Collection of correspondence from various scientists presenting their arguments, and collaboration on research into various aspects of the analysis of action current curves, muscle heat and nerve heat, includes letters from: Ralph S. Lillie, Ralph W. Gerard, Philip Bard, Archibald V. Hill (Nobel Prize, 1922) and A. C. Downing, both typescript and manuscript, dated 1928-1931. Along with related material.

        The correspondents include:

        Ralph Stayner Little, biologist, was born August 8, 1875 in Toronto, Canada. He received i=his B.A. from the University of Toronto in 1896, and briefly attended graduate courses at the University of Michigan before going on to obtain his Ph.D. at the University of Chicago in 1901. From 1902 to 1924 he held posts as instructor and research assistant at institutions including the Carnegie Institute and Johns Hopkins University. In 1924, Lillie was appointed Professor of General Physiology at the University of Chicago, a post he held until his retirement in 1940. He served as a Professor Emeritus from then until his death in 1952. Lillie’s specialty was research into the fundamental properties of life, and the physiology of stimulation, growth and cell division. He was also noted for his work on the physiological effects of radiation, and for his views on the philosophical aspects of biology.

       Ralph Waldo Gerard LLD DLitt (1900-1974) was an American neurophysiologist and behavioral scientists known for his wide-ranging work on the nervous system, nerve metabolism, psycho-pharmacology, and the biological basis of schizophrenia.

        Philip Bard (1898-1977) was a doctoral student of Walter Cannon’s, and together they developed a model of emotion called the Cannon-Bard Theory. Cannon was an experimenter who relied on studies of animal physiology. Through these studies, Cannon and Bard highlighted the role of the brain in generating physiological responses and feelings; a role that is important in their explanation of emotion experience and production.

        Archibald Vivian Hill CH OBE FRS (1886-1977) known as A. V. Hill was a British physiologist, one of the founders of the diverse disciplines of biophysics and operations research. He shared the 1922 Nobel Prize in Physiology or Medicine for his elucidation of the production of heat and mechanical work in muscles.

       Archibald V. Hill – Biographical. NobelPrize.org. Nobel Media AB 2020. Fri. 6 Nov 2020. <https://www.nobelprize.org/prizes/medicine/1922/hill/biographical/>

A.  C. Downing, a British scientific instrument maker, active 1920-1960.

       William Ruthrauff Amberson (1915-1977), was a professor at the University of Tennessee Medical School at Memphis, 1930-1937, advisor to the Southern Tenant Farmers’ Union and trustee of the Delta and Providence cooperative farms in Mississippi. Amberson later taught at the University of Maryland School of Medicine in Baltimore 1939-1959, and the Marine Biological Laboratory in Woods Hole, Mass., after 1960.

       Sample Quotes:

      Three Corners, Ivy Bridge S. Devon, Aug. 29, 1928, A. V. Hill, to William R. Amberson, Autograph Letter Signed, two pages

       “Dear Amberson,

1.     No, I do not know of any young Englishman who would like your job & would be competent to fill it properly. We have rather a scanty supply, I fear, at present of promising young men There might be some at Oxford or at Manchester. Ask C.G. Douglas of Oxford or H. S. Roper of Manchester for recommendations.

2.     Your curves are very interesting. There is no doubt of a considerable “delayed” element even in your nerve in AIR, & of course a huge delayed part in CO2 mixture (only 5% corresponding presumably to the nerve’s own environment too) You ought to be able to analyse such curves: if you find it difficult I suspect it is because your galvanometer is not quite damped. I notice in your “physical” curve (presumably with the nerve in circuit to provide the usual resistance – otherwise damping alters) that there is a return to the negative side of zero – is this not a sign of underdamping? Underdamped curves we have always found difficult to analyse. Moreover an analysis of a two-phase curve (+ at first and – after – of your “after positivity” in all) is always more difficult than that of a simple plane curve. Still an analysis should give the order & size of the delayed current , if your records are good enough. Probably it would  merely show this [small sketch in letter] however It is certainly striking that the “retention” under more “normal” conditions (expired air) is so large You could CERTAINLY get an approximate analysis of the expired air curve. The underdamping ought not completely to spoil that. The differ betwn “live” & “conted” is relatively larger than Hartree & I have had to deal with.

3.     The failure to “recover”: can the “retention” be analogous to the after discharge  in a veratine contraction, where the second of the stimuli provokes far less after discharge than the first. I suspect this is the cause – much retention for the first shock, less retention for the second, probably still less for a third. Can you try 3? This explanation would, in its effect be indistinguishable from yours.

4.     I shall be glad to see all your staff next week. We are very pleased to hear that you are coming down here. Yes – we shall be very glad to see you on Thursday. Parkinson will tell you all about us, & how to get to us. You ought to have a walk on the moor just to see what it is like, & if you will come out early I will take you up there. I shall probably see you in the Lab before Thursday anyway, but if not let us know what time, morning or afternoon, you will arrive here.

5.     Of course I shall be very glad to have Downing’s name on the title of the paper. His skill is such an essential part of the various things we are now all able to do that I am delighted that it should be recognized.

                                                                                                                      Yours very sincerely

                                                                                                                      A.V. Hill”

        Chicago, University of Chicago, November 1, 1928, Ralph W. Gerard, to William R. Amberson

        “My dear Amberson,

             I thank you heartily for your two interesting and friendly letters. From the slightly apologetic tone of your second one, I am afraid that mine must have seemed most scolding. Really, though, it never occurred to me that I had any claim to a field or that you might be trespassing; and I was mainly anxious to exchange information and ideas with a kindred soul in the wilderness of endocrines and kymographs.

     I can picture your early trouble with A.V., and sympathize. As you know, he is at times quite ruthless in the give and take of work, which often hurts even though one may be convinced of his good intentions. Incidentally, the paper of Zottermann’s on action current recovery to which you referred has just appeared in the October Jour. Of Physiology.

     The work you have been doing on analysis of action current curves sounds first-rate. It’s a never-to-be-forgotten experience, running those arithmetic analyses, isn’t it? The early negative and later positive remainders are surely significant, especially the changes in them with relatively physiological environmental changes. Have you been able to correlate them at all with the heat and chemical picture? Can the negative remainder mean a failure or slowing of the restorative reactions following the conductive break-downs, and the positive one represent “anabolism” a la Gaskell? But the time reactions don’t seem quite right. And why none in rested nerve?

      As to the changes in and after nitrogen, I’ve wondered some in connection with my experiments whether changes in electrical resistance in various parts of the nerve and sheath might be the important factor rather than changes in the potentials developed. Though I don’t believe this is the case I haven’t done anything to prove the point. My experiments were directed primarily in N2 , or at least to segregate the factors; failure of one fibre after another, prolonged the refractory period and decreased response in each fibre. To this end I led off in turn from several electrodes as follows: [small sketch]

1 and 4 are in O2 , 2 and 3 in N2 . A fall in 2 and 3 before 4 would rule out the first factor. If this fall occurred no earlier at 300 shocks a second than at 100 it would rule out the second.

       As regards the galvanometer deflection analyses I think at last that you are absolutely correct, not only because you have been able to demonstrated in test problems successful results, but because it immediately occurred to me when I saw Hartree’s letter, using an instantaneous control it should obviously start at the center of the block rather than at the beginning. Since this procedure gives the same results as your longer or built-up control, they must both be right.

      I remember offering to make some experimental determinations for you though I do not recall promising muscle heat. If I did I was very reckless since I have not a muscle thermopile. None the less I will try in the near future to rig up a photographic recording system and put some muscles in my nerve thermopile, and I do not see why I should not be able to give you some results you want.

     I congratulate you on working through your method of analysis so successfully. I am returning the various results and prints on this subject at once. If you would like me to return the nitrogen data to you, in case you have not a copy, let me know. I think this about covers things. I hope you will not be overworked because of departmental sickness and that the various misfortunes that have hit Goldsmith and Bazett are passing away …”

        Chicago, The University of Chicago, Dept. of Physiology, Ralph W. Gerard, to William R. Amberson, Dept. of Physiology, University of Pennsylvania

        “My dear Amberson,

                Your darned paper cost me the whole of New Year’s day doing calculations and thinking.

                 I must say that your numerical results certainly look good, much better than I would have expected, and your point may be perfectly valid; even if so I would suggest, before you send the paper in for publication, that you make your “attack” on Hartree a little milder and I am sure Hill would be hurt if you left him out even of a criticism.

                The only concrete criticism I have thought of lies in your major assumption, namely, that a synthetic control curve built up by adding short control curves at regular intervals corresponds to the actual curve that would have been obtained for the heating of a longer time, corresponding to the synthetic control. Of course, if this assumption is itself not valid then all your further calculations are subject to question. That this assumption must be made with considerable care is shown by the results in my paper on Two Phases of Nerve Heat. In this case I had a radiation thermopile in the system and the results I got may have all been due to this factor, but, as I told you, the same type of sical by a radiation thermopile should obey the differential equations very well. Now, the point I make is illustrated on p. 353 of my paper, where you see that the heat curve for 10 seconds does not agree perfectly with the synthetic curve of five two-seconds or two five-seconds curves.

              Undoubtedly, you are sending a copy of this paper to Hill for criticism. I strongly suspect that you would be happier in the long run if you held up this paper until you could back it up with some additional experiments of your own. If I ever reach the stage of getting the apparatus set up I would be glad to do this for or with you, and, of course, I think that you must limit your criticisms to the analyses of muscle heat since the only analyses of nerve heat are those in the “Two Phase” paper in which any error in the analyses due to a too short control is certainly small.

              I am returning your manuscript and also enclosing for your consideration some analyses I made on one experiment taken at random from those on which that paper is based. The analysis is very crude, as you will see, and I have not even checked over for numerical errors. The results, however, are about what might be expected. Here again the synthetic control curve does not agree with the observed control curve but the results of the analyses of a 10 second stimulation or warning by the observed two second control seem to be better than those with the synthesized control or with the observed 4 second control. If you can use any of this data you are welcome to it and if, or when, you are done with it you might send it back for I would like to have the record …”

        London, University of London, University College, February 3, 1929, A. C. Downing to William R. Amberson

        “My dear Dr. Amberson,

               … I have some news for you. I am coming to the Congress in August. AV seems to think I can give a demonstration with a galvanometer and other gadgets, so I shall look forward greatly to seeing you there. I am sorry that the other proposition did not materialize AV’s proposal was somewhat in excess of what I should have asked for myself, so don’t think it came from me. I told you, I think what I was prepared to take the trip for, never mind, perhaps some other time we can discuss matters if any, when we meet.

              With regard to the other matter nothing so far as I know has been settled, but I hope I shall not swell the ranks of the unemployed when the present session terminates. I am doing my best to obtain a degree, but even if I ever do, I feel that it will not help matters much, and I could make as much cash making instruments. I have little time for studies at the moment, and my hands are working better than my brain.

              I shall be delighted to meet your demand for quartz fibres. Shall I risk sending you some, or will you wait until I can bring them?

              I have told you, I think, that your system is out of date. With some proper treatment of some new steel, I can more than double your sensitivity for a given deflection time, and what is more important, give you an absolutely reliable zero. Would you like me to make you a new system and bring it along? I shall be making some when we get some better light. I had to give it up at a most interesting stage as my eyes failed to stand the strain any longer. …”

        Chicago, The University of Chicago, Physiology Dept., March 20, 1929, Ralph S. Lillie, to William R. Amberson, University of Pennsylvania

        “Dear Amberson,

             I read the two papers with much interest. They show persistent changes in potential very distinctly, and they remined me of effects I have often observed in passive iron wires. In particular the after positivity resembles the over-shooting of the zero level of potential always shown when a passive steel wire in 70-80% nitric acid, containing also an indifferent electrode preferably another steel wire (both connected to a voltmeter with central zero), is activated by touching with zinc. There is an excursion to about 0.7 volts followed by a return past the zero, usually of .05 volt or less. This variation from the original level of potential persists for a good many seconds if the acid is left undisturbed, but disappears at once on stirring. It is apparently a polarization effect dependent on a change in the composition of the layer of electrolyte in contact with the metal. The effect also shows well with a string galvanometer, but I have no tracings at present. I have never seen any evidence of a persistent difference in the potential of the wire during the relative refractory phase; if there is such a difference it is slight. The return to the zero level (and beyond) after a single activation is at first rapid and then quite gradual. I enclose part of a strip of a string galvanometer record showing this. In 65% (vol.) HNO3

        The whole variation lasts about a second in pure iron wire (Armco). In steel (piano) wire, where the refractory period lasts some minutes, the potential of the wire remains the same as during the fully reactive phase. In this case I believe the thickness of the oxide film determines the reactivity or transmissivity; but the potential would presumably not be influenced by variations in thickness above a certain minimum. Of course if the film becomes discontinuous the effect is shown in the potential. Just what relation these general conditions would have to those in nerve is not quite easy to say. There are possibilities of variation in both composition and structure of the surface film in nerve which would not exist in passive iron; but a consideration of the simpler model may perhaps suggest some of the factors concerned. In nerve the effect of CO2  and of slight acidity is remarkable; perhaps H-ions influence both the state of the film (e.g. its permeability) and the membrane potential independently, and the observed effect is an additive one. The persistent negativity apparently does not correspond to the period of delayed heat production. …”

      March 27, 1929, retained carbon copy of letter from William R. Amberson to A.V. Hill, London

      “Dear Professor Hill,

            I am sending herewith the three manuscripts with which I have been working for the last few months. They have been read by Erlanger, Gasser, Bishop, Davis, Forbes, Bronk, and R.S. Lillie, as well as by my colleague McCouch. I have attempted to embody some of their suggestions and criticisms. The St. Louis group, is, I think, somewhat skeptical. I am enclosing Bishop’s notes to me on the subject; also a letter from Davis. I would be glad to have these back later.

               I am sending you photographs in duplicate of my figures. On one copy I have written in the coordinate scales, etc., leaving the other blank for the use of the printer, who will, I presume, be able to set in all of these letters and figures. The photographs are reduced to the size proper for publication, and should be reproduced without any further change. I am also sending the original drawings, in case you prefer these. I thought that the printer might prefer the photographs.

              The two long papers should, I think, appear together. The third can be put in at some later time, at your convenience.

              I shall not attempt to indicate the various changes I have made in these manuscripts as the result of criticisms from my readers. I will only mention that I have recast the first paragraph in the discussion of my first paper, in which I previously criticized the “parallel-connection” views of the Harvard and St. Louis schools. They were both disturbed by this comment. I have since done a little checking with a physical model which has persuaded me that we cannot distinguish between “series” and “parallel” in this matter, and that the whole discussion is rather futile. Since it is no part of my main argument I have rather side-stepped the problem in the present draft.

            I have included a section on the effect of CO2 lack on recovery curves, but have not used my data on the change in form of deflection after readmission of CO2. After talking with Gerard I came to feel that he was really somewhat disturbed by my entrance into this field of study which he had marked out for his own. I therefore proposed that we combine forces on the material in which we had similar observations, i.e. on the great increase in action potential after readmission of O2. He is going on with this study, and I am sending him such of my data as bear upon this problem, which he is to use in any way he sees fit.

             I hope that Downing will be able to approve these papers in their present form. I somewhat modified his description of galvanometer so that it would better accord with the rest of the description; I hope these changes will not seem to be for the worse.

             You are, I think, aware that some of the points which I discuss do not rest upon very extensive experimentation. Thus my description of summation when CO2 is present rests upon three pairs of curves only. I am perfectly sure in my own mind about all of the material presented, but a carping critic might denounce me for too hasty conclusions. I have reached the point where I feel very confident concerning the reproducibility of any observation once made by this method non this material, and am willing to accept a result as sure even on the basis of comparatively few records. You must, however, realize this situation when you consider the acceptance of this work for publication. I look upon it as a sort of preliminary reconnaissance in which no quantitative results have been obtained, but believe it to be sufficiently clear to warrant publication in its present form.

              I attempted to follow your suggestion concerning a log time - % recovery plot for the data of the first paper, but was not satisfied with the result. The refractory periods are not clearly shown by this method, and there are other objections. I therefore come back to my former method of plotting. …”

       Chicago, University of Chicago, Dept. of Physiology, June 8, 1929, Ralph W. Gerard to William R. Amberson

       “Dear Amberson,

                On one point about this analysis business I certainly agree with you. If two careful analyses of the same curve by the same control with equally small remainders can differ so grossly as yours and Hartrees’ do, neither one can have much real value. I will certainly be interested to see, from the tests you are going to make, if the same be true over longer intervals of analysis.

              As regards my own analyses, and their remainders, the best test is a reanalysis. If you want to try your hand at it I think I can find most of the data necessary – and don’t worry about “blighting our budding friendship”. I feel quite confident, in offering a recheck, that the essence of my results must be correct. For direct observation of the 10 sec. stim. Curve and the 10 sec. warming shows that the former, with a more delayed maximum, must result from an increasing rate of production rather than a constant one. Therefore the first part of the heat must be something like my analysis [hand drawn diagram] (solid line. Further, there is no question, from the sharp fall in the stimulation curve, followed by a relatively flat slope [hand drawn diagram] That there is a fairly abrupt fall in heat rate followed by a very gradual fall. So the last part of my analysis must also be essentially proper [hand drawn diagram] The real question left is whether the fall at the cessation of stimulation is as rapid as I pictured it, and I should not be surprised, or distressed, if another analysis should show a more gradual falling off. [hand drawn diagram] I think the calculation of the change in any continuous system (as the equation chosen: [mathematical equation inserted here] will still indicate that a discontinuity is present, that is, that two separable phases exist. The only effect of a more sloped fall from the initial to the delayed rates would be to make the first phase longer (I think). Sound reasonable?

             I write to A.V. yesterday that I felt your longer control better at the center of the time interval rather than at the beginning; and that I hope to get you some muscle heat curves to analyze. This I think is about what I wrote you.

             I’ve had so much trouble with Downing’s galvanometer, due to mechanical (?) disturbance of the zero, that my readings are not accurate enough for this finer analysis. But in the course of playing around, the post asphyxia rise appeared, and the surprising item is this. Though only the central chamber is rendered oxygen free, electrode 1 shows some fall after 2 & 3 (&4) are low and a great subsequent rise when oxygen enters the middle chamber. I don’t believe there is any possible leakage of the N2 into the outer chambers, but to be certain I am trying a five chamber arrangement. This peculiar effect is very reminiscent of those found by Sybil Cooper with CO2. I am very uncertain of its explanation. Did you get anything like it?

              About the future. I have only a half dozen experiments like the above (though all consistent) and will not do more until I get that damn galvanometer to behave. Till then, also, photographic records and analyses are out of the question. I suspect you have much more material on this than I, and it would not be right to accept your very friendly offer of a collaborative publication. It would be well, however, if we did collaborate at least to the extent of coordinating our data and interpretations and publishing simultaneously. That is, unless I’m too slow for you, for with four hours teaching every day, preparation for it, etc., I am getting disgustingly little done in my own laboratory.

              Also please have no fear at all of encroaching on my work. Most of the last year I spent studying phosphates and ammonia in nerve (they behave much as in muscle), and I certainly have no corner on action currents. If we keep in touch we can avoid the accidental direct duplication of work; and that works equally both ways. None of the projects you mention hit my plans, which are chemical, central nervous system and nerve equilibriation. …”