A Bipolar Theory of Living Processes

stant: these phenomena are similar to those shown by a stimulated muscle. Moreover if the current be left on too long the accumulator becomes polarized, the current falls off and the magnetic field decreases: while if the accumulator be given a period of rest it recovers and provides its full E. M. Е. again, and the magnetic field rises to its previous value. The phenomena of muscular fatigue are analogous. "Disappearance of mechanical response. On opening the electric circuit the magnetic field of the electromagnet diminishes rapidly though not instantaneously to zero, and the pull on the piece of iron falls off. This process is analogous to relaxation.

"Performance of work. The current in the electromagnet develops a store of magnetie potential energy in the soft iron core and in the field round it. This magnetic energy will do external mechanical work, if allowed, by pulling up the piece of soft iron to the magnet. On the other hand no external mechanical work is done if the piece of iron be held fast. In the same way the muscle develops elastic potential energy on excitation: this energy may result in external mechanical work if the muscle be allowed to shorten, but in an isometric contraction no external work is done. The work actually performed depends, in both cases, on the ‘conditions of loading,’

"Heat liberated in the development of the mechamical response. The energy of the current passing through the electromagnet reappears in two separate forms: (a) in the magnetic potential energy of the field of the electromagnet, and (b) in Joule's heat liberated in the coils. If the current passes only for a very short time the main part of the energy appears first in the ‘free’ form (a); while if it passes for a longer time an increasing fraction of it appears in the ‘bound’ form (b). Similarly with the muscle, energy is liberated (a) as mechanical potential energy and (b) as heat, (a) being the greater in a short response and (b) the greater in a long one.

" Heat-production in the maintenance of the mechanical response. In order to maintain a constant magnetic field a constant current has to be maintained in the coils of the electromagnet, the whole of the energy of which is degraded into heat. This is analogous to a tetanie contraction. "Heat produced in the disappearance of the mechanical response. When the electromotive force in the circuit of the electromagnet is removed the potential energy of the magnetic field disappears in the process of inducing a current in the coil of the electromagnet or in neighboring conductors, the energy of this current being dissipated finally as heat. Thus, when we remove the E. M. F. exciting the electromagnet there is not a cessation of the heat-production; the heat-production continues until the whole of the magnetic energy of the field has been dissipated as heat through the intermediation of induced currents. Similarly in the muscle, as shown in this paper, when the stimulus ends the heat-production does not stop at once:

it continues until all the elastic potential energy of the muscle has disappeared. “The recovery process. ‘The whole of the phenomena described above are independent of the immediate presence of oxygen. When however it is required to recharge the accumulator an engine is started up, oxygen and fuel are consumed, heat and mechanical energy are liberated, a dynamo is turned and current is produced. Similarly in the muscle, when recovery is necessary some mechanism removing lactic acid is set in motion, oxygen is consumed, heat is produced and the muscle is restored to its previous condition.

“The heat produced at rest. It is known that accumulators left standing ‘run down’ gradually of themselves. This process of ‘running down’ must liberate heat, and if the accumulators are to be kept in condition it is necessary to recharge them. This continual recharging also involves a production of heat. Similarly, the muscle even when kept in oxygen-free atmosphere at rest liberates heat (together with lactic acid) continuously for long periods: if suffcient oxygen be present the running down process is balanced by a continual recharging one with an increased production of heat.

“The maintenance of tension in an unstriated muscle. Some unstriated muscles can, unlike the striated ones, exert a considerable tension for long periods without any appreciable increase in the CO, output. This fits into our analogy if we suppose that the core of the electromagnet is made of hard steel instead of soft iron, so that the magnetic pull is maintained with no further expenditure of energy until a current is sent into the electromagnet in the opposite direction to demagnetize it."

What Hill and Hartree express as an analogy we conceive to be an identity. The variations in the nuclear-plasma relation which accompany cell division have been analyzed by many biologists and various theories as to their significance have been offered. Many of these are summarized by Robertson in his monograph on “The Chemical Basis of Growth and Senescence," from which the following excerpts are taken: ° *Tt has been shown by R. Hertwig that immediately after the conclusion of cell-division a slight diminution of nuclear volume occurs which is sueceeded by a slow and almost uniform rate of growth which is termed by Hertwig the ‘functional growth’ of the nucleus. During this phase of nuclear growth the cytoplasm grows both abso-

lutely and relatively more rapidly than the nucleus. This is succeeded by a phase of extremely rapid nuclear growth, termed by Hertwig ‘divisional growth’ during which the nucleus increases in volume at a relatively greater speed than the cytoplasm. In this way the ratio of nuclear to cytoplasmic material which obtained at the preceding division, the ‘kernplasma-relation’ of Hertwig, is regained and at this moment cell-division normally recurs.

“All observers are agreed that the most rapid nuclear growth occurs shortly before mitosis. The rate of nuclear growth therefore undergoes acceleration as it proceeds. The velocity of cytoplasmic growth, on the contrary, is comparatively uniform... . “The kernplasma-relation is by no means constant in the different cells comprising an organism, or in unicellular organisms under varying environmental conditions. Thus Conklin, who agrees with Hertwig that ‘the growth of the nucleus is more rapid in the last stage of the resting period preceding mitosis than at any other time in the cell cycle, finds that the kernplasma-relation is extremely variable even in the earliest stages of embryonic development and Popoff has shown that by exposing infusoria to low temperatures abnormally high kernplasma-ratios may be obtained. We shall revert to the significance of these variations of the kernplasma-relation in later chapters, but for the present the fact which claims our attention is the autoacceleration which the growth of the nucleus displays, in contrast to the comparatively steady rate of accumulation of cytoplasm. Evidently we must infer that the whole of the accelerative agent is not shed from the cells into the medium which bathes them, but that a portion is also resident within the nucleus.

“There is also an entirely independent reason for ascribing the source of the autocatalyst of cell-multiplication to the nucleus. This is the fact, the experimental evidence of which will be described later, that the accelerative agent is only shed from cells into the pericellular fluid at the moment of division, when the nuclear membrané has been dissolved. The fact that it is shed at this period leads us to infer that no obstacle exists to prevent its issuance from cytoplasm, yet in the interdivisional periods it does not escape at all. Evidently, therefore, it is not present in the cytoplasm during the interdivisional period (at least in the necessary excess to permit issuance into the pericellular medium), and it must be prevented from escaping from the cell by the membrane which encloses the nucleus during this period.

«Tt is to the nucleus, therefore, that we must look, alike for the source of the accelerative agent in cellular multiplication, and the source of the autocatalytie time-relations which distinguish all types of growth. With certain special exceptions, such as the maturation of ova, or spermatogenesis, or the occasional formation of polynuclear cells, the growth of cytoplasm is determined by the multiplication of nuclei, for the obvious reason that nuclear division pre-

cedes and determines the moment of cellular division, and the subdivision of protoplasm ensures the accessibility of nutrients to ail its parts and hence the uninterrupted growth of cytoplasm. Thus, if the production of nuclear materials in a multicellular organism or a culture of unicellular organisms is autocatalyzed, then the total production of protoplasm must similarly display autocatalytie timerelations.” Loeb and Osterhout have both shown that the nucleus is primarily concerned in the variations in oxidation within the cell, especially in the processes which are controlled by fertilization.

Ewing gives a valuable discussion of the relation of tumor cells to sex cells: 18 “The abnormal capacity for growth has long suggested that tumorcells have some relation to sex cells. In some animals the entire series of sex cells from the fertilized ovum up to the new egg cell has been traced as a distinct series apart from the somatic cells. In this series the mitotic nucleus exhibits only one-half the usual number of chromosomes, and these instead of assuming a V shape and radial arrangement are ring or loop shaped cr composed of coarse granules. This gametogenous mitosis has also been observed in the growing edges of tumors (Farmer, Moore, Walker) and it may be produced by chemical irritants. Its occurrence does not signify that tumorcells are equivalent to sex cells, and yet in connection with the invasive properties and striking altruistic relations of both classes it shows that tumor-cells and sex cells have some interesting points of resemblance. Spencer, Hertwig, and others claim that the sex potencies of somatic cells are not lost, but only suppressed. On this basis Williams has built an elaborate and ingenious argument to show that tumor growth signifies the reawakening of the reproductive functions in the somatic cells. According to this theory tumor growth is a form of agamogenesis comparable to the budding of plants.

“Many have supposed that tumor-cells are fertilized cells, through conjugation with leukocytes (Klebs), by parthenogenesis (Waldeyer), by conjugation of endothelium and fibroblasts (Recklinghausen), by nuclear conjugation (Auerbach, Bashford), or by endogenous cell infection. “None of these hypotheses has survived criticism and the theory of cell autonomy remains content in the position that tumor-cells emancipated from growth restraints are merely exhibiting their natural capacity for growth.”

In considering the “nutrient level in relation to growth” Robertson cites the work of certain investigators in support of a conception which is especially pertinent to our own discussion. Many investigators have found that in starvation the cytoplasm of the cells is primarily affected, the nuclei being not reduced in size; that even with rupture of the cell boundaries the nuclei remain comparatively undisturbed; moreover “Tt has been observed by Morgulis that there is a great acceleration of growth-rate in salamanders after a period of inanition. This may be most strikingly demonstrated by comparing the proportion of the food intake which is converted into protoplasm before and after a period of inanition. If at a certain period of growth the proportion of food converted into protoplasm was 26 per cent, after starvation and the readmission of food it rose to as high as 73 per cent. He states that ‘it is possible that the reduction in size of the cells, , or rather the diminished ratio between cell and nucleus, has something to do with the observed processes of intense growth, and that the rejuvenescence of the organism is analogous to the condition in the embryo, where the cell-body is likewise small in relation to its nucleus.’ 7 *

Robertson extends his conception of the vital influence of the nuclear-plasma relation on the cells of the organism to the development of cancer as follows: “Normally the degree of differentiation attained in the repair of lost or injured tissue does not exceed that which is still subject to control by the competition of adjacent cells, and the prevailing accumulation of autocatalyst. But this process, if repeated again and again, becomes virtually a process of selective breeding, whereby the cells of the lowest nuclear ratios are favored and enabled to propagate. Should the inherited variability of the cells in that locality enable, at length, the appearance of a type of cell so physiologically differentiated from its competitors, as to be able to multiply freely at the prevailing nutrient level, and in the presence of the prevailing accumulations of autocatalyst, then an outburst of reproductive activity must inevitably ensue, and the successful type of cell will inaugurate, if it is sufficiently differentiated, a malignant tumor. .

“The tumor, in the light of this hypothesis, owes its origin to an abnormal variability of the nuclear-cytoplasmic ratios in the tissues OCDE host 5s. “Thus the development of cancer may be regarded as a phenomenon of hyper-differentiation of the cells of the host, brought about by repeated selection of types suitable for multiplication under conditions which inhibit the multiplication of cells of the host. The increase of autocatalyst due to the cells of the tumor itself must, however, render the nutrient medium even less suitable than before

for nuclear synthesis in the cells of the host, so that senescence of the host should be accelerated by cancer. This effect would be most intense locally and radiate outwards from the cancer tissue, forming an autocatalyst gradient descending from within outwards. The maintenance of normal nuclear ratios by the tissues immediately surrounding the tumor will thus be rendered more and more difficult. It is probably to this factor that the invasive quality of malignant tumors must be ascribed and its magnitude will depend simply upon : the difference between the prevailing nuclear ratios in the adjacent tissues and the nuclear ratio which obtains in the neoplasm. Аз Whitman has pointed out, increase of the rate of multiplication of any tissue by itself would merely lead to hyperplasia and not to invasion and destruction of adjacent tissue. But if the rate of multiplication be sufficiently rapid then this second effect will supervene also and hyperplasia will be succeeded by invasion. For е · same reason we can understand why cancer is so preéminently a disease of old age, because the increasing senescence of the normal tissues renders the advancement of their senescence to the point of ineompatibility with life a comparatively easy matter, and their invasion by the tumor tissue is facilitated."

Robertson assigns to a hypothetical “nuclear autocatalyst" the function of maintaining the variations in nuclear-plasma relation which result in growth, cell-division, differentiation, ete. We assign the cause of these variations to variations in the energy— electric energy—which is the result of the essential bipolarism of the living cell. 6. Haas and Нил. An Introduction to the Chemistry of Plant Products, London, 1921, Vol. 2, p. 13. of the Department of Development and Research of the American Telephone and Telegraph Company New York *

THERE is considerable experimental evidence that impulses sent by the brain to the various organs and muscles of the body have an electrical character. ‘These nerve impulses have been found to travel at the rate of 80 feet per second, which of course is much less than the velocity of electrical impulses along a wire or through space. If the speed 80 feet per second is correct, then the impulse along a nerve is not of the exact character of those along wires. Nevertheless one can well imagine a shift of electric fields by displacements of ions, which move at a velocity through solutions much slower than impulses along a wire.

The outstanding point to consider is that nerve impulses are electrical in character. The nerves have been found to be unaffected in temperature when impulses are sent along them, but one knows that the core of the nerve is a very good conductor. The amount of energy transformed to heat when small currents traverse this low resistance would be too small and perhaps too difficult to determine experimentally in a minute nerve structure. То repeat, the outstanding fact is that nerve impulses are electrical in character, Therefore there must be an energy transformation with the necessary condition that one of the aspects of energy has been electrical. In other words, to make possible and to give rise to these electrical impulses there must be a supply of electrical energy. Fundamentally a supply of electrical energy means a difference in potential, that is, a voltage.

* The author wishes to express his appreciation of Dr. Perrine's consent to the publication of this analysis of the bipolar theory from the point of In every dynamic electric circuit, the discrete electrical charges must, in their coursing through the circuit, take on energy in part of the circuit, and give out energy in other parts. When these electrical charges are raised in potential, that is, pass from a lower to higher potential, that is, go from negative to positive, they take on energy. If the circuit is not closed, this passing from negative to positive potential stops very quickly, with the result that one has a static condition established, as in a dry battery not connected to any electrical device. If, however, there is a closed circuit, then in the external circuit, as one says, the electrical charges pass from a high potential to a low potential, that is, from positive to negative, and in so doing give out energy. This energy given out may result in heat, mechanical motion, or chemical decomposition. This means, of course, that the difference in potential originally established statically must now be maintained dynamically within the internal circuit, if there is to be a continuous energy transformation maintained. In the body the network of nerves corresponds to the external circuit, where energy is given out by the nerve to the muscle. This amount of energy is very small, and could be considered as a trigger to release a greater amount of energy in the muscle or the organ concerned. This trigger action, in which a small amount of energy releases a great amount of energy, that is, the nerve impulse having in it the concept of an amplifier, is a striking fact for consideration. The nerve impulses are sent out by the brain. Hence it is feasible to regard the brain as the positive pole of the battery.

On account of conductivity and temperature experiments already performed together with the outstanding fact that a number of organs except the liver can be removed and life ensue, the liver can be regarded as the negative pole of the battery, that is, it is reasonable to consider that the liver is the only organ which is absolutely essential in the body’s electrical circuit. The proposition is, therefore, that as long as there exists a potential between the brain and the liver, there would be available a supply of electrical energy from which the nervous system could get energy for its nerve impulses, and thereby life could be maintained. If there is no supply of electrical energy, that is, in electrical terms, if no potential exists between these two organs, then death ensues, since no stimulus could be given to any muscle or organ.

As previously stated, the fundamental fact'to consider is energy transformation. Тһе potential between brain and liver must not only exist, but must be maintained. This means energy must be supplied in either the brain or liver, or in both, in order to drive electrical charges from negative to positive, thereby storing electrical potential energy. This energy could be very well supplied by the oxidation, which means a release of energy which takes place in these two organs. The oxidation which takes place in the cortex of the brain is greater per unit volume than anywhere else in the body. It would seem, therefore, that as a result. of this oxidation in the brain, there could be a very definite rise in potential between certain parts of the brain structure itself. As stated above, oxidation means release of energy and this could be utilized to give an increased potential within the brain cells, that is, between the nucleus and its environs. It has been shown experimentally that within the cells of both the liver and the brain the hydrogen ion concentration differs very definitely in the nucleus and its environs. This would mean that there could exist a difference in an increase in potential in both organs. This means that the outstanding difference in potential between brain and liver might be an additive result of the two potentials existing in both the brain and the liver. Of course, oxidation in both organs would supply the energy necessary for the establishment of a voltage in each case.

It is a further experimental fact that the blood stream surrounding the cells of the liver contains bile, and if the bile fails, death ensues. This might indicate that a major portion of the outstanding potential between the two organs exists in the liver. However, a greater amount of oxidation in the brain would indicate that the major portion of the outstanding potential is developed in the brain. It is not easy to see how either organ as a whole obtains a potential, since the nuclei of the separate cells are not connected so as to be analogous to one large plate of a battery. On the other hand, it is easy to see how the outer portions of each cell could be in contact, and thereby form one big plate of a battery. In any event, however, the greater number of discrete cells in which individually there is potential would mean not an increased potential with increased number of cells, but rather an increased availability of energy. This picture of the battery in the body is similar to the picture of the action present in the battery invented by Daniell, sometimes called in one of its forms the “crow foot battery.” In this battery a zinc bar is placed in zinc sulphate contained in a porous cup. The porous cup and its contents are then placed in a copper sulphate solution, into which a copper plate is also placed. The two solutions are kept separate by use of this porous earthenware cup. In the internal circuit of this battery, if one travels from the zinc plate to the copper plate, one finds a rise in potential

of about 0.5 as one passes from zinc to zine sulphate, and later a. second rise in potential as one passes from copper sulphate to copper plate, giving an outstanding voltage of 1.1 volts. 'To compare the battery in the body to the Daniell cell seems a more valid comparison than comparing it to a common battery of zinc and copper in a sulphuric acid solution, where the entire rise in potential occurs as one passes from zinc to sulphurie acid, with a copper terminal acting as a means to get in contact with the high potential solution with no change in potential occurring at the interface of solution and copper.

The experimental evidence that the hydrogen ion concentration differs in the nuclear part of the cells of both brain and liver from that of the outer portion, together with the fact that oxidation supplies energy in both organs, indicates fairly definitely that there could exist a potential difference between the two portions of the cell itself. These two discrete potential differences existing in the two organs could very well add to give an outstanding potential between the brain and liver with the blood stream between the two organs.serving as the connectiug medium for that part of the battery commonly called the internal circuit. Аз stated above, the magnitude of these two distinct voltages would undoubtedly be different, and from two different points of view one could argue that the major portion of the voltage exists in one of the organs. In any event, just what the actual relative magnitudes of these potentials might be, it is not easy to surmise.

It is an experimental fact that the nerve sheath is а very poor electrieal conductor, while the herve core is a good conductor. This would make it very possible for the network of nerves along which electrical impulses are passing to be imbedded within the battery structure itself, and thereby function completely as an electrical circuit. This would mean that the internal and external circuits would be inter-twined in contrast to the usual picture of an electrical circuit where the external circuit is well removed on the outside of the battery structure itself. The returning blood stream from the muscle back to the liver, thence to the heart, could be pietured as a possible return path for the discrete electrical charges sent out by the brain to the individual muscles and organs, and finally to the point of low potential, namely the liver. То recapitulate, electrical impulses must be supplied to the organs and muscles of the body in order that a living organism be maintained. This necessitates a supply of electrical energy which in turn means a transformation of chemical energy, in this case oxidation, into electrical potential, which is one of the two factors involved in elec-

trical energy, the other being quantity of electricity, which for sake of easy understanding we will call current, measured in amperes. Hence the availability of energy supply to the organs and muscles, or rather the energy supply available for the trigger action fed by the nerve impulse is dependent upon a potential and a conducting path existing between brain and liver, both for the internal and the external circuit. On the one hand, if the potential between these organs is lowered, it means that the amount of available energy output is lowered, provided, of course, the electrical resistance is kept constant. Now it has been shown that the electrical resistance of these two organs changes with fatigue and shock, that is, the conductivity is changed. This change of resistance would mean a possible change in energy supply output, even if the potential were not changed.