertrude and Dewey Ziegler Professor of Neurology University Distinguished Professor Vice Chancellor for Research President Research Institute Research & Discovery Director, Frontiers: The University of Kansas Clinical and Translational Grand Rounds Institute February 14, 2018 1 Alfred Nobel 1833-1896 • Born , • Father involved in machine tools and explosives • Family moved to St. Petersburg when Alfred was young • Father worked on armaments for in the Crimean War… successful business/ naval mines (Also steam engines and eventually oil).. made and lost fortunes • Alfred and brothers educated by private teachers; never attended university or got a degree • Sent to Sweden, , and USA to study chemical engineering • In met the inventor of nitroglycerin Ascanio Sobrero • 1863- Moved back to Stockholm and worked on nitro but too dangerous.. brother killed in an explosion • To make it safer to use he experimented with different additives and mixed nitro with kieselguhr, turning liquid into paste which could be shaped into rods that could be inserted into drilling holes • 1867- Patented this under name of DYNAMITE • Also invented the blasting cap detonator • These inventions and advances in drilling changed construction • 1875-Invented gelignite, more stable than dynamite and in 1887, ballistics, predecessor of cordite • Overall had over 350 patents

2 Alfred Nobel 1833-1896 The Merchant of Death

• Traveled much of his business life, companies throughout Europe and America • Called " Europe's Richest Vagabond" • Solitary man / depressive / never married but had several love relationships • No children • This prompted him to rethink how he would be • Wrote poetry in English, was considered remembered scandalous/blasphemous. Some were first published • His one page will established 5 Nobel Prizes: in 2003 and 2010 Physics, , or , • Interested in philosophy Literature; and "furtherance of peace". • Brother died and a newspaper mistakenly it Awarded annually out of Stockholm (except was his death and wrote obituary describing him as" Peace in Norway/Oslo) the Merchant of Death" • First prizes awarded 1901 • Economics prize came later 3 Neuro Winners

*Green = European ; Blue = American Name Year Topic 1904 Conditioned reflex

Santiago Ramon y Cajal & 1906 Structure of the

Julius Wagner-Jauregg 1927 therapy for dementia paralytica

Edgar Adrian & Sir Charles Scott Sherrington 1932 Function of / Neurophysiology reflexes

Sir & 1936 Chemical transmission of impulses

Joseph Erlanger & 1944 Functions of single nerve fibres

Carl Ferdinand Cori, Gerty Theresa Cori & Bernardo 1947 Discovery of the catalytic conversion of glycogen Alberto Houssay

4 Neuro Nobel Prize Winners *Blue = American; Green = European Name Year Topic

Walter Rudolf Hess & Antonio 1949 Interbrain coordinator internal organ activity/therapeutic value of leucotomy Caetano Egas Moniz Sir John Carew Eccles, Sir Alan 1963 Excitation & inhibition in the peripheral & central portions of the nerve cell Lloyd Hodgkin & Sir Andrew membrane Fielding Huxley

Ragnar Granit, Haldan Keffer 1967 Neurophysiology of vision- Hartline, Sir , , 1970 Discoveries concerning the humoral transmitters in nerve terminals & the mechanism for their , release and inactivation Baruch S. Blumberg & D. Carleton 1976 New mechanisms for origin & dissemination of infection diseases Gajdusek Allan M. Cormack & Sir Godfrey 1979 Development of computer assisted tomography Hounsfield Roger Sperry, David Hubel & 1981 Information processing in the Rita Levi-Montalcini 1986 Nerve growth factors

Stanley Prusiner 1997 Discovery of prions; a new biological principle of infection 5 Neuro Nobel Prize Winners

*Green = European; Blue = American

Name Year Topic

Arvid Carlosson, , & 2000 Signal transduction in the nervous system/

Paul Lauterbur & Sir 2003 Magnetic resonance imaging

Richard Axel & Linda B. Buck 2004 Odorant receptors and the organization of the

May-Britt Moser, John O’Keefe, 2014 Cells that constitute a positioning system in the Edvard I. Moser Jeffrey C. Hall, Michael Robash & 2017 Michael W. Young 6 Ivan Petrovich Pavlov MD 1849-1936 • Born in a Central Russian farming village, Ryazan. Father was a Russian orthodox priest-expected Pavlov to enter into local seminary • Received free education (primary and seminary) made possible by Czar Alexander II for gifted/poor students • In seminary, he read Darwin “Origins” and Ivan Sechenov’s “Reflexes of the Brain” • Left seminary (without graduating), enrolled at the Univ. of St. Petersburg where he studied Medicine/Natural Science • Sechenov was the Professor of physiology • Graduated in 1875 • Research was his goal, not to practice • Won 2 year fellowship in Germany (/Breslau) investigating circulation and gastric secretion • Studied experimental back in St. Petersburg • Doctorate on centrifugal of the (discovered independently of Gaskel special tropic nerves of the heart 7 • 1891-Professor of Physiology at the Institute of Experimental Medicine • Researched until he died in 1936, he was 86 years old Ivan Pavlov MD

 In 1890s: Digestion . Surgically created dog’s a pouch with a fistula implanted (Pavlov's pouch) in order to observe secretion of gastric juices when dogs began to eat without contamination of food. . These findings about gastric secretions led to the Nobel Prize in Medicine and Physiology in the 1904 book The Work of  Research in 4 Fields: The Digestive Glands (right), published in 1897 in and translated to English in 1. Cardiac physiology 1902. 2. Digestion . In 1907, became full member in the 3. Russian Academy of Sciences.

8 4. Ivan Pavlov MD and The Conditioned Reflex  1897-1900 : Observed the following in the course of gastric reflex research

• Dogs would secrete gastric juices and saliva when saw or heard keeper- initially this was considered a nuisance

• Recognized there must be an explanation since there was no food in the dogs mouth. The dog realized mealtime was near

• produced secretions

• A “psychic secretion” is due to a reflex in the brain caused by the of

sight or sound of the person who was 9 usually bringing food.  Early Experiments of the Ivan Pavlov MD Conditioned Reflex • 1902-Began to study how and when such a stimulus was capable of causing secretions.

• Instead of stomach pouch with fistula he implanted a fistula in salivary gland to a collection/recording device

• Dogs trained to stand on the table- praised, pelted or fed

• Faced wall w/ window; bowl of food could be placed in

• When dog had food in it’s mouth-saliva flowed

• FOOD=UNCONDITIONED STIMULUS

• SALIVARY RESPONSE=UNCONDITIONED REFLEX 10 IVAN PAVLOV M.D.

SOUND = CONDITIONED SALIVARY STIMULUS RESPONSE=CONDITIONED REFLEX  Sound (ring, bell, buzzer)  After a number of sequences, in preceded food drop bowl by sound alone caused saliva to flow. various amounts of time, usually 5 to 30 seconds.

11 1927 Ivan Pavlov MD Conditioned Reflex

 Did not believe this was a psychological process-but a physiologic one.  Many variations on experiment  Claimed indebtedness to Descartes and Sechenov  instead of sound  Change length of time between neutral stimulus and food drop  Neutral stimulus could be made into conditioned stimulus w/ varying degrees of ease • Neutral odor might require >20 pairings  Pavlov considered unconditional response a brain reflex • Rotation of object in dogs view might  Conditioned response was a result of new reflexive pathways require >5 pairings created by conditioning process in the cortex12 • Sounding bizarre might require only 1  Early concept Ivan Pavlov MD His Dogs  While he experimented on He erected a stone dog dogs, he took great care of statue in the courtyard of them and loved them. He did the Institute of not destroy them. Experimental Medicine  Considered them man’s best (below) friend and science martyrs

13 Pavlov’s Dogs

14 Ivan Pavlov MD Anti-Semitism • Attributed negative dimensions of Bolshevism to Jewish influence

• 1928 he complained to Gantt that the occupied “high position everywhere” and that it was “a shame Russians can not be rulers of their own land”

• 1935/1936 when he expressed a more positive attitude towards Bolsheviks he minimized the Jewish presence in the communist party as a “thin stratum”

• 1934/1935 even Pavlov was scolding the Jews and on learning one woman among his listeners was Jewish he said : “Why didn’t anyone warn me?” Lina Stern and Ivan Pavlov among15 the delegates of XIV International Congress of Physiology, Rome 1932 Nobel Prize 1906 Visualizing the Nervous System with New Microscopic Techniques

Camillo Golgi 1843-1926 Santiago Ramón y Cajal 1852-1924 16 Santiago Ramón y Cajal MD 1852-1934 Humble Origins • Born in Petilla de Aragón in Navarre, Spain (in the Pyrenees) a region occupied by baturros (people who are not very bright) • Father-Justo Ramón Casasús-struggling barber surgeon, second class who amazingingly got a medical degree at University of Zaragoza- country doctor, then teacher • Cajal’s teachers declared him a dolt • Apprenticed to a barber and shoemaker to self discipline but they said he was lazy • Went to jail for taking shots at a palace • Was very good at drawing • Father took him to graveyards to find remains for anatomical studies and had sketches for anatomy atlas father was making (never published) • Became interested in anatomy and this led to medical school Was a gymnast 17 Santiago Ramón y Cajal MD 1852-1934 • 1873-Med School University of Zaragoza • 1884-Professor Anatomy, Valencia Then: Regimental surgeon-Cuba (got TB and malaria!) • 1887-Professor Anatomy, Barcelona • 1877-Assistant and then Professor of Anatomy, U. Zaragoza -Began histologic studies which made him famous • 1982-University of -Almost no lab funds so he put as many sections on a Cajal with Verick microscopes slide that he could • 1887-In Barcelona, used silver impregnation staining of nervous system that was developed by Golgi in (1870) • Used old Verick microscope • Sent first paper to The Catholic Daily in Zaragoza of a nerve cell and it’s emergent fiber -Then “groped to find another” • Sent reprints throughout Europe-initially no response And Ridiculed by his peers in Zaragoza for his egotism

18 Santiago Ramón y Cajal MD 1852-1934 Spreading Fame • Sent early papers beyond Pyrenees-they were accepted -Editors then began to seek him out • 1889-Demonstrated silver impregnation of brain sections at meeting- German Anatomical Society • 1894-Croonian Lecture at Royal Society, -Oxford honorary degree -Both arranged by Sherrington • Then went to US to speak after Spanish/American War • 1906-Nobel Prize in Physiology or Medicine with Camillo Golgi

19 Santiago Ramón y Cajal MD 1852-1934 • 1922-Established Laboratorio de • Initial Writings Investigaciones • 1889-Manual of Biológicas in Normal and University of Madrid Micrographic • Later called Cajal Technique Institute • 1890-Manual of • Many trainees-a General Pathological “school” was formed Anatomy- 7 Editions • 250 papers-normal • 1897-Elements of and pathological Histology histology of nervous system in animals and man 20 Santiago Ramón y Cajal MD 1852-1934

Neuron Doctrine Structure of Central Nervous System in Birds • Demonstrated relationship between nerve cells was (1905) continuous and showed how nerve cells are connected. • Supported theory (not reticular-Golgi) • Nerve cell is an independent entity • Nerve transfer nerve impulses from one cell to another

21 Santiago Ramón y Cajal MD 1852-1934 “In the intricate warp of the brain one can advance only step by step, and if one is to do so safely, the front trenches must be dug by men like Theodor Meynert, Camillo Golgi, Ludwig Edinger, Paul Emile Flesheig, Albert von Kölliker ,Auguste Forel, and the other great ones…” “I threw myself into the task with the sure faith that in the dark thicket, where so many explorers had been lost, I should capture, if not lions and tigers, at least some modest game scorned by the great hunters.”

22 Camillo Golgi MD • Born in Corteno (, Italy) small town • Father practiced medicine 1843-1926 • 1865-MD from University di Pavia • 1865-1872-Resident in Pavia, Instituto di Pathologia Generale • Published on pellagra and small pox • Read Virchow’s Cellular and decided to study the nervous system • 1870-First papers on neuroglia of cortex and white matter • Worked isolated in small lab in small town with microscope; often by candlelight • Discovered a chromate of silver method for staining • Revolutionized concept of histologic structure of nervous system • Published this in 1873 and 1875 • 1875-U Pavia and spent remainder of his academic life • Many students : Marchi, Monti, Sala, Negri… • 1883-Studi Sulla fina anatomia Delhi organi centrali del system nervosa • Believed nerve fibers in cortex, efferent and afferent, lose individuality and break up into many secondary branches forming networks/reticula • Argued with Cajal about this for years 23 • 1906-In Nobel Prize speech, bitter denunciation of Cajal Santiago Ramón y Cajal MD Recollections of My Life 1901-1917 • On Nobel Prize and Golgi

• I must state that in the aforesaid lecture I made a cordial eulogy of my colleague, Professor C. Golgi…

• Contrary to what we all expected, he attempted in it to refloat his almost forgotten theory of interstitial nets…

• He made a display of pride and self-worship so immoderate that they produced a deplorable effect upon the assembly…

• I have never understood these strange mental constitutions which are devoted throughout life to the worship of their own egos, hermetically sealed to all innovation…

• What a cruel irony of fate to pair like Siamese twins united by the shoulders, scientific adversaries of such contrasting character!...

• My colleague displayed the same Olympic pride and pretentious mien in his toast at the official banquet… 24 The Beautiful Brain The Drawings by Santiago Ramón y Cajal Edited with commentaries by Eric A. Newman, Alfonso Araque, and Janet M. Dubinsky Essays by Larry W. Swanson, Lyndel King, and Eric Himmel

The Beautiful Brain (2016) Pyramidal neurons of the and their Structure and connections 25 of the pathways Cajal monument crafted by the sculptor Victorio Macho in 26 1926 Parque del Buen Retiro in Paseo de Venezuela, Madrid 27 Spain, July 2017 Early British Experimental Neurophysiologist Nobel 1932 “for Discoveries Regarding Functions of Neurons"

• Charles Scott Sherrington (1857-1952); , London and Ipswich – Trained by Foster/Langley/Gaskell – Worked at the Brown Institution for veterinary research • Studied animals with chronic spinal lesions – Then Liverpool, then Oxford

• Edgar Douglas Adrian (1889 – 1977); Hampstead,

28 Sir Charles Sherrington (1857 – 1952) 1st research on pathologic degeneration of Concepts: corticospinal tract in dog, (decorticate) One-way transmission at the “” Convergence of reflexes on “final common path” Then systematic analysis of spinal reflex Inhibition is an active process, like excitation activity in chronic spinal dogs Reciprocal inhibition Decereberate posture from animals Book: The Integrative Action of the Nervous System (1906) 1932: Nobel prize in medicine/physiology, Classic in neurophysiology shared with

29 Adrian and Zotterman 1926; Ibid. 61: p. 151. Sir/Baron Edgar Adrian (1889 – 1977) • Pre WWI- trained with J.N. Langley and Keith 1919 Lucas. Studied All-or-None response in nerves; Lucas died in WWI • Learned about vacuum tube amplifiers & showed he could multiply tiny potentials up to 5,000 times from American, Forbes. • Read about Erlanger/Gasser’s multistage amp 1921 • Began building a new one • Recorded from single neurons in his lab 1926 • Wrote: The Impulses Produced by Sensory Nerve Endings with Zotterman • Along with Bronk, isolated single motor 1928 neurons • EEG studies confirmed & extended Berger’s 1929 findings 1932 • Nobel Prize winner (shared with Sherrington) 1950 • Research in Olfaction 30 Stanley Finger. 2005. Minds Behind the Brain. Edgar D. Adrian: Coding in the Nervous System.

The Conduction of The Nervous by Keith Lucas

31 The Nobel Prize in Physiology or Medicine 1936 “for their discoveries relating to chemical transmission of nerve impulses”

32 Sir Henry Dale (1875 – 1968) • Worked under Langley in • Then London with Starling; met Otto Loewi • 1904 – Director of Welcome Physiological Research • Pharmacology of • 1914 – Director; Department and Pharmacology at the National Institute for Medical Research • 1914 – Identified acetylcholine as • 1936 – Shared Nobel Prize with Otto Loewi • Jewish, was imprisoned by Nazis in 1938 • Immigrated to USA & NYU

33 Sir Henry Dale (1875 – 1968) • 1940’s: • Dale – signaling at synapses was chemical • Eccles – signaling at synapses was electrical • Both were right! • Originated the scheme to differentiate neurons by they release • Dale’s Principle – each neuron releases only one type neurotransmitter • Ultimately NOT TRUE 34 Nobel Prize 1944 The Wash U “Axonologists” , MD (1874-1965)

1874 Born in , CA Parents were Jewish-German immigrants 1895 BS; UC Berkley 1899 John’s Hopkins Medical School and Internship • Worked under Osler • Patented a new type of Sphygmomanometer • Assistant & Associate Professor in Physiology & worked in GI and 1906 1st Chair of Physiology; Univ. of Wisconsin Madison Gasser was his student 1910 Moved to Wash U in St. Louis • Initial work in Cardiology then switch to • Influence from Gasser who wanted to record nerve action potentials 1922 Amplified action potentials of bullfrog sciatic nerve (Am J Phys) Also studied frog nerves, cat tibia nerves, & dog phrenic nerve 1921 Landmark Publication in Neuroscience

35 Nobel Prize 1944 The Wash U “Axonologists” Herbert Gasser, MD (1888-1963) •1888 – Born: Platteville, WI; Father was an Austrian immigrant & physician •1907 – University of Wisconsin for undergraduate & medical school •1909 – Began working under Erlanger •1913 – Transferred to John’s Hopkins to finish MD •1916 – Went back to Univ. of Wisconsin briefly then to Washington Univ. • Break to serve in WW1 in physiology of chemical warfare • Then Rockefeller grant in London Paris and Munich-learned about new lab equipment •1921 – Professor in Pharmacology at the age of 32 •1931 – Professor of Phys at Cornell Medical College NYC •1935-1953 – 2nd Director of the Rockefeller Institute (after ) •1936 – Gasser and Erlanger gave a series of lectures at the Univ. of Penn summarizing their research into the actions of human nerve cells.

•1944 – Jointly received the Nobel Prize 36 Herbert Gasser, MD & Joseph Erlanger, MD Their Discoveries FIRST DISCOVERY •Increased amplification of nerve recordings by 2 techniques: 1. New Western Electric cathode ray tube for displaying nerve impulses oscillography defibrillator • A 3 (multistage) vacuum tube amplifier 2. Recorded actions potential of nerve trunk with greater accuracy & reproducibility & magnified nerve events up to 7,000 times •1921 – American Physiological Society showed plot of •1922 – A Study of the Action Current of Nerve with the Cathode Ray Oscillograph (Amer. J. Physiol., 1922;62:496-524)

37 Herbert Gasser, MD & Joseph Erlanger, MD Additional Discoveries

•2nd Discovery: • Showed actions potential was • Indicated conductions at diff velocities for diff nerve fibers and also that thresholds for stimulation was different •3rd Discovery: • Showed velocity of impulse is greater in larger fibers •4th Discovery: • This ultimately led to classification of fibers as 1. Type A. largest/fastest 2. Type C. unmyelinated/slowest 3. Type B intermediate •Fiber types associated w/ functions-light touch, dull & sharp pain, temp •1944 - Nobel citation for “discoveries relating to the highly differentiated functions of nerve fibers" Amer J Physiol. 1922;62:496-524) 38 Nobel Prize 1963 Nerve Membrane Physiology

Sir John Carew Eccles (1903 – 1997) • Concept of EPSP & IPSP • Australian • Studied under Sherrington

• Sodium & Potassium ions & Sir Alan Lloyd Hodgkin (1914 – 1998) membrane conductance • Learned to dissect squid at • Excitation & inhibition in the peripheral & central portion of the nerve cell Sir Andrew Fielding Huxley (1917 – 2012) membrane due to ion flow • Mentee of Hodgkin at Cambridge

39 The Hodgkin- Huxley Model

40 The Nobel Prize in Physiology or Medicine 1970 “for their discoveries concerning the humoral transmitters in the nerve terminals and the mechanism for their storage, release and inactivation”

41 Sir Bernard Katz (1911 – 2003)

1935 • Fled Germany to London, trained under A.V. Hill

1939 • Then to Australia, trained under Eccles • Joined the Air Force & became citizen

1946 • Then to Cambridge, trained under Hodgkin's/Huxley

1950’s • Unraveled role acetylcholine at junction • “Quantum” theory of nerve junction biochemistry • Is constant low level release of ACH producing “resting” signal, due to release of “quanta” of ACH platelets, produces corresponding signal receiving all • Signal strength increases through increased frequency • Central role of acetylcholine & its key enzymes

1970 • Nobel Prize winner in Medicine/Physiology for his role of acetylcholine at nerve endings Father of Modern Neuro- • Shared with Julius Axlerod (USA) & Ulf von Euler (Sweden) Pharmacology 42 DAVID H. HUBEL (1926-2013) • Born Ontario, Canada • McGill Med school & Neurology residency • 1959-Hopkins Neurology Fellowship to P&L for the • Korean War-drafted into Army-Walter Reed Army Institutiongame of Research (WRAIR) – Began recording from primary of awake cats – Invented modern metal electrodes – Measured firing of brain cells in cats as they watched moving spot on screen • Learned basic machinist skills • 1958-Hopkins: began collaborating with Dr. Wiesel – Both recruited to Harvard; collaborated 20 years • 1959-Hubel spent career at HMS till he died

43 Torsten Wiesel MD 1924-present • Born Uppsala, Sweden • MD- • Fac-Physiology & child • 1955-Hopkins under Dr. • 1958 -Fellowship in Ophthalmology – Then Asst. Prof – Met Dr. Hubel • 1959- Moved to Harvard with Hubel – Instructor in Pharmacology • 1968-Prof Neurobiology; Chair 1971 • 1983- • 1991-1998 President of RU • Still at RU

44 David Hubel MD & Torsten Wiesel MD Nobel Prize 1981 Discoveries • Neurophysiology of vision • Information processing in visual system • Cells in occipital cortex respond to straight lines, movement, and contrast • Some cells fire rapidly in response to horizontal lines, others to vertical lines or angles (edge motion, stereoscopic, color detectors) • Cells with similar functions are organized

into columns (ocular dominance columns) 45 David Hubel MD & Torsten Wiesel MD . Nobel Prize 1981 Discoveries

• Vision does not develop normally if the brain fails to make connections with the eye early in life. • Experiments; sealed eye shut at birth in cats. Blind in that eye & light not enough to provide stimulation

46 YEAR ACHIEVEMENT Roger Sperry, PhD 1913 Born in Hartford, CT (1913 – 1994) 1935 Oberlin College, OH • Majored in English, but took Intro To Psychology • R.H. Stenson, who worked with

1937 Masters in Psychology; Oberlin College 1941 PhD in ; Univ. of Chicago 1942 Post Doc; Harvard with and at Primate Research Center in FL 1946 Faculty in Dept. of Anatomy at Univ. of Chicago; Assistant then Associate 1954 Professor in Psychobiology at California Institute of Technology • Experiments with Joseph Brogden, MD & many Nobel Prize 1981 others (Michael Gazaniga)

47 Split Brain Experiments, Lateralization of Brain Functions • In cats and monkeys first • Cut optic nerves in the eye, so left eye connected to left hem and right connected to right hem • Also cut corpus callousness • Taught to distinguish triangle from square with right eye covered • Then presented same problem with left eye covered • Showed left and right hemispheres functions separately when not connected by corpus callous 48 Split Brain Experiments, Lateralization of Brain Functions • In humans undergoing corpus callous splitting for intractable • Present word to either left or right visual field • If presented to right visual field, image processing left hemisphere • If presented to left visual field (right hem) the patient could not report seeing the word, only left side of brain could articulate speech

49 Roger Sperry Awards

• California of The Year 1971

• Wolfe Price in Medicine 1979

• Albert Lasker Medical Research Award 1979

• Nobel Prize in Physiology of Medicine 1981 • Shared with Hubel & Wiesel

• National Medal of Science 1989 Nobel prize ceremony - 1981

50 Roger Sperry, PhD (1913-1994)

“The great pleasure and feeling in my right brain is more than my left brain can find the words to tell you.” -Roger Sperry

51 Stanley B. YEAR ACHIEVEMENT Prusiner 1942 Born in Des Monies IA • 1896 Grandfather emigrated from Moscow to Sioux City, IA U of Penn BS (64) MD (68) • Intellectual environment • Research project on hypothermia in the summer before senior undergrad year 4th yr. Med School did adipose research in Stockholm UCSF intern NIH research 3 years on E. coli & enzymes (Public Health Service) 1968 UCSF Neurology residency • Saw pts with CJD stimulating his research career 1974- Faculty @ UCSF his entire career Nobel Prize 1997 present • Began scrapie research Head Institute for Neurodegenerative Disease 52 Stanley Prusiner MD Prions • 1982 coined the word “prion” • Comes from words proteinaceous & infectious • Prions accumulate in neurodegenerative • disease in animals and humans • Scrapie • Bovine spongiform encephalopathy • ("mad cow disease“) • KURU disease in humans (cannibalism) - New Guinea • Creutzfeldt–Jakob disease (CJD) Novel Proteinaceous Infectious Particles Cause Scrapie. Science. 1982 Apr 9;216:136–144 53 • Prions have no DNA or RNA Stanley Prusiner MD Prions • Novel disease paradigm • Prions cause diseases that can manifest as • Sporadic • Inherited • Infectious • Prions are proteins that acquire an alternative shape that becomes self-propogating • Single protein can posses multi biologically, active shapes • Critiques’ Initially said this was impossible and had to be slow virus but they were wrong! • Prions can assemble into amyloid fibrils • causing diseases • All the pivotal research done over a decade Molecular of Prion Diseases Science. 1991 Jun 14;252:1515–22 54 Stanley Pruisner Awards

• Gairdner Foundation International Award 1993

• Albert for Basic Medical Research 1994

• Nobel Prize in Physiology or Medicine 1997

2010 • Presidential National Medal of Science

• Member: • National Academy of Science Medal of Science Ceremony • Institute of Medicine with President Obama • Royal Society, London

55 The Nobel Prize in Physiology or Medicine 2000 “for their discoveries concerning signal transduction in the nervous system”

56 YEAR ACHIEVEMENT 1929 B. , Eric Kandel MD • Mother born in /Father Galicia • Moved to Vienna after WW1/ assimilated Jews

1938 Fled Vienna to when annexed by Germany/Nazis • He observed Kristallnacht Judaic studies (Yeshiva)and 1948-52 -History and Literature • became interested in learning &

1952-56 University Med School, exposed to Stephen Kuffler/neuron experiments in • Learned from Stanley Crain how to make intracellular microelectrodes to record crawfish giant axons 57 Year Achievements Eric Kandel MD 1957 NIH Record from hippocampus neurons/intracellular • Residency in psychiatry, studied

1962 Paris; studied Californica under Ladislav Tauc 1965 Published first paper about learning Aplysia

1965 Faculty in Physiology and Psychiatry Depts. NYU

1966 James Schwartz joined; biochemical changes assoc. w/ learning 1971 Tom Carew joined team. Short and long term memory 1973 Dept. Psychiatry Nobel Prize 2000 1983 Formed Howard Hughes Medical Research Institute at Columbia devoted to molecular neural science 58 Habituation and Dishabituation of the Gill-Withdrawal Reflex in Aplysia

Science 1970 167 ;(3926):1740-2.

59 Eric Kandel, MD Aplysia Learning • In Psychiatry residency began plan to study memory and learning • Select simple animal model to do electrophysiologic analysis of synaptic changes of learning and memory storage • In Paris studying Aplysia: simple learning such as habituation, , , and operant conditioning • Could be demonstrated in Aplysia • Neurons 1mm wide • Sensory cells detect danger and send signals to motor neurons (6) • Snails breathe by exposing gills, covered by siphon • Stimulus cause muscles around gill to pull gill and siphon back • He studied this circuit • As snail learned to avoid shocks, its nervous system changed: enhancing synaptic connections, more powerful connections recorded by microelectrodes • First evidence that learning led to neuro plastic strengthening of connections between neurons • Repeated shocks - sensitization and learned fear/over-react to more benign stimuli (like anxiety in humans) 60 • Gently touching siphon- habituation Eric Kandel Awards • 1983

• Lasker Award 1983

• Gardner Foundation International Award 1987

• National Medal of Science 1988

• 1993

• 1999

• Nobel Prize in Physiology or Medicine 2000 Eric R. Kandel after receiving • Austrian Decoration for Science and Art his Nobel Prize from his 2005 Majesty the king of at the Stockholm Concern Hall 2000 61 Eric R. Kandel MD

62 Linda Buck, Ph.D. YEAR ACHIEVEMENT 1947 • Born- Seattle, Washington

1975 • B.S. in Psychology from Univ. of Wash • Father was a engineer, mother was a homemaker, solved puzzles

1980 • PhD in Neuro-Immunology from UTSW - Dallas • Moved to Columbia, NY • Post-doc with Dr. at Columbia, Neuroscience • 1st project – Kandel’s Aplysia lab; cloned in Aplysia in neuron • Then began map of the olfactory process at the molecular level 1991 • Identified family of gene in rats • Code for >1000 odor receptors-GI Paper Nobel • Assist. Professor of Neurobiology, Harvard Medical School Prize 2004 1993 • Published how inputs from different odor receptors are organized in the nose 2002 • Moved to Fred Hutchinson Cancer Research Center, Seattle 63 Richard Axel MD Nobel Prize 2004 Year ACHIEVEMENT 1946 Born in Brooklyn, NY

Parents were Polish immigrants who fled the Nazis • Father- tailor; nonacademic upbringing • Interests: basketball; as a teenager, played 7’2” Lew Alcindor, who asked him “What are you going to do, Einstein?”

1963 HS- scholarship to Stuyvesant HS, Manhattan • Embraced culture & aesthetics of NYC • Esp. Reading Room in NYC public library

1967 College- Full scholarship to Columbia Univ. ; worked in DNA lab (was fired as glassware cleaner)

1970 Med School- John Hopkins (military deferment) • “My clinical incompetence was immediately recognized” • “ I sewed a surgeon's finger to a patient ” • “I was allowed to graduate med school if I promised never to practice medicine on live patients.” • After 1 year Pathology internship “I was asked never to practice on dead patients” With Kareem Abdul-Jabbar, 2011 64 Richard Axel MD

• 1980s- Switched to of neuroscience problems • Worked with Eric Kandel & on Aplysia genetic issues • Then pursued Interest in problem of With Linda Buck, PhD • Linda Buck joined his lab 2004-Jointly awarded The Nobel Prize in Physiology or Medicine • “A creative fellow in the lab, we began to consider how the chemosensory world is represented in the brain. The problem of olfaction was a perfect intellectual target for a molecular .” 65 Linda Buck & Richard Axel A Novel Multigene Family May Encode Odorant Receptors: A Molecular Basis for Odor Recognition Landmark Paper • code for odorant sensors in olfactory neurons in nose • Each receptor is a protein that changes when an odor attaches to the receptor, then sends signal to the brain • Differences between odorant sensors under certain odors cause a signal to be sent to brain • We then interpret varying sensory signals from our receptors as speech &

Buck, L. and Axel, R. (1991) Cell, 65, 175-187. sounds

66 Linda Buck & Richard Axel A Novel Multigene Family May Encode Odorant Receptors: A Molecular Basis for Odor Recognition

• Showed olfactory receptors belong to family of -coupled receptors • Analyzed rat DNA & estimated there are approx. 1,000 different genes for olfactory receptors in mammalian • Led to further work of genetic & molecular analysis of mechanisms of olfaction • Each neurons only expresses one kind of olfactory receptor protein • Input from all neurons expressing the Buck, L. and Axel, R. (1991) Cell, 65, 175-187. same receptor is collected by a single dedicated of the olfactory 67 bulb Linda Buck Ph.D. Awards • Takasago Award for Research in Olfaction 1992

• Unilever Science Award 1996

• Gairdner Foundation International Award 2003

• National Academy of Sciences 2003

• Nobel Prize in Physiology in Medicine with Richard Axel 2004

• Institute of Medicine 2006

68 Linda Buck, Ph.D. Secrets of Smell

69 Linda Buck Ph.D. Retracts Papers

• In 2008, Buck had to retract 2001 paper • Inability to produce results “inconsistencies between some of the figures and data published the original data” • Paper in question is tied to the “mapping of olfaction to discrete parts of the brain” • Initial groundbreaking work with Richard Axel still valid • Later retracted PNAS 2005 & Science 2006 papers citing she could not reproduce data of these papers • Buck stated most of questionable date came from post-doc Dr. Zhihua Zou

70 .

A team of including Linda B Buck, who shared the 2004 Nobel Prize in Physiology or Medicine, has retracted a scientific paper after the scientist could not reproduce their original findings.

The Harvard Medical School, where the researchers worked when the findings were published in the journal Nature in 2001, has begun a review of the research to determine if there is any evident of misconduct. 71 .

Science; 2006: 311, 5766,; 1477-148

72 Linda Buck, Ph.D. Retracts Papers

PNAS Nature

73 May-Britt Moser • Along with her husband Edvard I. Moser in 2005, discovered a type of cell that is important for determining position close to the hippocampus. • Found that when a rat passed certain points arranged in a hexagonal grid in space, nerve cells that form a kind of coordinate system for navigation were activated.

Awarded The Nobel Prize in Physiology or Medicine 2014 “for the discoveries of cells that constitute a positioning system in the brain”.

74 My attempt to invite a Nobel Prize winner to KU

Denied….

75 Some Neuro Nobel’s came from humble origins

Many had immigrant backgrounds

Many from USA

Some infamous or have a dark side

Many either fled from the Nazi’s or were a Nazi

Too many men Four women

At least one was accused of subsequent research misconduct and had to retract papers

Still the story of the Neuro Nobel’s is a pillar of western scientific knowledge and

accomplishments 76