Ashmore, J

Cull-Candy, S

UCL Discovery

1Paul Fatt1924-2014Faces left to right: Murdoch Ritchie, Paul Fatt and Doug Wilkie in conversationin the old Physiology classroom, UCL 1979. Photo: Martin Rosenberg, with permission of The PhysiologicalSociety.With the death of Paul Fatt on 28th September, we lost one of the founders of moderncellular neuroscience. He ranks among the most distinguished neuroscientists andbiophysicists of the twentieth century. Working with Bernard Katz and a number of otherexceptional collaborators, notably John Eccles and Bernard Ginsborg, Paul Fatt realized astaggering series of fundamental discoveries on excitatory and inhibitory synaptictransmission, and ion channel function.The second of three scientifically-minded brothers from Chicago, Paul Fatt received hiseducation in Biochemistry at UC Berkeley on the G.I. Bill after serving with the US Army inWWII. As a young graduate student, he joined UCL’s Biophysics Research Unit (later theBiophysics Department) in the summer of 1948. He and Katz decided that they would ‘have ago’ at using intracellular microelectrodes to examine the endplate potential (EPP). It is noexaggeration to say that the decision opened up a new era in our understanding of synaptictransmission. Together they carried out the first analysis of the endplate potential usingintracellular microelectrodes - an experimental tour de force. This was the first compellingdemonstration that synaptic receptors were chemically gated ion channels.During the spring of 1950, Fatt and Katz made the chance observation that, when examined on ahigh recording gain, the endplate region of skeletal muscle was the site of spontaneous ongoingelectrical activity. This they ascribed to the discharge of multimolecular ‘quanta’ ofacetylcholine (ACh) from the nerve terminal. In a series of elegant experiments, theydemonstrated that these events, dubbed miniature endplate potentials (MEPPs), represented the‘basic coin’ of chemical synaptic transmission – and that the full sized EPP triggered by a nerveimpulse, represented the superposition of a large number of synchronously occurring MEPPs.2The EPP, and its constituent ‘miniatures’ became the fundamental model against whichtransmission at other chemical synapses, including those in the brain, have subsequently beencompared.In the summer of 1952, on completion of his PhD, Fatt left UCL for the Australian NationalUniversity in Canberra to work with John Eccles, where, working in motoneurons, theyidentified the ionic mechanism underlying postsynaptic inhibition as arising predominantlyfrom an increased chloride conductance. During this study, Fatt developed the double-barrelled microelectrode technique - two glass barrels fused and twisted together by melting,and then pulled into a fine tip with a diameter less than a micron. One barrel was used torecord the synaptic potential changes while the other injected current to alter the ioniccomposition or preset the membrane potential.Fatt further identified the different regions on the neuron associated with the electricalcomponents of the spike, recognizing for the first time the ways in which the initial segmentand soma dendrite determine the action potential properties of central neurons. He has alsobeen widely credited with the prediction that transmission could be mediated electricallyrather than chemically at certain synapses – something confirmed soon after in a classicstudy by Furshpan & Potter.Fatt came back to London in 1956 to take up a position in UCL’s Biophysics Departmentwhere he returned to the more accessible synapses offered by crayfish muscle. Here, heestablished the general mechanisms underlying postsynaptic inhibition by demonstrating thatexternally applied GABA and inhibitory nerve impulses both produced postsynaptic chlorideconductance increases, mediating the inhibitory current at these synapses. Furthermore, Fatt,together with Bernard Ginsborg, worked on the ionic requirements for action potentialgeneration in crayfish muscle, discovering for the first time the existence of Ca2+-mediatedaction potentials, one of the most important currents present in biological tissues.In the mid 1960s, Paul Fatt worked with his then wife Gertrude Falk on the membranesystem of skeletal muscle using the electrical impedance methods developed by K.S. Cole tounderstand how skeletal muscle had a membrane capacitance which far exceeded the valuepredicted from muscle fibre size. Supported by subsequent electron microscopic evidence,they showed that the muscle surface included a connecting internal membrane system, thetransverse tubule network, responsible for spreading excitation into the centre of the musclefiber.Paul Fatt was part of a remarkable generation of highly talented and practical scientists whoreturned from WWII and populated Physiology and Biophysics departments. Paul remainedat UCL for nearly his entire career - preferring to spend time experimenting himself ratherthan running a large research group. Even so, he influenced generations of UCL Physiologyand Pharmacology students as a result of his annual Biophysics Course - a six week practicalcourse which he ran with Gertrude Falk (and other members of the Biophysics Department).His lectures were admirably unpretentious, utterly engaging, sometimes baffling, but alwaysenjoyable. We recall Paul being asked during a lecture why MEPPs always seemed toappear on the oscilloscope screen in groups if they did indeed occur randomly. Paul’sresponse was typical: he pointed out that if you waited on Tottenham Court Road for the 24bus (his daily route home to Hampstead) you would notice these also always arrived in twos3or threes. And, like MEPPs, if you plotted the interval between them they fitted anexponential. It not only conveyed his point in a charming way but, to our great amusementas students, suggested London buses were entirely random. Paul’s infectious enthusiasm forhis subject contributed greatly to the fact that such a high proportion of students taking thecourse (the authors included) ended up as neuroscientists.Although Paul never set much store by accolades, his significant contributions were markedby election to the Royal Society in 1969. Paul was never tied by convention and was fiercelyliberal in his views. His warm and generous personality and sharp intellect had a formativeeffect on many of his younger colleagues. And his remarkably large number of landmarkdiscoveries have guaranteed that his name will long remain familiar to seasonedneuroscientists and students alike.Stuart Cull-Candy and Jonathan Ashmore are in the Department of Neuroscience,Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BTe-mail: s.cull-candy@ucl.ac.uk, j.ashmore@ucl.ac.uk

Paul Fatt 1924-2014 OBITUARY

http://discovery.ucl.ac.uk/1460407/1/Paul%20Fatt%20-%20Obituary%20_Cull-Candy%26Ashmore_%20-%20Archived%20version.pdf

Paul Fatt 1924-2014 OBITUARY

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