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DAVID NACHMANSOHN March 17, 1899-November2, 1983 BY SEVERO OCHOA DA V ~ D N A C H M A N S O H N S scientific lifepath was strongly influenced by his early studies on the biochemistry of muscle in Otto Meyerhof's laboratory. This experience led to an interest in the biochemistry of nerve activity, a field of study to which he wouIcl devote most of his scientific life. In so doing, he contributed perhaps more than any other in- vestigator to our understanding of the molecular basis of bioelectricity. David Nachmansohn was born in Jekaterinoslav, Russia (now Dnjetropetrowsk, USSR). His parents came from mid(lle-cIass families among whom were many lawyers, phy- sicians, anc! other professionals. Before David and his two sisters reacher! school age, the family moved to Berlin where they had many relatives. Thus, Davicl's background and eclu- cation were essentially, if not exclusively, German. His college education was strongly humanistic, with Latin, Greek, liter- ature, and history as mainstays, some mathematics, and the rudiments of physics. Through his readings, perhaps pri- marily through his reacting of the second part of Goethe's Faust when he was only seventeen years of age, he became interested in philosophyso much so that he continued to attend courses anc! seminars in philosophy even while a med- ical student at Heidelberg in 1920. 357

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358 BIOGRAPHICAL MEMOIRS When he entered the University of Berlin in the spring of HIS, Davict was strongly oriented toward the humanities. After Germany's defeat in World War I, however, the newly establishe(1 republic face(1 grave social, political, and eco- nomic problems, ant] David was advisect to study medicine, a profession that could provide economic indepenclence. He accepted this advice and became a medical student; but as time went on, he became more and more interested in biol- ogy through his avid readings about the lives and scientific accomplishments of Bernard, Pasteur, Helmholtz, Ehrlich, and others. Eventually, he deciclect to devote his life to bio- mectical research and after his graduation in 1924 joined the laboratory of Peter Rona at the Charite for training in bio- chemistry. The Charite was the university hospital of Berlin Univer- sity Medical School in whose Department of Pathology Rona directed a division of biochemistry. There, Nachmansohn joine(1 an exceptional company of bright young people: among them, Fritz Lipmann, Hans Adolph Krebs, Ruclolph Schoenheimer, Ernst Chain, Karl Meyer, and Hans H. Weber. Nachmansohn's first paper, "Vital Staining and Adsorption," was publisher! in collaboration with Krebs, an endeavor that began a lifelong friendship between the two. Nachmansohn also (lic1 some collaborative work with Weber that lecl to the publication of a paper entitIec3, "The Independence of Pro- tein Hydration anti lonisation." At Rona's, he became familiar with the work of the great Dahiem biochemists Meyerhof, Warburg, and Neuberg, which he found fascinating. Weber adviser! Nachmansohn to go to Otto Meyerhof at the Kaiser-Wilhelm Institut fur Biol- ogie in Berlin-DahIem for further training. But when Nach- mansohn approached Meyerhof, the eminent researcher in- formec! him abruptly that he die] not accept beginners a position he reversed after speaking with the young Nach-

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DAVID NACHMANSOHN 359 mansohn awhile. In Meyerhof's laboratory, Nachmansohn's postcloctoral contemporaries included Fritz Lipmann, Her- mann Blaschko, Francis O. Schmitt, and this author. Karl Lohmann, who later discovered ATP, was Meyerhof's assist- ant, and Dean Burk was a visiting scientist. Hans Krebs was also in the same building, in Otto Warburg's laboratory. Nachmansohn often mentioned that it was Meyerhof who had had the most profound! impact on his later work anct scientific outlook. Nachmansohn joined the Meyerhof laboratory in ~ 926. At that time, Grace and Philip Eggleton at the Cambridge biochemical laboratory had recently discovered a new phos- phorylated compound in muscle they called "phosphagen" because it liberated inorganic phosphate cluring contraction. Soon thereafter, Fiske anc! Subbarow at Harvard Medical School showed the new compound to be phosphocreatine in which phosphate is linked to creatine through a phosphoam- icle boncI. During this period, Meyerhof was interested in the ener- getics of muscular contraction. He worked to determine, as he had previously with various hexose phosphates, the heat of hy(lrolysis of phosphocreatine. It proved to be very high- of the order of 10,000 to 12,000 calories per mole- which contrasted with the low heat of hyclrolysis of hexose phos- phates (1,500 to 3,000 calories per mole). This finding en- ablec! researchers to ctistinguish between high- and low- energy compounds in metabolism. (Some years later, it was shown that the breakdown of ATP to ADP and inorganic phosphate was the energy-yielding process more immedi- ately related to muscular contraction, whereas the break- down of phosphocreatine served to resynthesize the AT P. Lactic acid formation, most of which took place after con- traction, was like phosphocreatine breakdowna recovery process aimed at restoring rapidly the relatively small ATP

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360 BIOGRAPHICAL MEMOIRS stores of resting muscle. Finally, the glycogen that gave rise to the lactic acid was resynthesized from lactic acid using the energy released by officiation of a fraction of the lactic acic! produced). These clevelopments fascinated the young David Nach- mansohn and greatly influenced his later work. During his early years in Meyerhof's laboratory, the function of phos- phocreatine was unknown, and interest in this compound was very strong. It is therefore not surprising that Nachman- sohn was given the assignment of looking for the relations among phosphocreatine breakdown, lactic acict formation, and the tension cleveloped by muscle during isometric con- traction in anaerobiosis. He also compared the phosphocrea- tine content of cli~erent kinds of muscle, especially muscles slivering in the rapidity of their contraction. He found that rapidly contracting muscles contained much more phospho- creatine than slowly contracting ones, a fact that was consis- tent with, and in a way foretold, the function of phospho- . . . creating In muscular contraction. Nachmansohn viviclly clescribed the atmosphere at Dah- lem in the 1920S2 when several Kaiser-Wilhelm research in- stitutes were concentrated in a relatively small area: the In- stitute of Physical Chemistry, with Haber, l~adenburg, Polanyi, Freun~llich, and Bonhoeffer; the Institute of Chem- istry, with Beckmann, WilIstatter, Otto Hahn, and Lise , . 1 ~ ~ ~ ~ . ~ ~ . ... . ~ ~ . ~ Meatier; the Neuberg Institute of Biochemistry; and the In- st~tute ot Biology, with Meyerhof, Warburg, Gol(lschmidt, Correns, and Hartmann. The young Nachmansohn was par- ticularly stimulates! by the "Haber Colloquia" in which Fritz Haber, the discoverer of the process for conversion of nitro- gen and hydrogen into ammonia, attempted to bridge the ' Nachmansohn Ascribed these influences in an unpublished manuscript entitled "Molecular Aspects of Bioelectricity: An Autobiography." 2 David Nachmansohn, "Molecular Aspects of Bioelectricity"; "Biochemistry As Part of My Life," Annual Review of Biochemistry 41(1972):1-27.

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DAVID NACHMANSOHN 361 gap between physicists, chemists, and biologists so as to pro- mote better unclerstancling and cooperation among them. Nachmansohn credited these monthly colloquia, which were regularly attencled by many members of the various insti- tutes, with having greatly expanclect his scientific and spiri- tual horizons. Like so many others of Jewish origin, Nachmansohn left Germany when Hitler came to power. He was offerer! the opportunity of working at the Sorbonne, and in 1933 estab- lishecl himself in Paris with his wife, Edith, ant! their baby daughter, Ruth. From Paris, Nachmansohn made several vis- its to London, only a few hours away, to attend meetings of the British Physiological Society. As he explainect in the 1972 autobiographical article in the Annual Review of Biochemistry, he could never have anticipated that, by attending those meetings, his scientific interests wouIc] take a new, unex- pectec! turn. He conic! also not have preclictect that this new turn wouIc! determine the direction of his scientific work for the rest of his life. At that time, one of the main topics of discussion in the London meetings was the role of acety~choline in nerve ac- tivity. Following the pioneering work of Otto Loewi and of Dale and his colleagues, Dale proposed that acety~choline acts as a transmitter of nerve impulses across junctions (synapses) between neurons or between nerve and muscle, in contrast to the electric currents that propagate impulses along nerve ant! muscle fibers. This idea was supported by two main lines of observations: (~) the release of acety~choline at synaptic junctions, as judges! by its appearance in the perfusion fluid of certain ganglia, or striated muscle motor enclplates, upon electrical stimulation of the adherent nerves; and (2) the pow- erful stimulating action of acety~choline when applied locally to synaptic junctions, which was in striking contrast to its failure to elicit a response when applied to nerve fibers. Acety~choline was known to be rapidly hy(lrolyzecl by an

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362 BIOGRAPHICAL MEMOIRS enzyme, acetylcholine esterase, which is strongly inhibited by the alkaloid, eserine. In fact, no acetylcholine was found in the perfusion fluid of stimulated ganglia unless the fluid con- tained eserine, an indication that the acetylcholine released by electrical stimulation was rapidly hydrolyzed. It seemed to Nachmansohn that much more knowledge was needler} on the nature, distribution, and concentration of acety~choline esterase in various tissues and that such infor- mation might provide clues to the role of this enzyme in nerve activity. He began work on this problem in Paris in 1936 and soon fount! that acetylcholine esterase was present at high concentrations in many different types of excitable fibers of nerve and muscle ant! in brain tissue, in both ver- tebrates and invertebrates; it was hardly detectable, however, in such organs as the liver or kidney. In aciclition, the con- centration appeared! to be several-fold higher at the neuro- muscular junctions than in the nerve fibers. In his study of the literature on the neuromuscular junc- tion, Nachmansohn came across an article by I. Linhard in which the electric organs of fish were clescribect as moclified muscle fibers, comparable to motor en(lplates, in which the muscular elements were either missing or present only in rudimentary form. He thought it would be of interest to cle- termine the acety~choline esterase content of electric tissue. Nachmansohn had happened to see live Torpedo at the 1937 Paris Worlds Fair; he manager! to procure some for study and found the concentration of acety~choline esterase in the electric organ to be exceedingly high. In his own words, "The result was simply stunning: ~ g of electric tissue (fresh weight) hyclrolyzecl 3-4 g of acetylcholine per hour, although the tissue is 92% water ant! only 3% protein."3 3 David Nachmansohn, "Biochemistry As Part of My Life," Annual Review of Bio- chemistry 45(1972):1-27.

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DAVID NACHMANSOHN 363 The importance of this discovery, which opened the way for the elucidation of the molecular mechanisms involved in the generation of bioelectricity, can hardily be overestimated. In collaboration with Egar Lederer, Nachmansohn soon used the electric organ of the Torpedo fish to purify acety~choline esterase. (This work was reported in a 1939 paper publishect in the Bulletin de la Societe de Chimie Biologique EParis].) In ad- clition, Nachmansohn carries] out experiments on the same organ in June 1939 at the Marine Biological Station at Ar- cachon, near Bordeaux. Together with W. Feldberg (a phar- macologist from Dale's group) ant! A. Fessarc! (an electro- physiologist at the Sorbonne), Nachmansohn provider} the first unequivocal evidence for the electrogenic action of ace- ty~choline; the results were published in 1940 in the Journal of Physiology. His next paper on electric tissue, prepared in colIabora- tion with C. W. Coates and R. T. Cox, was publishecT from Yale in 1941 in the journal of General Physiology. This paper dealt with the correlation between the electrical potential and the acety~choline esterase content of different sections of the electric organ of the electric eel. The use of electric tissue later made possible the crystallization and biochemical char- acterization of acety~choline esterase in Nachmansohn's lab- oratory as well as the isolation of choline acetylase anct the acety~choline receptor. In 1939, John Fulton invitec! Nachmansohn to join his department at Bale University. He stayed in New Haven until 1942, when he mover! to Columbia University and became associated with the Departments of Neurology and Biochem- istry at the College of Physicians and Surgeons. In New Ha- ven, he hac] aIreacly begun to work with the electric organ of the electric eel (which he obtainer! from the New York Aquar- ium) and found not only that the acety~choline esterase con- centration was as high as in Torpedo but that the electric tissue

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364 BIOGRAPHICAL MEMOIRS contained phosphocreatine and ATP in concentrations com- parable to those in striated muscle. Furthermore, the electri- cal discharge was accompanied by phosphocreatine break- down. These observations suggested to him that the energy required for resynthesis of the acety~choline hydrolyzect clur- ing the electrical discharge was supplied by the same pro- cesses that provide the energy required for muscular con- traction, namely ATP ant! phosphocreatine breakdown, lactic acid formation, anti, in the last instance, carbohydrate oxi- clation. Soon after Nachmansohn moved to Columbia, he tested the Plea that electric tissue contains enzymes capable of uti- lizing the energy of ATP for the acetylation of choline, an idea that indeed prover! to be the case. This was, in many respects, key because it was the first time that ATP was found to drive a synthetic reaction other than through phosphory- lation. Nachmansohn soon found that choline acetylase, the enzymeks) responsible for the acetylation reaction, requires! a coenzyme because the activity of the acetylase-containing extracts was lost after dialysis ant! was restorer! by the addi- tion of boiled enzyme. The identity of this coenzyme re- mainec! obscure, however, until Lipmann and coworkers found that an enzyme catalyzing the formation of acetyIsul- fonamicle from ATP, acetate; and sulfonamicle also required a coenzyme (coenzyme A, or CoA for short) for activity. They elucidates! the structure of this coenzyme in 1947. The discovery of choline acetylase was published by Nach- mansohn ant! Machaclo in the journal of Neurophysiology in ~ 943. Ironically, three journals (Science, Journal of Biological Chemistry, and Proceedings of the Society for Experimental Biology and Medicine) refused to publish this eminent and trail- blazing biochemical paper. The reviewers apparently could not believe that ATP would participate in reactions other than phosphorylations. In retrospect, they cannot be blamed

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DAVID NACHMANSOHN 365 for their skepticism because Nachmansohn's finding was to- tally unexpected. Acetylation was eventually found to result from the coupling of two reactions: (~) ATP + acetate + CoA ~ AMP + inorganic pyrophosphate + acetyI-CoA; and (2) acety! CoA + choline (or sulfonamicle) ~ CoA + acetyI- choline (or acetyI-sulfonamide). Work proceeded in a number of laboratories on the To- calization of acety~choline esterase using biochemical assays (e.g., of the extrucled axoplasm and the sheath of the giant axon of the squid) and electron microscopic observations. The results of these studies macle it appear highly probable that the enzyme was a component of excitable membranes everywhere not only of synaptic membranes but also of the membranes of axons anct conducting fibers in general. In his Harvey Lecture entities! "Metabolism and Function of the Nerve Cell" (cleliverec} in 1953 and publishecl in 1955), Nach- mansohn acivanced the view that acety~choline acts as a signal recognizes! within the membrane by an acety~choline recep- tor protein; this results in a conformational change that leacis to increased local permeability to ions and membrane depo- larization, thus generating an action potential an idea that prover! to be correct. Ernest Schoffeniels, in Nachmansohn's laboratory, was able to isolate the electroplax, the single- celled elementary unit of electric tissue, which was found to be extremely rich in acety~choline esterase ant] receptor protein. If one considers that receptors are now recognized as the initial elements in the response of all cells to specific stimuli and that the concept originated with the acety~choline recep- tor, it becomes evident that Nachmansohn set a biological lancimark. This was also the first neurotransmitter receptor to be characterizes! biochemically, thanks to its accessibility in the vertebrate muscle endplate and its abundance in the spe- cialize{l electric organ of electric fish.

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366 BIOGRAPHICAL MEMOIRS The finding that acety~choline esterase activity is very high in excitable membranes including nerve fiber mem- branes ant! that the localization of the acety~choline recep- tor is the same as that of the esterase led Nachmansohn to postulate that the nerve impulse is generated through a de- polarization of the membrane by acety~choline releaser! by the stimulus from an inactive complex with protein. The ac- tion potential thus generated wouIc! give rise to the release of acety~choline in adjacent sites leading to propagation of the current along the fiber by successive acety~choline bursts. Rapid hycirolysis of acety~choline by the esterase anct the ion pump mechanism coupled to the breakdown of ATE wouIc! restore membrane polarization at each point as the impulse travelled down the fiber. Nachmansohn's theory, aIreacly suggested in earlier pub- lications, was presenter! in cletai! in his book, Chemical and Molecular Basis of Nerve Activity, first publisher} in 1959. A revised edition appeared! in 1975 with considerably more ex- perimental support for his Fleas. The revised edition also container! two supplements, one by Nachmansohn on the properties and functions of proteins of the acety~choline cycle in excitable membranes anct one by E. Neumann that presented a molecular mode} for bioelectricity. Nachmansohn's ideas, however, were not accepted by neu- rophysiologists. His molecular theory of nerve conduction is still highly controversial, despite the fact that a variety of experiments by Nachmansohn and others (detailec! in the 1975 edition of his book) would appear to nullify objections to his theory. The fact, for instance, that acety~choline when appliecl locally stimulates at synaptic junctions or motor end- plates but has no effect on axons, may be explainec! by im- permeability of the intact axonal membrane to quaternary ammonium ions. Acety~choline, therefore, stimulates axons when applied at the Ranvier node sites where the myelin

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DAVID NACHMANSOHN 395 of axonal conduction by curare. Biochim. Biophys. Acta, 75:116-28. With W. H. Harrison. Ascorbic acid-induced fluorescence of a noradrenaline oxidation product. Biochim. Biophys. Acta, 78: 705-10. With H. B. Higman, T. R. Podleski, and E. Bartels. Apparent dis- sociation constants between carbamylcholine, d-tubocurarine and the receptor. Biochim. Biophys. Acta, 75:187-93. With T. R. Podleski and E. Bartels. Difference between tetracaine and d-tubocurarine in the competition with carbamylcholine. Biochim. Biophys. Acta, 75:387. With W.-D. Dettbarn. Hydrolysis of choline esters by invertebrate nerve fibers. Biochim. Biophys. Acta, 77:430-35. With F. C. G. Hoskin. Stereospecificity in the reactions of acetyl- cholinesterase. Proc. Soc. Exp. Biol. Med., 113:320-21. The chemical basis of Claude Bernard's observations on curare. Biochem. Z., 338:454-73. With F. C. G. Hoskin and C. von Eschen. Stimulation by quinones of initial pentose phosphate pathway steps in soluble brain preparations. Arch. Biochem. Biophys., 103: 111-16. 1964 With P. Rosenberg, E. A. Machey, H. B. Higman, and W.-D. Dett- barn. Choline acetylase and cholinesterase activity in dener- vated electroplax. Biochim. Biophys. Acta, 82:266-75. With H. B. Higman, R. R. Podlewski, and E. Bartels. Correlation of membrane potential and K flux in the electroplax of Electro- phorus. Biochim. Biophys. Acta, 79:138-50. With H. C. Lawler. The preparation of a soluble acetylcholinester- ase from brain. Biochim. Biophys. Acta, 81:280-88. Chemical control of ion movements across conducting membranes. In: Symposium on New Perspectives in Biology, BBA Library vol. 4, ed. M. Sela, pp. 176-204. Amsterdam: Elsevier. With F. C. G. Hoskin and P. Rosenberg. Alteration of acetylcholine penetration into, and effects on, venom-treated squid axons by physostigmine and related compounds. ~. Gen. Physiol., 47: 1117-27. With W.-D. Dettbarn. Action of acetylcholine and curare on lobster axons. Life Sci., 12 :910 -16. With E. Bartels and T. R. Podleski. Action of nicotine on the elec-

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396 BIOGRAPHICAL MEMOIRS troplax and difference of potency between ionized and union- ized forms. Biochim. Biophys. Acta, 79:511-20. With W.-D. Dettbarn and P. Rosenberg. Restoration by a specific chemical reaction of "irreversibly" blocked axonal electrical ac- tivity. Life Sci., 3:55-60. With W.-D. Dettbarn. Distinction between action on acetylcholin- esterase and on acetylcholine receptor in axons. Biochim. Bio- phys. Acta, 79:629-30. With F. A. Davis. Acetylcholine formation in lobster sensory axons. Biochim. Biophys. Acta, 88:384-89. With H. D. Markman, P. Rosenberg, and W.-D. Dettbarn. Eye drops and diarrhea: Diarrhea as a first symptom of phospholine iodide toxicity. New Engl. I. Med., 271:197-99. With P. Rosenberg and W.-D Dettbarn. Increased acetylcholines- terase activity of intact cells produced by venoms. Biochem. Pharmacol., 13: 1157-65. Perspectives in research on the molecular basis of nerve activity. In: Tribute to ~ A. Engelhardt. Molecular Biology: Problems and Per- spectives, pp. 282-303. Moscow: Academy of Sciences of the USSR. Chemical control of bioelectric currents in membranes of conduct- ing cells. I. M. Sinai Hosp. N.Y., 31 :549-83. With A. Karlin. The association of acetylcholinesterase and of membrane in subcellular fractionations of the electric tissue of Electrophorus. ]. Cell Biol., 25: 159-69. With F. C. G. Hoskin. Stimulation of respiration and inhibition of glycolysis in lobster axons by quinones. Arch. Biochem. Bio- phys., 108:506-9. With A. M. Gold and D. Fahrney. Sulfonyl fluorides as inhibitors of esterase. II. Formation and reactions of phenylmethanesul- fonyl cx-chymotrypsin. Biochemistry, 3:783 -91. With I. Steinhardt and S. Beychok. Interaction of proteins with hydrogen ions and other small ions and molecules. In: Proteins, vol. 2, ed. H. Neurath, pp. 139-304. New York: Academic Press. With S. Beychok. Effect of ligands on the optical rotatory disper- sion of hemoglobin. Biopolymers, 3 :575-84. With S. Beychok and G. D. Fasman. Circular dichroism of poly-L- tyrisine. Biochemistry, 3: 1675 -78. . , . .. ~ . .

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DAVID NACHMANSOHN 1965 397 With W.-D. Dettbarn, H. B. Higman, E. Bartels, and T. R. Podleski. Effects of marine toxins on electrical activity and K ion efflux of excitable membranes. Biochim. Biophys. Acta, 94:472-78. With S. Beychok. On the problem of isolation of the specific ace- tylcholine receptor. Biochem. Pharmacol., 14:1249-55. With G. D. Webb. Affinity of benzoguinonium and ambenonium derivatives for the acetylcholine receptor, tested on the electro- plax, and for acetylcholinesterase in solution. Biochim. Bio- phys. Acta, 102: 172-84. With E. Breslow, S. Beychok, K. Hardman, and F. R. N. Gurd. Rel- ative conformations of sperm whale metmyoglobin and apo- myoglobin in solution. }. Biol. Chem., 240:340-49. With H. Greenberg. Studies of acid phosphomonoesterase and their inhibition by diisopropylphosphorofluoridate. J. Biol. Chem., 240:1639-46. With M. Brzin, W.-D. Dettbarn, and P. Rosenberg. Acetylcholines- terase activity per unit surface of conducting membranes. I. Cell Biol., 26:353-64. With A. de Roetth, Jr., W.-D. Dettbarn, P. Rosenberg, i. G. Wilen- sky, and A. Wong. Effect of phospholine iodide on blood cholinesterase levels of normal and glaucoma subjects. Am. I. Ophthalmol., 59:586 -91. With M. Brzin, W.-D. Dettbarn, and P. Rosenberg. Penetration of enostigmine, physostigmine and paraxon into the squid giant axon. Biochem. Pharmacol., 14:919-24. With P. Rosenberg and W.-D. Dettbarn. Cholinesterase activity of rabbit aorta. Life Sci., 4:567-72. With A. Karlin and N. I. A. Overweg. An inhibitor of oxytocin from the urinary bladder of the toad, Bufo marinus. Nature (London), 207: 1401-2. With E. Bartels. Relationship between acetylcholine and local anes- thetics. Biochim. Biophys. Acta, 109:194-203. With F. C. G. Hoskin and P. Rosenberg. Penetration of sugars, ste- roids, amino acids and other organic compounds into the in- terior of the squid giant axon. }. Gen. Physiol., 49:47-56. Chemische Kontrolle des Permeabilitaetszyklus. Erregbarer Mem- branen Wahrend Elektrischer Aktivitat. Nova Acta Leopold., 30:207-33.

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398 BIOGRAPHICAL MEMOIRS With P. Rosenberg and W.-D. Dettbarn. Use of venoms in testing for essentiality of cholinesterase in conduction. In: Animal Toxin. Oxford: Pergamon Press. With E. Bartels. Molecular structure determining the action of lo- cal anesthetics on the acetylcholine receptor. (Ochoa Anniver- sary Volume.) Biochem. Z., 342:359-74. With P. Rosenberg and F. C. G. Hoskin. Penetration of acetylcho- line into squid giant axons. Biochem. Pharmacol., 14: 1765-72. With P. Rosenberg. Effects of venoms on the squid giant axon. Toxicon,3:125-31. Chemical control of the permeability cycle in excitable membranes during activity. Isr. J. Med. Sci., 1: 1201-19. 1966 Sechs deutschjuedische Wissenschaftler: Haber, Willstatter, Neu- berg, Meyerhof, Bergmann and Schonheimer. Das Neue Israel (Zurich), 18:826 -33. Chemical forces controlling permeability changes of excitable membranes during electrical activity. In: Nerve As A Tissue, ed. K. Rodahl, pp. 141-61. New York: McGraw-Hill. Role of acetylcholine in neuromuscular transmission. (Presented at a symposium on myasthenia gravis.) Ann. N.Y. Acad. Sci., 135: 136-49. With H. G. Mautner, E. Bartels, and G. D. Webb. Sulfur and selen- ium isologs related to acetylcholine and choline. IV. Activity in the electroplax preparation. Biochem. Pharmacol., 15: 187-93. With A. K. Prince. Spectrophotometric study of the acetylcholin- esterase-catalyzed hydrolysis of 1-methyl-acetoxyquinolinium iodides. Arch. Biochem. Biophys., 113:195-204. With A. K. Prince. A sensitive fluorometric procedure for the de- termination of small quantities of acetylcholinesterase. Bio- chem. Pharmacol., 15:411-17. With F. C. G. Hoskin. Anaerobic glycolysis in parts of the giant axon of squid. Nature (London), 210:856 -59. With S. H. Bryant and M. Brzin. Cholinesterase activity of isolated giant synapses. J. Cell. Physiol., 68: 107-8. With P. Rosenberg, W.-D. Dettbarn, and M. Brzin. Acetylcholine and choline acetylase in squid axon, ganglia, and retina. Nature (London), 210:858 - 59. With F. C. G. Hoskin, P. Rosenberg, and M. Brzin. Reexamination

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DAVID NACHMANSOHN 399 of the effect of DFP on electrical and cholinesterase activity of squid giant axon. Proc. Natl. Acad. Sci. USA, 55:1231-35. Properties of the acetylcholine receptor protein analyzed on the excitable membrane of the monocellular electroplax prepara- tion. In: Current Aspects of Biochemical Energetics: Lipmann Dedi- catory Volume, ed. N. O. Kaplan and E. P. Kennedy, pp. 145-72. New York: Academic Press. With A. de Roetth, ir., A. Wong, W.-D. Dettbarn, P. Rosenberg, and i. G. Wilensky. Blood cholinesterase activity in glaucoma patients treated with phospholine iodide. Am. J. Ophthaln~ol., 62:834-38. Chemical control of the permeability cycle in excitable membranes during electrical activity. Isr. I. Med. Sci., 1:201-19. With W.-D. Dettbarn and P. Rosenberg. Effect of ions on the efflux of acetylcholine from peripheral nerve. l. Gen. Physiol., 50: 447-60. With P. Rosenberg and H. G. Mautner. Similarity of effects of ox- ygen, sulfur, and selenium isologs on the acetylcholine receptor in excitable membranes on junctions and axons. Proc. Natl. Acad. Sci. USA, 55:835-38. The biochemical basis of cholinergic drugs. In: Biochemistry and Pharmacology of the Basal Ganglia, ed. E. Costa, L. J. Cote, and M. D. Yahr, pp. 1-15. Hewlett, N.Y.: Raven Press. With M. Brzin, V. M. Tennyson, and P. E. Duffy. Acetylcholinester- ase in frog sympathetic and dorsal root ganglia: A study by electron microscope cytochemistry and microgassometric anal- ysis with the magnetic diver. J. Cell Biol., 31:215-42. With G. D. Webb, W.-D. Dettbarn, and M. Brzin. Biochemical and pharmacological aspects of the synapses of the squid stellate ganglion. Biochem. Pharmacol., 15: 1813-19. With A. Karlin and E. Bartels. Effects of blocking sulfhydryl groups and of reducing disulfide bonds on the acetylcholine-activated permeability system of the electroplax. Biochim. Biophys. Acta, 126:525-35. With T. R. Podleski. Similarities between active sites of acetylcho- line-receptor and acetylcholinesterase with quinolinium ions. Proc. Natl. Acad. Sci. USA, 56:1034-39. With M. Brzin. The localization of acetylcholinesterase in axonal membranes of frog nerve fibers. Proc. Natl. Acad. Sci. USA, 56: 1560-63.

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400 BIOGRAPHICAL MEMOIRS 1967 With P. Rosenberg and E. Bartels. Drug effects on the spontaneous electrical activity of the squid giant axon. I. Pharmacol. Exp. Ther., 155:532. With W.-D. Dettbarn. The acetylcholine system in peripheral nerve. (Presented at a symposium on cholinergic mechanism.) Ann. N.Y. Acad. Sci., 144:483. With M. Brzin and W.-D. Dettbarn. Cholinesterase activity of nodal and internodal regions of myelinated nerve fibers of frog. I. Cell Biol., 32:577. With P. Rosenberg and H. G. Mautner. Acetylcholine receptor: Similarity in axons and junctions. Science, 155: 1569. With W. Leuzinger and A. L. Baker. Acetylcholinesterase. I. Large scale purification, homogeneity, amino acid analysis. Proc. Natl. Acad. Sci. USA, 57:446. 1968 With }.-P. Changeux, W. Leuzinger, and M. Huchet. Specific bind- ing of acetylcholine to acetylcholinesterase in the presence of eserine. FEBS (Fed. Eur. Biochem Soc.) Lett., 2:77. 1969 With W. Leuzinger. Structure and function of acetylcholinesterase. In: Progress in Brain Research, ed. K. Ackert and P. G. Waser, vol. 31, pp. 241-45. Amsterdam: Elsevier. With E. Bartels. Organophosphate inhibitors of acetylcholine- receptor and -esterase tested on the electroplax. Arch. Bio- chem. Biophys., 133: 1-10. With W. l. Deal and B. F. Erlanger. Photoregulation of biological activity by photochromic reagents. III. Photoregulation of bioe- lectricity by acetylcholine receptor inhibitors. Proc. Natl. Acad. Sci. USA, 64:1230 - 34. 1970 Proteins in bioelectricity. In: Protein Metabolism of the Nervous System, ed. A. Lajtha, pp. 313-33. New York: Plenum Press. Proteins in bioelectricity. In: Colloquium Macromolecules, Biosyn- thesis and Function, vol. 21, ed. S. Ochoa, C. F. Heredia, and C.

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DAVID NACHMANSOHN 40 Asensio, pp. 321-28. FEES Proceedings of the Sixth Meeting, Madrid, April 7-11, 1969. London and New York: Academic Press. With E. Bartels, W. Deal, A. Karlin, and H. G. Mautner. Affinity oxidation of the reduced acetylcholine receptor. Biochim. Bio- phys. Acta, 203 :568-71. Proteins in excitable membranes. Their properties and function in bioelectricity. Science, 168: 1059-66. With W.-D. Dettbarn, E. Bartels, F. C. G. Hoskin, and F. Welsch. Spontaneous reactivation of organophosphorus inhibited elec- troplax cholinesterase in relation to acetylcholine induced de- polarization. Biochem. Pharmacol., 19:2949-55. With H. G. Mautner and E. Bartels. Interactions of p-nitrobenzene diazonium fluoroborate and analogs with the active sites of acetylcholine-receptor and -esterase. Proc. Natl. Acad. Sci. USA, 67:74-78. 1971 With E. Bartels. Depolarization of electroplax membrane in cal- cium-free Ringer's solution. I. Membr. Biol., 5:121-32. With E. Bartels, N. H. Wassermann, and B. F. Erlanger. Photo- chromic activators of the acetylcholine receptor. Proc. Natl. Acad. Sci. USA, 68:1820-23. With E. Bartels and T. L. Rosenberry. Snake neurotoxins; effects of disulfide reduction on interaction with electroplax. Science, 174: 1236-37. Similarity of chemical events in conducting and synaptic mem- branes during electrical activity. Proc. Natl. Acad. Sci. USA, 68:3170-72. 1972 Bioenergetics and properties and function of proteins in excitable membranes associated with bioelectrogenesis. In: Molecular Bioenergetics and Macromolecular Biochemistry (Meyerhof Sympo- sium, Heidelberg, July 1970), ed. H. H. Weber, pp. 172-93. Heidelberg: Springer-Verlag. Biochemistry as part of my life. (Prefatory chapter.) In: Annual Review of Biochemastry, pp. 1-28. Stanford: Annual Reviews. With T. L. Rosenberry, H. W. Chang, and Y. T. Chen. Purification of acetylcholinesterase by a~nity chromatography and deter-

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402 BIOGRAPHICAL MEMOIRS mination of active site stoichiometry. I. Biol. Chem., 247: 1555- 65. With E. Bartels and P. Rosenberg. Correlation between electrical activity and phospholipid splitting by snake venom in the single electroplax. J. Neurochem., 19: 1251-65. With I. Del Castillo, E. Bartels, and }. A. Sobrino. Microelectro- phoretic application of cholinergic compounds, protein oxidiz- ing agents and mercurials to the chemically excitable mem- brane of the electroplax. Proc. Natl. Acad. Sci. USA, 69:2081- 85. 1973 The neuromuscular junction. The role of acetylcholine in excitable membranes. In: The Structure and Function of Muscle, vol.3, Phys- iology and Biochemistry, ed. G. H. Bourne, pp.32-117. New York: Academic Press. With E. Bartels and T. L. Rosenberry. Modification of electroplax excitability by veratridine. Biochim. Biophys. Acta, 298:973- 85. With E. Neumann and A. Katchalsky. An attempt at an interpre- tation of nerve excitability. Proc. Natl. Acad. Sci. USA, 70:727- 31. Proprietes et fonction des proteines dans les membranes excitables. Un modele integrate de l'excitabilite nerveuse. Biochimie, 55: 365-76. 1974 Importance of structure and organization for the chemical reac- tions in excitable membranes. In: Central Nervous System: Studies on Metabolic Regulation and Function, ed. E. Genazzini and H. Herken, pp. 121-37. Heidelberg: Springer-Verlag. Organophosphate insecticides. A challenging problem of environ- ment control. Rehovot, 7:4-6. With E. Neumann. Properties and function of proteins in excitable membranes. An integral model of nerve excitability. (Presented at the New York Academy of Sciences Conference on the Mech- anism of Energy Transduction of Biological Systems. Ann. N.Y. Acad. Sci., 227:275-84. With Y. T. Chen, T. L. Rosenberry, and H. W. Chang. Subunit het-

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DAVID NACHMANSOHN 403 erogeneity of acetylcholinesterase. Arch. Biochem. Biophys., 161 :479-87. With H. W. Chang. Purification and characterization of acetylcho- line receptor-I from Electrophorus electricus. Proc. Natl. Acad. Sci. USA, 71:2113-17. With T. L. Rosenberry, Y. T. Chen, and E. Bock. Structure of 11 S acetylcholinesterase. Subunit composition. Biochemistry, 13: 3068-79. With E. Neumann. Nerve excitability- towards an integrating con- cept. In: Biomembranes, ed. L. A. Manson. New York: Plenum Press. Biochemical foundation of an integral model of nerve excitability. (Presented at 25. Mosbacher Colloquium der Gesellschaft fuer Biologische Chemie, April 25 - 27.) In: Biochemistry of Sensory Functions, ed. L. Jaenicke, pp. 431-64. Berlin/Heidelberg/New York: Springer-Verlag. Chemical and Molecular Basis of Nerve Activity, 2d. rev. ed. including: Suppl. 1, "Properties and Function of the Proteins of the Ace- tylcholine Cycle in Excitable Membranes," and suppl. 2 (by E. Neumann), "Towards a Molecular Model of Bioelectricity." New York: Academic Press. 1976 Highlights of a friendship. In: Repections on Biochemistry, pp. 405- 11. London: Pergamon Press. The transduction of chemical into electrical energy. Proc. Natl. Acad. Sci. USA, 73:82-85. 50 years ago: Acetylcholine its role in nerve excitability. Trends Biochem. Sci., 1:237-38. 1977 Nerve excitability: Transition from descriptive phenomenology to chemical analysis of mechanisms. (Herken Festschrift.) Klin. Wochenschr., 55:715-23. Nerve excitability: From descriptive phenomenology to molecular interpretation. In: P. ~ S. Biomedical Sciences Symposia, Arden House Conference on Neuronal Information Transfer, ed. H. Vogel.

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404 BIOGRAPHICAL MEMOIRS FURTHER READINGS First Conference of Physicochemical Mechanism of Nerve Activity. New York: Academy of Sciences, 1946. Metabolism and Function: Anniversary Volume in Honor of Otto Meyer- hof. Biochim. et Biophys. Acta. Amsterdam: Elsevier Publishing Co., 1950. First Conference on Nerve Impulse. New York: Josiah Macy, fir., Foun- dation, 1950. Second Conference on Nerve Impulse. New York: Josiah Macy, fir., Foundation, 1951. Fourth Conference on Nerve Impulse. New York: Josiah Macy, Jr., Foundation, 1953. Fifth Conference on Nerve Impulse. New York: Josiah Macy, fir., Foun- dation, 1954. Ion Transport Across Membranes. (Symposium at Columbia Univer- sity.) New York: Academic Press, 1954. Chemical and Molecular Basis of Nerve Activity. (Monograph.) New York: Academic Press, 1959. Second Conference on Physicochemical Mechanism of Nerve Activity. New York: New York Academy of Sciences, 1959. Molecular Biology. Elementary Process of Nerve Conduction and Muscle Contraction. New York: Academic Press, 1960.

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