Gregory C. O'Kelly, firstname.lastname@example.org
THE UNEVEN DEVELOPMENT OF SCIENCE AND ITS EFFECTS ON NEUROPHYSIOLOGICAL THEORY AND CLINICAL PRACTICE
I. The Uneven Development of Science
Throughout the history of science can be seen a phenomenon termed by philosophers of science the uneven development of science. This development is the advance of scientific knowledge in one area that has related or pertinent significance to another area, and this advance furthers developments in that other area. Examples of this phenomenon can be seen in the 17th century predictions of Robert Hooke that there was such a thing as stellar parallax, something which could not be detected for almost another two centuries when optics were advanced so that telescopes could detect it. Another example is the theory of continental drift. The idea that this could be possible was first suggested by Diderot in 1772 and again by Alfred Wegener in 1912, but was not widely accepted until the study of magnetic patterns in sea floor stone and sea floor rifts in the 1960s led to the theory of Hess's of sea floor spreading, and the 1980s development of satellites and lasers led to the actual measurement of this drift.
The uneven development of science has also had great impact both on cellular biology in general and upon neuroscience in particular. For at least a century prior to the beginning of the twentieth century it was believed that the nervous system functioned electrically. Luigi Galvani hypothesized the existence of what he called animal electricity in the late 18th century as a result of his experiments, and figured it was the fluid that Descartes in the 17th century said the nerves conducted. He was overruled by Alessandro Volta in 1800 when Volta announced what later became known as the battery or voltaic pile. Volta said that animal electricity was nothing more than regular electricity like that which he could produce using his apparatus.
In the 19th century the study of the effects of electrical stimulation upon the body became widely taken up. In 1855 Guillaume Duchenne, for whom Duchenne's muscular dystrophy is named, recommended that AC was preferable to DC for electrical stimulation since it was not characterized by the skin blistering and pitting that resulted when DC was used to make muscles contract. Duchenne, the father of electrotherapy, did not have the knowledge to understand the difference between the two sorts of current, but the physical scientists did not either. His decision was made on the basis of the effects of the two currents on the patient. In 1870 Gustave Fritsch and Julius Hitzig began the study of the brain by electrical stimulation, and this study was furthered by the work of Sir Charles Sherrington who published his The Integrative Action of the Nervous System in 1906, a book that was reprinted until 1947.
Entering the picture also in 1902 was Julius Bernstein who hypothesized that the nerve cell should have a detectable voltage across its membrane if it were to function electrically. Like Duchenne, Hitzig and Fritsch, and Sherrington, Bernstein knew next to nothing about the phenomenon of electricity. Bernstein appealed instead to the 1888 equation of Walter Nernst to account for the hypothesized voltage. Nernst's equation was not about electricity however. There is not a single electrical term in it. What Nernst was dealing with was the thermodynamic, entropic pressure figured to cause two separate concentrations of an ion to mingle so that the concentration gradient between the two solutions would approach the value of one. Nernst, because he was dealing with ions and pressure, called this pressure a voltage, which is, in the world of electricity, an electrical pressure acting to drive amperes along a conductor. Nernst's voltage was not an electrical voltage, it was an entropic pressure. Nernst's equation came at a time when there was increasing acceptance amongst chemists that things such as ions and molecules and atoms were real things with shapes rather than hypothetical entities.
At the end of the 19th century the world of the physical sciences was beginning to change quite dramatically, especially with regard to the belief that the molecules and atoms once widely believed to be hypothetical explanations for the periodicity noted and tabled earlier by Mendeleev, were real entities and assembled themselves in shapes, like the Benzene ring of Kekule's dream. Furthermore the 'atoms of electricity' posited by von Helmholtz by 1881 and the quanta of energy hypothesized by Max Planck, furthered the belief of Clerk Maxwell that atoms have a structure far more complex than the rigid bodies of Newtonian classical mechanics, for they seemed to be made up of electrical charges. So in addition to chemists attributing shapes to molecules, the theoretical physicists were saying the components of these molecules, the atoms, were more intricately assembled still.
Until the very last years of the nineteenth century, most if not all physicists who believed in the reality of atoms shared Maxwell's view that these particles remain unbroken and unworn...It is true that many of these same physicists (Maxwell among them) were convinced that something had to rattle inside the atom in order to explain atomic spectra. Therefore, while there was a need for a picture of the atom as a body with structure, this did not mean (so it seemed) that one could take the atom apart. However, in 1899, two years after his discovery of the electron, Joseph John Thomson announced that the atom had been split: 'Electrification essentially involves the splitting of the atom, a part of the mass of the atom getting free and becoming detached from the original atom.'1 Thomson spoke of electrification in terms of the behavior of electrons, the fluid that is the current under the pressure of voltage. Although the ammeter had been used by electrical engineers as early as 1884, it was not until 1908, three years after an international conference on electrical units in Berlin, that the ampere, the unit of flow of electrical fluid, was adopted at the International Conference on Electrical Units and Standards in England. In the next ten years the understanding of the position of the electron in the atom went from as raisins in a pudding to Niels Bohr's planetary model of electrons orbiting a nucleus. By 1928 quantum understanding of the periodicity of the elements based upon electron 'shells' and proton/neutron nuclei had been worked out, and ten years after that Linus Pauling had accounted for chemical bonding in terms of ionic and covalent bonds involving electrical charge and electron sharing. These were times of rapidly advancing understanding of atomic phenomena and of electricity as electronic, not molecular or ionic. This was the articulation of what became known as the second fundamental force of nature, electromagnetism, and it contrasted with the celestial, gravitational mechanics of Newton which dealt with things like fluid dynamics.
But at the same time as these advances the neurophysiologists were probing and testing, measuring and speculating on the basis of 19th century treatments of electricity. Not being up on the advances in the physical sciences, the world of the neurophysiologists was restricted to the use of equipment and technology made possible by advances in the hard sciences, but it was overshadowed by philosophical preconceptions of nervous system functioning from the 17th century and by early nineteenth century treatments of electricity as a fluid in which the movement of molecules or ions took place. One philosophical prejudice from Descartes was a version of dualism in the nervous system which called for there to be sensory and motor nerves. This was in keeping with the explanation of nerve impulses as involving a stimulus/response 'mechanism'. In 1811 Charles Bell's New Anatomy of the Brain discussed the difference between motor and sensory nerves, but the distinction could hardly have been made on the basis of experiment since nothing yet was known of biological cells or neurons. James Mills's 1829 Analysis of the Phenomena of the Human Mind, following Descartes, tried to show that the mind was nothing more than a machine. This mechanistic approach was taken up by others, e.g., Johannes Peter Muller's 1834 Handbuch der Physiologie des Menschen. In 1865 Claude Bernard's Introduction a l'etude de la medicine experimentale declared that living systems followed the same laws as inanimate systems. Yet in 1865 very little was known about the laws of inanimate systems, especially electromagnetism, and the electron had not even been hypothesized.
In 1902 Julius Bernstein used the Nernst equation as the theoretical framework on which to develop the hypothesis that the resting potential of neurons is based on the selective permeability of the membrane to K+ [potassium ions]. Bernstein's idea could not be tested quantitatively until the 1940's when techniques for intracellular recording were developed, and voltage potentials were found across the membranes of cells.2 When voltages were found across cell membranes, as Bernstein had hypothesized, it was assumed that Bernstein's hypothesis about these voltages being due to ion concentration gradients was also verified. It was never considered that these voltages could be due to something else, something truly electromagnetic, electrochemical, rather than thermodynamic or entropic. Cellular biology and neuroscience seized upon both of Bernstein's hypotheses as if they were one, and still to this day regard them as one.
This is apparent both in John Koester's treatment of membrane voltages in his essays in the 1991 Principles of Neural Science and in Lynn Margulis and Dorion Sagan's 1995 What is Life?. That electrical voltages or potentials can be found from one ion concentration to a differing one is not an indication that Nernst voltages are about electricity. Such voltages are not detected with a voltmeter, but are instead a reading of varying charge densities in the two solutions taken with another sort of instrument entirely. The only thing electrical about the Nernst equation is the sign for valence; the equation was a mathematical construct and had nothing to do with measurement. What was involved in Nernst potentials was essentially thermodynamics, not electrodynamics. "The post-Maxwell, pre-Einstein attitude [about electricity and electromagnetism] which eventually became preponderant was that electrodynamics is Maxwell's equations plus a specification of the charge and current densities contained in these equations plus a conjecture of the nature of the aether."3 And the Nernst equation had nothing to say about this. Bernstein's hypothesis about the nature of membrane voltages was retained and elaborated upon. In 1994 Bert Sakmann, who won the Nobel in physiology in 1991 for his development of patch clamping which allowed for the extremely fine study of cellular electrical functioning through the divination of the meaning of electrical measurements, stated, "It's very difficult to explain how the current is carried by ions and not by electrons. The way the cell signals and how messages are sent by action potentials or impulses that travel down the axon is hard for people to grasp."4 What is even harder to grasp is why this ionic current is measured in amperes, a unit of measurement for electron flow accepted universally by physicists in 1908. F.S.C. Northrop comments, "One of the basic problems in the unification of scientific knowledge is that of clarifying the relation between those concepts which a given science uses in the early natural history stage of its development and those which enter into its final and more theoretical formulation as a verified deductive theory."5 As will be seen below the unification of scientific knowledge has not yet taken place in the area of neurophysiology because of the perpetuation of 19th century notions of electricity.
In his 1991 Ionic Channels of Excitable Membrane, Bertil Hille writes, "In much electrophysiological work, current is applied as a stimulus and the ensuing changes in potential are measured," and "Cells that can make action potentials can always be stimulated by an electrical shock." Sakmann (1994) states: "Membrane potentials are the means by which cells communicate with each other...the requirements for signaling in the nervous system." The motor neurons, types of cell which send signals to the muscle to contract, "...generate action potentials that travel along the nerve...it's all done electrically." Here can be seen the instrumentalist emphasis on measured potentials, on voltages, with little or nothing ever said about amperage. If electricity is considered a fluid, and if the nerves function electrically, then it would seem that the difference between fluid pressure and the fluid itself would merit some investigation. For the physicist the fluid itself became the electron, for the neurophysiologist it remained the ion. For the physicist electrodynamic and entropic pressure were not the same, for the neurophysiologist then and now, they are. This can be seen in the quote from Bertil Hille from his 1991 about electricity to the effect that "Electrical phenomena arise whenever charges of opposite sign are separated or can move independently. Any net flow of charges is called a CURRENT, and Ionic fluxes are electric currents..."
Hille writes, "Nernst's (1888) work with electrical potentials arising from the diffusion of electrolytes in solution inspired numerous speculations of an ionic origin of bioelectric potentials."6 This is a distortion of what Nernst's work was about, and his traditional view, however archaic, has prolonged the clinical inconsequence of neuroscience. Sakmann (1994) writes, "Now that I think I understand the neuromuscular synapse, I am curious to know more whether similar principles govern synapses in the central nervous system. When I began working again in this area, one of the most surprising things was how little had changed. People are asking the same questions I was confronting twenty years ago." Twenty years earlier John Eccles, in his The Understanding of the Brain, wrote, "No engineer could design or imagine anything so beautiful and efficient and effective as a nerve impulse and the communication that it gives along nerve fibers, and so from one nerve cell to others."7 In 1963 John Eccles received a Nobel with Alan Hodgkin and Andrew Huxley for what became known as the ionic channel model of nerve impulse propagation. Twenty years later, in 1983, Nobel winner Sir Peter Medawar was to note in his essay "Osler's Razor" that "Neurology today is very like medicine in general fifty to a hundred years ago, in its preoccupation with interpretation and diagnosis and the relative backwardness of treatment." The intellectual conceit that separates the life sciences from the physical sciences perpetuates the legacy of archaic notions about electricity handed from Bernstein to Sherrington, to Eccles, to Sakmann, and still serves to render neuroscience clinically irrelevant. Let's take a closer look now at Sakmann's and neuroscience's claims to understanding the neuromuscular synapse on the basis of 19th century understanding of electricity.
Lewis P. Rowland, in his "Diseases of the Motor Unit"8 writes that speed of nerve impulses is influenced by two things. "First , the axons of myelinated fibers tend to be larger in diameter, and there is a direct relationship between conduction velocity and axon diameter." But with electricity the increased conductor cross-sectional area does not result in speeded up movement of electrons, just decreased resistance to their movement, and so greater current flow at the same speed. There is no direct relationship between conduction velocity and conductor diameter, contrary to Dr. Rowland who, carrying on neuroscientific tradition, was thinking of electricity still as a fluid. Fluids under a constant pressure move at the same speed through conduits of different gage, and speed up when the conduit narrows, not increases in diameter, and only if flow rate remains the same. Ohm's law applies to both fluid and electrical flow, and in either case does not address the speed of that flow.
In the attempt to model the nature of nerve impulse propagation after an electrical circuit the old analogy of wires was initially rejected because there was no spark occurring at the neuromuscular synapses, which were widely and intensely studied in the first half of this century. The synapse was predicted to exist by Sherrington at the turn of the century; yet its role as an amplifier of nerve signals using neurotransmitters was not understood until the late 1930s, and even then not understood well. Yet this effect is easily understood in terms of the equations of electricity, something which the 1930s understanding did not incorporate. The idea from Bernstein that neuron membrane voltages were due to ion concentration gradients was harmonized with the detected change of membrane voltages as a nerve signal passed by appeal to the idea that the ion gradient was running down and then being restored by an hypothesized pump. How this model can possibly be manipulated to provide a definition of the power of the nerve impulse, and how that power is amplified across the synapse, is a mystery. This mystery is not made more clear by the introduction of an hypothesized 'sodium pump' to restore the ionic gradient. As will be seen below the notion of such a pump, later termed a 'proton pump', further obscured the electrochemical nature of the nervous system.
If the nervous system works electrically, and if in electrical terms power is voltage times amperage then the nerve impulse can only be amplified across the synapse through the effect of a neurotransmitter by increasing either voltage or amperage. The nervous system resorts to increased amperage, and it does this in the case of the muscle by diminishing the resistance to the movement of amperes along the post-synaptic fiber of the muscle called the transverse tubule. Resistance is diminished by the increased cross-sectional area of the muscle's type II fiber or transverse tubule over the relatively minuscule microtubule in the axon which delivers the impulse to the synapse. This is seen in the equation r=1/x2 where r is resistance and x is conductor cross-sectional area. Increasing conductor cross-sectional area does not result in increased velocity of the electrons along the conductor.
In the ionic channel model of molecular electricity the gradient is figured to run down as a result of ion flow laterally across the wall of the axon, not longitudinally. This flow takes place through ion channels that are allegedly not only selective to the type of ion, but were also voltage 'gated', that is, they are opened or shut as a result of voltage changes. The voltages are alleged to be not only dependent upon the concentration gradient, but also, somehow, are able to be changed independently of that gradient, the voltage change causing the gradient to change. This is a bit of circularity that defies logic. Sakmann (1994) writes, when asked what the channels look like, "A funnel and a gate large enough to pass one ion at a time...at least this is one theory. The actual mechanism remains a mystery." Hille writes, "Much of what we know about ionic channels was deduced from electrical measurements...as this book is concerned with channels and not techniques of measurement, the essential principles are few."9 The essential principles apparently do not concern themselves either with the equations of electricity or with hypothetico-deductive logic. Given that the neuroscientific understanding of electricity is so nineteenth century, it is hard to imagine that these deductions about ion channels, e.g. their 'voltage gating', can be very reliable. Their clinical irrelevance has already been noted. In an attempt to gain access to the equations of electricity Nernst had to be convertible to Ohm's law, V=IR. Hille writes, "Cole and Curtis (1939) correctly (sic) deduced that if conductance is 'a measure of the ion permeable aspect of the membrane' and capacitance, of the 'ion impermeable' aspect, then the change on excitation must be very 'delicate' if it occurs uniformly throughout the membrane, or, alternatively, if the change is drastic it 'must be confined to a very small membrane area'." This was an attempt to justify resort to what is called the RC time constant where R is resistance and C is capacitance. This was necessary for the idea that the difference in speed of nerve impulses on myelinated nerve was faster than that on unmyelinated nerve because the myelin wrapping resulted in a form of biological, capacitative discharge or, as Lewis P. Rowland in his "Diseases of the Motor Unit" prefers to call it, discontinuous propagation, the second reason he claimed for nerve impulses on myelinated fibers being faster than on unmyelinated.10 Curtis and Cole even say as much when they write, "...we shall assume that the membrane resistance and E.M.F. [electromotive force] are so intimately related that they should be considered as series elements in the hypothetical equivalent membrane circuit," but in honesty they qualify their resort to this membrane circuitry and its arrogation of RC time factors by saying that this is an assumption, a hypothetical.11 But it was a hypothetical that was never tested; it was accepted as doctrine from the start and is still taught as fact, just as Bernstein's cell membrane voltages being inextricably tied to the Nernst equation.
In 1980 in a Scientific American article Pierre Morell and William T. Norton report in their essay "Myelin" in all seriousness that "...the mechanism by which Myelin facilitates conduction has no exact analogy in electrical circuitry," this despite that fact that the equations of electrical circuitry are resorted to mathematically to 'prove' that myelin facilitates conduction in the very way for which there is no exact analogy.12 Elaborating on this crude model Hille writes, "One can draw an analogy between Ohm's law for electrical flow and the rule for flow of liquids in narrow tubes."13 For Hille this analogy is so compelling that he is able to justify the equating of fluid dynamics with electrodynamics, of alpha radiation with beta radiation, or, worse still, of beta radiation with atoms.14 Also Hille writes: "In this heroic time of what can be called classical biophysics (1935-1952) the membrane ionic theory of excitation was transformed from untested hypothesis to established fact...The story illustrates the tremendous power of purely electrical measurements in testing Bernstein's membrane hypothesis."15 Here quite graphically is the reason it can be said that the uneven development of science still haunts biology and neuroscience and renders them academic pursuits on a par with theology or philosophy. Purely electrical measurements, interpreted in an early 19th century understanding of the phenomenon of electricity, allow for the movement from untested hypothesis to established fact without ever testing the hypothesis. Biology, unlike the physical sciences, even has a 'central dogma' from Francis Crick which has been repeatedly shown to have exceptions but which is still taught as if it were something that had more import than being merely a correct answer on a test question..
Although the Nernst potential as defined by Nernst dealt with states in which there was no flow between the two concentrations, and so there was no change in Nernst voltage, in the case of changing membrane voltages Hille writes, "...[the] simplifying rule of equilibrium cannot be applied, and the derivation must make assumptions about the structure of the channel," i.e., about the values to be assigned to the permeability of the channels so that restrictions of ion flow could be treated as the R in Ohm's law V=IR where V is from Nernst, and R is assumed. I, expressed in amperes, was not then measurable, or even pertinent to the movement of fluid borne ions, and so conveniently disregarded. Hille writes, "The physical chemist would say, 'Yes, you have a concentration gradient, so Ohm's law doesn't work.' But the biophysicist would then suggest that a gradient is like a battery." Hille would not, evidently, consider John Koester a biophysicist for Hille's version of what is happening immediately clashes with the model Koester offers in "Membrane Potential" (Principles of Neural Science). Koester speaks of this gradient as not like a battery, but a chemical force (when in fact it is a thermodynamic pressure and does not involve chemistry at all) while Hille claims that chemistry is not a concern, that what is important is the electrical measurements. Both of these men are experts in the same field, neuroscience, a field known for its clinical poverty.
John Koester in his "Membrane Potential" in Principles of Neural Science shows a graph of cell membrane potentials versus potassium ion concentration gradients, and it is seen that measured membrane potentials deviate quite significantly from the potentials predicted by Nernst, with the two slopes intersecting once and otherwise diverging, especially at low concentration gradients. Rather than question the viability of Bernstein's demonstratedly feeble theory, which Hille says has been tested and proven, Koester makes the claim that this divergence is due to the presence of still other 'species' of ions. He then goes on to describe how the Goldman equation helps to account for this mathematically. The Goldman equation purports to combine Nernst voltages with Ohm's law, to unite electrodynamics with thermodynamics and fluid dynamics, to give Nernst's mathematics some empirical content. It is used to make theory and fact, calculation and measurement fit more closely. Koester points out how this is done by assuming values for permeability that vary for each 'species' of ion. These values are not measured or calculated, they are assumed so that the mathematics more closely approximate the measurements. And these assumptions are at the heart of selective voltage gating, a concept which is still not fully articulated
Cellular biologists, who analogize the cell with a battery (a primary cell, in electrochemical terms), place the ground, when cell membrane voltages are being measured, externally. But to the extent that the cell is a battery the ground electrode placement should be in the nucleus while that cathodic electrode is in the cytoplasm. Hille justifies the location of the ground extracellularly by saying that the biological cell is not really a primary cell or battery-like after all, but instead is measured as an electrolytic cell. This suggests that Dr. Hille does not understand electrochemistry, for if the cell is actually an electrolytic cell then the ground should be intracellular since the source of cathodic electrons or photons energizing an electrolytic cell is external to the cell. The suggestion is that, as with neurophysiologys incomplete understanding of electricity, the understanding of electrochemistry also has gaps. Placing the ground intracellularly however, results in voltage readings opposite in sign to what Nernst equations have been claimed to predict. This is just another indictment of the misguided reliance of neuroscience in appealing to Nernst rather than considering electrochemistry, yet it is not considered so by electrophysiologists who feel, like many biologists, that the subject matter of the life sciences excuse it from the scientific rigor of the physical sciences.
Hille writes, "The biophysical method fosters sensitive and extensive electrical measurements and leads to detailed kinetic descriptions," and "...cares less about the chemistry of the structures involved than about the dynamic and equilibrium properties they exhibit."16 The exhibitions of these properties are merely the electrical measurements taken when the cell or fiber is tweaked certain ways or bathed in various solutions of ion, and interpreted in such a way that Bernstein's hypothesis is not threatened. Such knowledge has never been of any consequence for it does not allow for the actual simulation of nerve impulses without either (1) pumping ions across a membrane or somehow tampering with the ion concentration gradient, an obviously problematic way of simulating the impulse; or (2) introducing an actual electrical voltage change by touching a wire through which courses AC to the nerve membrane so that the expected instrument readings can be obtained. It will be seen below that this latter method of 'simulating' a nerve impulse was the preferred method of proving Bernstein's hypothesis, and embodies a breathtakingly archaic notion of what the nature of electricity is in another example of the uneven development of science..
In the late 1940s two schools of thought contested the issue of the nature of the nerve impulse as revealed by the measurements made possible during the 1940's. Bertil Hille in his 1991 calls these two schools the ionic channel school and the epiphenomenalist school. The beliefs of the ionic channel school have been presented. For the epiphenomenalist school Hille writes, "...propagation of the nervous impulse was a chemical reaction confined to axoplasm and the action potential was only an epiphenomenon - the membrane reporting secondarily on interesting disturbances propagating chemically within the cell." For the epiphenomenalists the cell and axon were black boxes about which not enough was known. This seems a wise stance - to wait and see before making any conclusions, to get more 'facts'. This is the way biology usually worked. The epiphenomenalist position suggested the role of electrochemistry rather than fluid dynamics; the ionic channel school said all instrument readings should be interpreted to support the conclusions already made. The claims to certainty were convincing enough for the Karolinska Institute which award the ionic channel school the Nobel in '63 and, by so doing, put an end to the epiphenomenalists in a research world in which the gaining of research funds was driven by political considerations and prizes rather than clinical consequence.
With its award the Karolinska Institute became complicit in the perpetuation of biological misunderstanding of electricity and chemical energy that is the uneven development of science. Consider the role of chemical energy in cellular functioning. Professor Franklin Harold in his 2001 The Way of the Cell writes, "The two major pathways that generate and regenerate ATP are called oxidative phosphorylation and photophosphorylation, driven by respiration and light absorption respectively....Just how ATP is produced remained mysterious for many years, until it was discovered that the process is at bottom electrical." ATP is the universal molecule of energy storage and creation by mitochondria in the cell's cytoplasm. In 1978 Peter Mitchell received a Nobel in chemistry for his study of biological energy transfer. At this point it must be made clear that 'biological energy' is not chemical energy. Chemical energy is electrons, that is, beta radiation, not alpha radiation, which is protons and neurtrons. There simply is no way that the two can be equated in the essentialist world of the physicist although, in the world of the biologist, they are mutually substitutable. Professor Harold writes, "Both the respiratory chain..., and the analogous photosynthetic cascade, generate a current of protons across the membrane in which these protons are inserted. These currents power ATP synthesis, and also serve directly as for certain [cellular] work functions. We can thus think of ATP and the proton current (more precisely the proton potential) as alternative and incontrovertible energy currencies." Here it is seen that biology still holds to the idea that electricity can be the movement of protons, that electrons and protons are so analogous that they are mutually substitutable.
Of Peter Mitchell's award Professor Harold writes, ""In Mitchell's view, then, the coupling of electron respiratory transfer to ATP synthesis is effected not by a chemical interaction but by a circulation of protons across the membrane. What that proton current does is quite analogous to the role of the electron current in coupling a flashlight battery to the bulb." The trans-membranal circulation of protons is such a widely accepted notion throughout biology and medicine that it is used not only to model the function of the neuron's impulse but also is invoked to explain the contraction of muscle, with protons being pumped across the muscle fiber and traveling on the transverse tubule from its electrical synapses at the sarcolemma to act upon the sarcomeres. This dynamic is seen again in the functioning of the apical hypha in the growth of the cell. The apical hypha, also known as the centrosome, is seen to function by hydrostatic pressure acting from within the cell, and by a proton pump located without, which pumps protons into the cell. This view of the nature of electricity and chemical energy is quite at odds with that accepted by physical scientists. It is called the chemiosmotic hypothesis. It features a pump whose nature and structure has never been explained, a pump which can be completely discarded if instead the movement of protons is seen as a result of the movement of free electrons within the cell that are a part all oxidation-reduction reactions. This explanation, however, has been all but ruled out by the insularity and myopia of biology whose sholars see no relevance for biology of quantum mechanics, and by the Nobel awards of the Karoliska Institute whose judgement is considered final by the biological community.
Professor Harold writes, "Publication of the chemiosmotic hypothesis touched off a vigorous, sometimes acrimonious controversy over fundamental principles as well as experimental data; this continued for some fifteen years, subsiding only after the award of the 1978 Nobel Prize in chemistry to Peter Mitchell. By then the hypothesis had been as rigorously scrutinized as any proposition in biology and judged to be essentially correct." The fifteen years of that controversy started with the award to Eccles et al. in '63 for an explanation of the nerve impulse that hypothesized a sodium pump, later called a proton pump by Mitchell. It should be pointed out that, as Dr. Harold notes, the controversy subsided, but was not settled, with the award of the Nobel. The Karolinska Institute was merely reaffirming its choice in 1963 rather than admit it could have made a mistake. 'Rigorously scrutinized as any proposition in biology [perhaps like Bernstein's hypothesis] and judged to be essentially correct' by the Karolinska Institute, the final arbiters in the field of biological science as to scientific truth, the chemiosmotic hypothesis is now as accepted and institutionalized as the clinical impotence of neurological theory.
The electrochemical nature of the nervous system is still an idea whose time has not come despite the fact that it does not conflict with the idea that there are such things as ionic channels and trans-membranal ion movement. The epiphenomenalist school would merely correct this model by insisting that what causes the ions to move is not entropic pressure or proton pumps, but the presence and movement of free electrons which attract rather than pump the protons through the influence for example of the Oersted effect. That effect is the magnetic field induced by the movement of an electron at a 90 degree angle to the movement of that electron. And so what moves down the axon's microtubule is an electron which pulls ions laterally across the membrane of the axon. To focus exclusively on the ion, the epiphenomenalists would say, is to get only half the picture.
Some fundamentals of the epiphenomenalist school are presented in "The Electro-Dynamic Theory of Life" by H.S.Burr and F.S.C.Northrop in which the authors argued that 'living systems are physical systems in the sense prescribed by field physics.'17 This description is a bit more detailed than that of Claude Bernard in 1865 who spoke only of natural laws. The two later in 1939 published "Evidence for the Existence of Electro-Dynamic Fields in Living Organisms" in Proceedings of the National Academy of Sciences. Northrop and Burr sought to provide a principled account for the organization of cells that comprised an organism, especially for those organisms with nervous systems. Northrop preached that 'the central difficulty of biology' was the problem of organization. In their essay "Causality in Field Physics in its Bearing upon Biological Causation" they warn against the "...danger of falling back upon the rejected mechanical models by surreptitiously using the particle and wave of quantum mechanics in the sense of the particle and wave of Newtonian mechanics and hydro-dynamics."18 In a 1936 Yale Journal of Biology and Medicine article entitled "The History of Modern Physics in Its Bearing Upon Biology and Medicine" Northrop wrote:
The insufficiency of the thermo-dynamical theory as a complete account of biological organization centers in the fact that there is nothing in the theory to prescribe the particular relatedness into which energy organizes the moving chemical materials. This can be put in more technical language by saying that there is nothing in thermo-dynamics itself which prescribes at what point precisely in the tendency toward a state of maximum entropy the energy from outside the system compensates that tendency, to produce the steady state, or the state of mean compensated entropy, which is a living organism.19 [The chemiosmotic hypothesis holds that biological/proton energy driven by a pump, not chemical, electronic energy driven by oxidation-reduction reactions and electro-magnetics, is what compensates the tendency to maximum entropy.]
p.155 Life depends for its very existence upon energy radiated to it upon the earth from the sun. This radiation is an electromagnetic phenomenon. Consequently, living organisms depend for their very existence upon electro-magnetics.
So the epiphenomenalists were concerned with electromagnetics and energy, in particular, chemical energy, which is galvanic or direct current. And thermodynamics, favored by the heroic neurophysiologists in their attempts to model nervous functioning, was grossly inadequate for any analysis of an organism since it did not address such things as principles of organization or the electronic nature of two terms found throughout texts on biology but never elaborated upon, electricity and energy. When Dr. Albert Szent-Gyorgi, who had worked for years with x-ray diffraction to study the molecular structure of protein molecules, ventured in the 1950s that the protein molecule was crystalline enough in its lattice to support semiconduction at certain temperatures which were the temperature of the body, he was greeted with indifference if not hostility from those who had a vested interest in maintaining the thermodynamic model upon which their own status as experts was based.
The attitude seen above, the description of Hille of the ionic channel school not caring about the chemistry of the structure, just the measurements, also carried over to the structure of the nerve itself. The Nobel in physiology in 1963 went John Eccles, Alan Hodgkin, and Andrew Huxley for a model that stressed the primacy of measurements over structure. In particular, John Eccles, in his 1973 The Understanding of the Brain implies that the structure of the nerve fiber is not at all important to the way it works naturally, that the contents of the axon could be considered as a resistor as well as a capacitor, and could be dispensed with entirely in the attempt to show that the hypothesized measurements of the model would still result. In a clear case of the confusion between digital and analog, that is, a conflation of instrument measurements with the actual way the nerve conducts, Eccles writes of the 'proof' that the ionic channel theory was correct:
The content of the axon has the consistency of jelly, and for most purposes you can substitute an appropriate salt solution without deteriorating impulse conduction by the fiber. For example Baker and Shaw were able to squeeze out the contents of the giant squid axon with an open end by a kind of microroller, leaving a collapsed, flattened axon that appeared destroyed. Yet when they reinflated it by an appropriate salt solution, a potassium salt, the fiber was restored and conducted well for hours.
To prove how the nerve conducted, in other words, it had to be altered from its natural state so that the right readings could be obtained. This treatment of the dispensability of the axoplasmic interior of the nerve was never challenged by other neuroscientists and competitors for academic prizes. In the multi-editioned Principles of Neural Science (1991) James H. Schwartz shows in detail the fine structure of this axoplasmic substance, with its complement of microfilaments, neurofilaments, microtubules, and vesicles of acetylcholine, all of which are not, apparently, necessary for nerve functioning of myelinated nerve, if John Eccles is to be believed. The model of nerve functioning Eccles championed is presented in detail in Principles of Neural Science by John Koester. One of the editors of this book, Eric Kandel, received a Nobel in physiology with two other neuroscientists in the year 2000. At the same time three electrochemists received a Nobel for their work developing non-metallic polymers which semi-conducted electricity. Polymers are long chains of organic molecules. Proteins are polymers. All of the proteins of the body, all the DNA and RNA, are the result of polymerization involving organic chemistry. In the January 2001 edition of the IBM Journal of Research and Development is an article entitled "Organic Electronics: Introduction" by Shaw and Seidler which tells of this new area of work. The authors speak of the movement of electrons on this circuitry, not ions. Just as in the first part of this century with the heroic, pioneering neurophysiologists who did not see any relevance for their work in the work of the particle physicists, so now Dr. Kandel and the other winners do not think that the work of the electrochemists applies to neuroscience. This is the uneven development of science. The work of the Nobel-winning electrochemists has been said to presage great technological developments and to have united physicists, engineers and chemists. The work of the Nobel-winning neuroscientists does not threaten the traditional poverty of clinical neurology.
The limitations of the ionic channel model of nerve impulse propagation are especially stark when the idea of the information processing role of the nervous system is considered. How, given the ionic channel model of the nerve impulse, can meaningful information be encoded for the cell and the synapse? Sakmann (1994) writes, "Information is not contained in one action potential, but in the different rates or frequencies at which they transmit. This is called frequency encoding, but how it actually works is a complete mystery." The belief is then that by varying the rate of meaningless impulses made possible by voltage gating and the entropic rundown and re-establishment of ion concentration gradients by means of an hypothesized proton pump these impulses are somehow imbued with meaning for the central nervous system. How this meaning is decoded by the cell or the synapse is necessarily a mystery too then, but at least the neuroscientists have a name for this mystery, just as the neurologists have a name for the syndromes and nervous afflictions that they diagnose but can seldom do anything about. Frequency encoding has been used by those working with radio for over a century. FM radio uses this principle and there is nothing mysterious about it. One must escape the limitations of ions and molecular electricity and turn to electrons, cathode rays, beta radiation. If the nerve impulse is seen as electrochemical, on the other hand, then the meaning of the impulse is dependent upon the origin of the impulse, its destination, and whether what is transmitted is a cloud of electrons or a hole that is the lack of an electron. The last thing determines the nature of the electrochemical reaction triggered at the cell or at the synapse, and the information value of the impulse is identical to this reaction. This sort of arrangement may be analogized to a row of dominos that are so interconnected that they may be pushed or pulled from either end, thereby multiplying the information-carrying value of the nerve's microtubule four times over what would be possible in the ionic channel model before even considering frequency encoding. This is certainly more likely than an extremely extravagant nature that must resort to separate nerves for sensation and motor functioning with the fibers of these nerves each relying upon unidirectional transmission, which is current neuroscientific doctrine..
The uneven development of science can be seen throughout all of the sciences down through the history of science. It is when these unevennesses are removed by the cross-disciplinary movement of knowledge that dramatic progress is made in a particular field. At the start of the 20th century the physical sciences made great progress in the understanding of the second fundamental force of nature, electromagnetism, and in the understanding of sub-atomic particles and their role in chemistry. This knowledge was thought to pertain to biology and neuroscience only in a very limited way, usually in the instrumentation used such as x-ray diffraction study of proteins and DNA. The results of this uneveness therefore have been perpetuated because of the insularity of biological science, as can be seen in the comments of Ernst Mayr in his 1982 The Growth of Biological Thought, in which he states that the essentialism of the physical sciences, and indeed the philosophy of science that characterises those sciences, is not directly translatable to the biological sciences because of the difference in and specialness of the subject matter. This is a widely held belief amongst biologists. The late Stephen J. Gould, who taught geology, biology, and the history of science at Harvard University, even says that the difference is due to the historical nature of the appearance of and evolution of life. It is still a common notion amongst biologists that quantum mechanics has little relevance to biology. It is also a common notion amongst neuroscientists that the reason so little can be done for any neuromuscular disorder is that not enough is known yet about the nervous system, but what is claimed to be known and to have been awarded prizes is correct. Therein is the problem.
II. The Effect of the Uneven Development of Science on Clinical Neurological Practice
In 1887 Walter Gaskell of Cambridge University mapped out as thoroughly as possible the sympathetic and parasympathetic nervous systems. This was long before the synapse was discovered, so it was way too soon for drawing distinctions between presynaptic and postsynaptic nerve fiber. Given this the question arises as to the criterion for determining whether a nerve was sympathetic or parasympathetic. For the early neuroanatomists the functioning of the nervous system was something divined from philosophical preconceptions which, as seen in the last section, gave great weight to the dualistic idea that nerves were either sensory or motor. Consequently roles were assigned to the anatomical structures of the system based upon this philosophical scheme and not upon measurements. The sympathetic nervous system was that emerging from the brain without passing through the spinal cord, e.g., the vagus nerve, the sympathetic chain, the accessory nerve, etc., while the parasympathetic nervous system was deemed to be that which passed down the spinal cord and comprised the dorsal column of horn cells while the anterior column of horn cells were those associated with motor activity, and so were associated primarily with the contraction of skeletal muscle.
Rather than associate the dorsal horn cells with extensor muscles and the anterior horn cells with flexor muscles, it was assumed that the presence of the dorsal ganglion outside the cord, signaled that the dorsal horn cells were for sensation while the anterior horn cells were for motor activity. This fit the preconception, from Descartes, that animals, including humans, were stimulus-response mechanisms. There was no experimental evidence supporting this scheme; it was strictly philosophical, and is still taught today despite the unlikely presumption that nature is so extravagant with nervous systems that it does not use cells capable of both afferent and efferent impulses. Sir Charles Sherrington, working with decerebrated cats in the early 1900s, noted that when a stimulus was provided to the limb of the cat the limb would tend to extend. He hypothesized that what was involved was an impulse entering the spinal column via the dorsal nerve roots which arced to the anterior part of the column and emerged as the nerve signal causing the contraction. He called this then a spinal reflex, and reckoned it to be the result of firing of neurons in the spinal cord (lower motor neurons) independently of input from the brain. The scheme was accepted and is still part of the corpus of neuroscientific knowledge, with neurologists checking for reflexes with little hammers before rendering a diagnosis, and rehabilitationists seeking to train the spinal reflexes of the spinal cord injured paralytic to get him to ambulate. The idea that such reflexes played a part in behavior was dismissed as simplistic by researches studying brain injuries during WWII.
In 1934 a Dr. Feldberg working in the lab of Sir Henry Dale (who was to later receive a Nobel prize with Otto Loewi for the discovery of acetylcholine as a neurohumor in the early 1920s) found that all synapses functioned using acetylcholine, whether they were sympathetic or parasympathetic. This was peculiar given that epinephrine was considered the active neurotransmitter for the sympathetic nervous system. Epinephrine speeded up the heart and caused the veins to constrict while the parasympathetic and somatic, skeletal muscle systems appeared to function on only acetylcholine, which slowed heartbeat. What Feldberg discovered was that all nerves functioned with acetylcholine.
The speeding up of the heart then, to the extent that it was driven by epinephrine, could not have been due at all to nervous activity, but only could be the effect of changes in blood chemistry which was altered by such things as oxygen deficit or the acetylcholine-mediated secretion of epinephrine triggered by organs of sensation like the eyes or the ears. The tradition of seeing the occurrence of vasoconstriction and the speeding up of the heart as a result of direct nervous activity rather than the effect of local blood chemistry had its origins in the experiments of Claude Bernard and Charles Edouard Brown-Sequard in 1852.20 Bernard, who claimed that animate objects behaved according to the laws for inanimate objects betrayed a bit of ignorance with regard to his understanding of electricity as it was even then understood. He was not aware then that his use of galvanism may have caused vasodilation when applied to the sympathetic trunk if he had applied that stimulation with the anode rather than the cathode, which is associated with vasoconstriction. This would have changed what has instead become a traditional explanation of the dichotomy between sympathetic and parasympathetic nervous functioning, especially celebrated in what is called the fight/flight mechanism.
The only time this mechanism was ever tested was during the 1920s when two physicians at the Mayo Clinic, Alfred Adson and Leonard Rowntree sought to limit vasoconstriction by cutting sympathetic nerves. They found that in the treatment of hypertension surgically the vasodilating effects of a sympathectomy were insignificant, but very short term, and soon vasoconstriction would occur again. But this time it could not have been the result of nervous activity. Julius Comroe writes, "For ten to twelve years, the neurosurgeons dominated the treatment of hypertension. They have now vanished from the hypertension scene without a trace...but they served a useful purpose...They kept alive the knowledge that malignant hypertension was amenable to treatment..."21 This treatment was just not surgery. The trouble was the view of the sympathetic/parasympathetic dichotomy which justified these infirming, clinical experiments was allowed to live on unquestioned.
Because of the failure of orthodox neuroscience to understand and assimilate the developments of the physical scientists with regard to the electromagnetic nature of electricity, that same neuroscience was never able to simulate the nerve impulse. This has meant that an otherwise promising mode of intervention for a wide variety of trophoneurotic nervous and somatic disorders has been allowed to remain untapped. Understanding of the nervous system as an electrochemical one, as if the neuron were a battery, suggests that the way to simulate the nerve impulse is to introduce electrons [beta radiation] at the site of the synapse or ganglion. In this way post-synaptic reduction reactions necessary for the building of protein are triggered.
For example consider the question of enduring paralysis following stroke or traumatic, concussive, but not destructive injuries to the brain or spinal cord. When the blood/brain barrier is disrupted the lower motor neurons will cease to fire until the barrier is reestablished. During the time it takes for this barrier to be reestablished and for the blood to be absorbed the muscle cells that lie post-synaptically are not galvanized by acetylcholine released by the lower motor neuron into propagating an action potential to the type I muscle fiber. Consequently the type II muscle fiber or transverse tubule which grows from these post-sysnaptic muscle cells and forms the electrical synapses at the type I fiber, diminishes in cross-sectional area through disuse atrophy. This means that the synaptic amplification of power of the nerve impulse is reduced, which means muscle contraction is weaker, less energetic when the nervous system starts to function again even healthily. The more the type II fiber diminishes in cross-sectional area the greater is the loss of power amplification. There comes a point at which the lower motor neuron can no longer act upon the type I fiber, and the muscle is unusable, but not because of enduring damage to the upper or lower motor neurons. The suggestion is then that stimulation with the anode of the DC with the emphasis on amperes over voltage when power is considered, triggers the post-synaptic anabolism necessary for the building of the transverse tubule as if the muscle were actually being used. This sort of intervention has implications not just for the weak and the enfeebled, but also for those concerned with fitness, and for those paralyzed from nervous injuries that even destroy the upper and lower motor neurons. From the level of a complete spinal transection on down there is still a length of cord that has intact connections from its lower motor neurons to the muscle. These muscles, given electrochemical stimulation, can be maintained in a highly fit state even if they are not usable. This sort of intervention applies to more than just muscle however, extending to all somatic structures that receive innervation, whether from the cord or the peripheral, sympathetic nervous system.
Current neurological understanding of electricity prompts the clinician, when using electrotherapy or electrical stimulation, to use AC rather than DC. Electrochemistry is not possible with AC; AC is used for voltage transmission and for the transduction of mechanical power. This transduction shows up either as the turning of a motor, or as lighting from the equivalent of the heat of friction in incandescent light bulbs. Although fluorescent lights do not work on the same principle, there is no chemical reaction triggered with AC. When a muscle is made to contract with AC the mechanical properties of the type I fiber are directly engaged without action upon the type II fiber. If the type II fiber is not acted upon and made to build in response, then the strength of the muscle is not increased, the atrophy is not reversed. This is why no amount of stimulation using AC has ever been known to build muscle. Not even DC will build muscle if it is not applied to the neuromuscular junction where the post-synaptic muscle cells originate the growth of the transverse tubule.
Current thinking about rehabilitation of the paralyzed from stroke or concussion or incomplete spinal injury fails to consider the problem of the muscle cell's loss of integrity with the withering of its transverse tubule. Because the electromyographer fails to notice more than a nominal difference between healthy and atrophic muscle, but a big difference between atrophic and denervated muscle, he concludes that atrophic muscles fail to work because of lower or upper motor neuron problems, and does not consider deterioration of the muscle cell itself because of disuse. The t-tuble, coursing through the muscle, is compartmentalized from the sarcomeres and the sarcoplasmic reticulum which contains them. The t-tubule can lose cross-sectional area to the point where it is useless, yet still not betray any gross structural differences on the electromyographer's screen. Paralysis from deterioration of the t-tubule might then still be thought of as involving 'learned non-use', the latest explanation for chronic paralysis following incomplete damage and trauma to the spinal cord or brain. Those who believe this try to put paralytics on tread mills as if the paralysis were just a problem of training, or they resort to what is called 'constraint-induced therapy' in which a hemiplegic's functioning muscles are mechanically impeded so that he is forced to use muscles he can only minimally if at all use. No attempt is made to build muscle using electricity because after a century and a half of work on muscle building no one has yet succeeded in doing it. The reason for this is the tremendous gap that opened between biology/neuroscience and the physical sciences at the start of the twentieth century. And this gap prevents neuroscience from understanding the electrochemical nature of the nervous system. This is the uneven development of science.
1 Abraham Pais, 'Subtle is the Lord...': The Science and the Life of Albert Einstein, Oxford University Press, 1982, p.85.
2 John Koester, "Membrane Potential", p. 84-5, in Principles of Neural Science, Kandel, Jessel, Schwartz, 3rd edition, Appleton and Lange, 1991.
3 Pais, Subtle is the Lord..., p.119.
4 Thomas A. Bass, Reinventing the Future, Addison-Wesley Publishing Co., 1994, p.165.
5 Northrop, "The Two Kinds of Deductively Formulated Theory" in The Logic of the Sciences and the Humanities, Meridian Books, 1959, p.102
.6 Hille, Ionic Channels..., p.2.
7 John Eccles, McGraw Hill, 2nd edition., p.18.
8 Principles of Neural Science, 1991
9 Hille, Ionic Channels..., p.6.
10 Principles of Neural Science, 1991. p.251.
11 Hille, p.29.
12 Scientific American, May, 1980.
13 Hille, p.8.
14 Alpha radiation is a proton-neutron combination without an electron, in other words, an ion of helium. To the extent that sodium or calcium or potassium are ions they contain one or more proton-neutron combinations that are unbalanced by missing electrons, and so have the same electromagnetic field as one or more helium ions
15 Hille, p.24.
16 Hille, 1991.
17 The Quarterly Review of Biology, 1935, no.10, p.322.
18 Northrop, 1959, p.222.
19 Northrop, 1959, p. 162.
20 Julius H. Comroe, Jr., M.D., Exploring the Heart: Discoveries in Heart Disease and High Blood Pressure, Norton and Company, 1983, p.232.
21 ibid., p.242.