Katz, Bernard
KATZ, BERNARD
(b. Leipzig, Germany, 26 March 1911; d. London, United Kingdom, 20 April 2003),
neurophysiology, action potential, neurotransmitter, synaptic transmission.
Katz shared a Nobel Prize with Alan Hodgkin in 1963 for their contribution to the development of the Goldman, Hodgkin, Katz (GHK) equations. The equations describe relations among electrical and chemical factors that influence electrical activity in nerve cell axons. He helped demonstrate that synaptic signaling between nerve and muscle or other nerve cells is driven by a chemical mechanism. In 1970 he received a second Nobel Prize for research that helped establish the role of the neurotransmitter acetylcholine (ACh) and the quantal nature of the mechanism that motor neurons use to influence activity at the end plates of postsynaptic muscle cells. He also helped make it plausible that nerve cells use similar chemical mechanisms to signal one other.
One of Hitler’s Gifts to British Science . Bernard Katz was born of Jewish parents in Leipzig, Germany. Because his Russian father never became a German citizen, Katz was born stateless as well as Jewish, and he remained a stateless alien until 1941, when he became a British subject. He lived in Leipzig until he finished his medical degree at the University of Leipzig in 1934. In 1935 he migrated to London to work with Archibald V. Hill at University College. Katz was attracted by Hill’s work in physiology, as well as his outspoken public opposition to anti-Semitism and Nazism. Hill’s personality and attitude toward science inspired him. The motto Katz chose for an autobiographical essay—“To tell you the truth, sir, we do it because it’s amusing”—is Hill’s reply to an indignant crank who challenged Hill to say what practical use could be made of his highly technical work on muscle physiology. Throughout his career, Hill kept a picture of Adolf Hitler in his office as an expression of his gratitude for Katz and the other gifts the Führer gave him.
The disadvantages of being a Jew in Germany were more than obvious to Katz by the age of sixteen, when his reading of Theodor Herzl, the founder of the Zionist movement, and his conversations with like-minded friends inspired him to become a Zionist. Zionism helped sustain him in the face of German anti-Semitism, and eventually it led to an interview with Chaim Weizmann, who arranged some financial support for his move to England. By the end of Katz’s time at the University of Leipzig, Hitler had assumed power. (After arriving in England Katz changed his name from Bernhard to Bernard in solidarity with his new home.)
Early Work . While Katz was in Leipzig, his teacher, Martin Gildenmeister, and other physiologists were working to construct precise mathematical descriptions of electrical activity in nerves. Although he later expressed reservations about the value of this enterprise, Katz wrote some successful manuscripts on related research topics. Several were published in Pfluger’s Archiv, and one was awarded a prize for physiological research. Katz submitted his prize paper under the name Thomas Müller, partly in honor of Hermann Ludwig Ferdinand von Helmholtz’s teacher, but mainly because, unlike “Katz,” “Müller” is a good Aryan name.
Katz had more trouble with his name in England. Hill arranged for the German publishers of Ergebnisse der Physiologie to invite him to write a review of recent literature on nerve fiber responses to electric stimulation. When Katz submitted his manuscript, the editor informed him that Ergebnisse could not publish it without an Aryan coauthor. Katz relates in his autobiographical essay that someone suggested approaching Winston Churchill for this purpose! Katz withdrew the manuscript and submitted it to the Oxford University Press, which published it in 1939 under the title Electric Excitation of Nerve. In his preface Katz acknowledges the editors of Ergebnisse, saying that his appreciation for their encouragement is “in no way diminished by the fact that the ms was refused on ‘racial’ grounds by the prospective publishers in Berlin.”
Katz’s book discusses equations developed by physiologists to capture patterns in data from artificially stimulated nerve preparations. To obtain the data, they immersed bits of nerve fiber in solutions whose temperature and chemical compositions they could control. They then inserted microelectrodes into the nerve tissue through which to send direct and alternating current pulses; recording microelectrodes a short distance away were used to monitor responses to the pulses. Stimulus currents of different signs, durations, and strengths were administered in different patterns and time intervals. Investigators manipulated the temperature and chemical composition of the bath to see how these factors influenced electrical activity, and also to damp confounding effects, and to speed up or slow down reactions to make it easier to record them. In some experiments, chemicals were introduced into the nerve itself through tiny pipettes. Stimulating and recording electrodes were arranged in different positions relative to each other so that investigators could measure current development, spread, and decay at different locations along the nerve. These were the experimental methods on which Katz would rely throughout his career.
Paul Fatt, one of Katz’s collaborators, recalls how difficult the experiments could be. In 1948 Katz worked in a rickety laboratory near a stairwell. When people tramped up and down the stairs, the floor vibrated so much that it was hard to implant the microelectrodes properly and keep them in position. Fatt recalls
many times that BK went storming out of the room to remonstrate with someone walking along the corridor or climbing the spiral staircase. … [One] time BK charged out of the room, only to come back silently with a sheepish look—his lovely grin. It was AV [Hill] on the staircase and he had a particularly heavy tread. (D. Katz, Huxley, Fatt, et al., 2003)
Many of the equations Katz reviewed in his book describe “passive” electrical effects, that is, effects that investigators could predict from features of the stimulating current and background conditions in accordance with standard electrical theory. But under some conditions, electrical activity in a nerve fiber spikes nonlinearly in a way that suggests that, instead of responding passively to a stimulus pulse, the nerve fiber itself is doing something to influence current flow. Waves of uniformly elevated electrical activity that travel rapidly without decay down the axon of an excited nerve are called action potentials for this reason. Katz concludes his review with an account of Hodgkin’s early investigations of the action potential propagation.
Electric Excitation in Nerve provides a vivid picture of state of the art of neurophysiology during Katz’s first years in England. Throughout the book he emphasizes that until a great deal more was known about the anatomy and physiology of the nerve cell, no one would be able to say enough about “the intimate mechanism of the ‘nerve membrane’ and its functional changes” to explain how and why electrical stimulation produces its effects, or to describe “the physico-chemical nature of ‘excitation.’” Katz wrote quotation marks around the terms nerve membrane and excitation to warn us that whatever they signified was poorly understood. Katz himself was more interested in investigating mechanisms than in describing regularities among their effects.
The question of whether chemical mechanisms figure in neuronal signaling, especially with regard to transmission across the synapse, was so far from settled that at a public lecture he attended in 1935 Katz was surprised to observe a rousing verbal battle on this subject between Henry H. Dale and John C. Eccles. Katz reports that as Edgar Adrian served as “a most uncomfortable and reluctant referee,” Dale argued that sympathetic nerves use acetylcholine to transmit signals across the synapse while Eccles objected vehemently on the basis of pharmacological evidence.
By this time Hill had given up the search for physical-chemical transmission mechanisms to devote himself to the development of some of the quantitative descriptions that Katz had reviewed in Electric Excitation. In his 1966 autobiographical essay, Katz says he thinks this was “in some respects … a retrograde step” back to a research program that exhibited a naive pride in mathematical formulations. But even so, he says it was not “entirely unfashionable” at a time when “some of the most eminent neurologists” had yet to accept “even the basic concept of the membrane potential being involved in the process of electric excitation.”
In 1939 Katz moved to Australia. He worked there with Eccles and Stephen Kuffler from time to time until he returned to Hill’s department in London in 1946. In 1941 they published the results of frog muscle experiments to argue that nerve cells initiate electrical activity in muscle end plates through chemical rather than purely electrical means. When they stimulated a nerve in a neuromuscular synapse sufficiently to produce action potentials, measurable electrical responses occurred in the end plates of postsynaptic muscle cells. These muscle end plate potentials set up currents that spread passively over a short distance. On repeated stimulation, these potentials sum to magnitudes sufficient to produce action potentials and contractions in the muscle fiber. End plate responses to presynaptic stimulation varied with temperature in ways suggestive of chemical rather than purely electrical interactions. When curare (a drug known to inhibit skeletal muscular responses to ACh) was added gradually to the preparation, the magnitudes and frequencies of end plate potential responses to presynaptic stimulation decreased to extinction. When they added esserine (this drug blocks inhibitors to facilitate ACh interactions), end plate
potentials occurred more often and their magnitudes increased. That made it plausible not only that neuromuscular signaling is chemical, but that ACh is the chemical that transmits impulses over the synapse. But the evidence that chemical mechanisms are involved in neuromuscular transmission did not convince the scientific community that nerve cells use neurotransmitters to signal one another. According to Eccles, the notion that central nervous system synaptic transmission is a purely electrical process lingered on until the early 1950s, when newly developed recording techniques enabled investigators to produce enough evidence to kill it.
The Goldman-Hodgkin-Huxley Equations . Katz enlisted in the Royal Australian Air Force as soon as he became a British subject. He served as a radar operator for three years, making use of electrical tricks he had learned from Otto Schmidt’s physiology laboratory. During the next year he finished his military career as a liaison officer assigned to the University of Sydney radiophysics laboratory. In Sydney he met and married Marguerite Penly. On his return to England he began the work that led to a paper on the GHK equations that he and Hodgkin published in 1949.
Nerve axons are membrane-lined tubes filled with and bathed in solutions containing K+, Na+, Cl-, and other charged ions. When a nerve is at rest, the charge on the inner surface of the axon membrane is negative relative to the charge on the outer surface. By convention, the membrane potential (the voltage difference between the charges on the inner and outer membrane surfaces) is said to be negative in this condition. From time to time the membrane depolarizes, which is to say that the inner surface becomes less negative relative to the outer surface. During depolarization, action potentials are generated. Action potential propagation stops during hyperpolarization, a redistribution of charges that moves the membrane potential back toward its resting value. According to what has become the standard account of these processes, the charges on either side of the axon membrane are carried by ions in solution at each surface.
Hodgkin and Katz conducted a series of experiments on squid giant axons immersed in salt solutions. They observed how membrane potentials and other electrical quantities changed at different temperatures during such manipulations as holding potassium and chlorine ion concentrations fixed while varying the amount of sodium in the solution. Their data indicated that membrane potential is sensitive to changes in potassium and chlorine concentrations, but that action potentials varied far more directly with sodium concentration. Sodium was the only ion whose addition to the bath produced action potentials, and action potentials did not occur when sodium content fell below a certain level. In keeping with David Goldman’s 1943 discussion of electrical activity in an artificial membrane, Hodgkin and Katz proposed that changes in membrane potential result from ion flows across the membrane and, furthermore, that the depolarization that initiates the action potential results from an inward flow of sodium ions.
The reversal potential is the membrane potential at which there is no net ion flow across the membrane in either direction, as happens when the nerve is at rest and at the instant when an ion current changes direction during depolarization or hyperpolarization. Hodgkin and Katz (like Goldman) accepted Walther Nernst’s assumption that charged ions in solution tend to flow toward regions of lower concentration and opposite charge. They also assumed that the membrane is not equally permeable to ions of different species. Accordingly, they proposed that at any given temperature the value of the reversal potential is a function of the ratios of inner to outer surface Na+, K+, and Cl- concentrations, weighted by
permeability coefficients. This is the GHK voltage equation. (The equation is written E rev= (RT/F) ln . For each ion species, S, PS is the permeability constant for S, [S]i is its concentration inside, and [S]o, its concentration outside the membrane. Erev is the reversal potential for the combined ion currents. T is temperature, F is Faraday’s constant, and R is the ideal gas constant).
Using the equation that Hodgkin and Andrew Huxley had developed to describe how ion currents vary with membrane potentials, Hodgkin and Katz transformed the voltage equation into several current equations. Each of these describes the cross membrane current for one ion species as a function of membrane potential together with the ion’s valence, the membrane’s permeability to the ion, and the ion’s concentrations on the inner and outer membrane surfaces. (The GHK voltage equations have the form is the current carried by ions of kind S. Ps is the membrane permeability for S ions. z is the valence of S ions. E is the membrane potential.) The GHK equations are accurate only to a rough approximation. Their importance derives from what neurophysiologists have learned about the action potential by investigating and finding factors to account for experimentally detectable discrepancies between GHK predictions and experimentally established values of the relevant quantities.
End Plate Potentials and Neurotransmitters . In 1946 Katz returned to University College in London. In 1948 he and Fatt began the investigations of signaling over neuromuscular junctions that earned him his second Nobel Prize. In 1952 he became professor of biophysics at University College. He chaired the department for twenty-six years.
With Fatt, and later with José del Castillo, Ricardo Miledi, and other distinguished collaborators, Katz measured electrical activity in neuromuscular preparations bathed in salt solutions. They found that when presynaptic nerves are at rest in the absence of any artificial stimulation, very small bursts of electrical activity occur at random intervals in muscle cell end plates on the far side of the neuromuscular junction. Katz and his associates called them miniature end plate potentials. Larger bursts of end plate electrical activity occurred in response to artificially induced presynaptic action potentials. End plate potentials came in different sizes, but their magnitudes appeared to be integral multiples of the magnitudes of the miniature potentials.
Katz and his associates established the chemical nature of neuromuscular signaling by demonstrating that they could both facilitate and damp end plate responses to presynaptic stimulation through manipulations that should have no such effects on the operation of a purely electrical mechanism. Neuromuscular interactions responded to temperature manipulations too small to facilitate or damp the flow of an electric current. Although calcium is not required for electrical transmission, presynaptic nerve cells did not excite muscle end plates in solutions that contained no calcium. Electricity can be transmitted through solutions containing magnesium irons, but presynaptic action potentials do not excite muscle end plates when calcium is replaced by magnesium. Furthermore, the relative magnitudes of electrical quantities in the axon, the synaptic cleft, and the muscle end plate were not related to one another, as would be expected for purely electrical transmission.
These and other experimental results suggested that end plate potentials are produced by neurotransmitter chemicals released in small quantities at random from resting nerves cells, and more regularly and in larger amounts in response to action potentials in excited cells. Such results suggest that miniature end plate potentials are caused by small amounts of a neurotransmitter chemical that leaks out resting presynaptic axons, and that full-fledged end plate potentials are caused by larger amounts of the same chemical released from excited axons in response to action potentials.
Assuming that the magnitudes of end plate potentials depend on how much neurotransmitter the axon releases, the fact that end plate potential magnitudes are multiple integrals of miniature end plate potential magnitudes suggests that neurotransmitters are not released molecule by molecule in continuously larger or small amounts. Accordingly, Katz and his collaborators proposed that neurotransmitter molecules are released in parcels, each one of which contains just enough of the chemical to produce a single miniature end plate potential. The size of the parcels may vary from case to case, but each one contains the smallest amount of neurotransmitter that can produce an end plate response under the circumstances. Similarly, miniature end plate potential magnitudes may vary, but whatever its magnitude may be, no smaller electrical response is possible in any given case. The reason that full-fledged end plate potentials differ from miniature end plate potentials as integral multiples is that the former are caused by the release of two or more parcels of neurotransmitter. Thus Katz could call the process “quantal” even though he recognized that the units of released neurotransmitter and of electrical response could vary in magnitude. By investigating synaptic transmission in squid stellate ganglia, Katz and his colleagues produced evidence that communication between nerves resembles neuromuscular signaling, in that it too depends upon a quantal
chemical mechanism that requires calcium for its operation.
Katz and his colleagues continued to argue that the neurotransmitter for neuromuscular synaptic transmission is ACh. ACh introduced into the neuromuscular junction without presynaptic (or any other electrical) stimulation produced the same end plate potentials as presynaptic action potentials. Drugs that damp or enhance end plate responses to artificially introduced ACh have the same effect on responses to presynaptic stimulation in the absence of artificially introduced ACh.
In his 1969 Sherrington Lecture, Katz recapitulated a working hypothesis from a publication he published with del Castillo in 1956. Their idea was that each unit parcel of neurotransmitter is “pre-formed within a synaptic vesicle in the nerve terminal.… The transmitter substance parceled up inside a vesicular bag is separated from its postsynaptic target by … the vesicular membrane … and the membrane of the axon terminal.” Katz supposed that axon potentials influence the membrane at the end of the axon to raise the probability that the vesicle will pass through it and release transmitter into the synaptic cleft. Some electron microscope evidence for the existence of neurotransmitter vesicles and the discharge of neurotransmitters from them was available to del Castillo and Katz in 1956. More visual evidence appeared during the next two years.
Katz completed his work on synaptic transmission by investigating the locations at which neurotransmitters are released, the postsynaptic locations at which they do their work, and the molecular biology of postsynaptic responses. His subsequent research included investigations of the biochemistry of the pineal gland and its role in melatonin production.
Katz retired in 1978 but continued for some years to referee papers for publication, and discuss ongoing research with erstwhile colleagues and students. In 1999 his wife died of a prolonged illness during which Katz visited her bedside every day to hold her hand and read to her. His son David says that after her death life lost much of its savor for Katz, and he gradually gave up his work. In addition to David, Katz was survived by another son, Jonathan, and three grandchildren.
BIBLIOGRAPHY
WORKS BY KATZ
Electric Excitation of Nerve: A Review. London: Oxford University Press, 1939.
With Alan L. Hodgkin. “The Effect of Sodium Ions on the Electrical Activity of the Giant Axon of the Squid.” Journal of Physiology (London) 108 (1949): 37–77.
“Depolarization of Sensory Terminals and the Initiation of Impulses in the Muscle Spindle.” Journal of Physiology (London) 111 (1950): 261–283.
With Paul Fatt. “Some Observations on Biological Noise.” Nature 106 (1950): 597–598.
“An Analysis of the End-Plate Potential Recorded with an Intracellular Electrode.” Journal of Physiology (London) 115 (1951): 320–350.
“Spontaneous Subthreshold Activity at Motor Nerve Endings.” Journal of Physiology (London) 117 (1952): 109–128.
“The Membrane Change Produced by the Neuromuscular Transmitter.” Journal of Physiology (London) 125 (1954): 546–565.
With José del Castillo. “Changes in Endplate Activity Produced by Pre-synaptic Polarization.” Journal of Physiology (London) 124 (1954): 586–604.
———. “Quantal Components of the Endplate Potential.” Journal of Physiology (London) 124 (1954): 560–573.
“On the Localization of Acetylcholine Receptors.” Journal of Physiology (London) 128 (1955): 157–181.
“The Croonian Lecture: The Transmission of Impulses from Nerve to Muscle and the Subcellular Unit of Synaptic Action.” Proceedings of the Royal Society (Series B) 155 (1962): 455–477.
With R. Miledi. “A Study of Spontaneous Miniature Potentials in Spinal Motoneurons.” Journal of Physiology (London) 168 (1963): 389–422.
“The Measurement of Synaptic Delay and the Time Course of Acetylcholine Release at the Neuromuscular Junction.” Proceedings of the Royal Society (Series B) 161 (1965): 483–495.
“Propagation of Electric Activity in Motor Nerve Terminals.” Proceedings of the Royal Society (Series B) 161 (1965): 453–482.
Nerve, Muscle, and Synapse. New York: McGraw-Hill, 1966. The Release of Neural Transmitter Substances. Sherrington Lectures X. Liverpool: Liverpool University Press, 1969.
“Sir Bernard Katz.” In The History of Science in Autobiography, vol. 1, edited by Larry R. Squire, 348–381. Washington, DC: Society for Neuroscience, 1996. Autobiographical essay.
OTHER SOURCES
Bennett, Max R. “Sir Bernard Katz.” Journal of Neurocytology 32 (June 2003): 431–436. Obituary.
Eccles, John C. The Physiology of Synapses. New York: Academic Press, 1964.
Hille, Bertil. Ion Channels of Excitable Membranes. 3rd ed. Sunderland, MA: Sinauer Associates, 2001. See pp. 449–470.
Katz, David, Sir Andrew Huxley, Paul Fatt, et al. “Memories of Bernard Katz: An Afternoon at University College, London, 8th October 2003.” Available from http://www.physiol.ucl.ac.uk/Bernard_Katz/.
Valenstein, Elliot S. The War of the Soups and the Sparks. New York: Columbia University Press, 2005.
Jim Bogen