A Bipolar Theory of Living Processes

On the day after a lobectomy has been performed, in an exquisitely nervous, excitable patient, the one conspicuous change conspicuous to the nurse, and of infinite comfort to the patient—is the diminution of the intolerable restlessness, the intolerable excitability. We may suggest, therefore, that the nervousness in fever is due to the increased action of the thyroid. Fever.—We have suggested the mechanism by means of which inereased chemical activity, including fever, is produced, but the following question remains: What adaptive purpose is served by the increased temperature? This question is of peculiar significance in view of the obvious fact that this mode

of defense is itself injurious to the organism, sometimes causing permanent injury or death. First of all, we may assume that the chemical invasion of bacteria ean be met only by a chemical defense; that is, that the foreign protein molecule in a foreign environment will be split up more readily then is the living protein molecule of the defending organ; therefore, the more intense the chemical action of the defense, the more certainly and readily will the foreign protein, living or dead, be split up; that is to say, the defense of the body against foreign proteins, such as toxins, is a “purification by fire.”

With each degree of rise in temperature in a physical or a biologic system, chemical activity—hence metabolism—is increased 10 per cent, and with each degree of rise in temperature, the electric conductivity is increased 2.5 per cent. The organism must maintain a standard of chemical purity, and this standard, as we suppose, is reached by burning the foreign proteins in the furnace of the living through intense chemical action, intense oxidation. The foregoing does not apply to the defense of the phagocytes, nor to defense by antibodies, but only to the defense against foreign proteins.

Dry Skin.—1£f the full benefit of the increased body temperature is to be secured, heat must be retained in the body. Sweating produces cooling of the body as the result of evaporation. Hence, in infections we have the high temperature with a dry skin in contrast to the active sweating which results from muscular exertion, when heat is not desired. Chills.—It is obvious that the active muscular contractions of the entire body in the chills which frequently accompany the inauguration of the response to an infection are but an added means of increasing chemical metabolism, just as shivering is a part of the process of increasing metabolism on a cold day. On the other hand, it is equally obvious that a man in surgical shock cannot shiver, because the electrical mechanism that fabricates the chill has broken down.

Why does the temperature fall during the night?—The foregoing discussion suggests that it is because the brain, being the driving battery, must be recharged. This recharging process is probably accomplished during sleep, but in order that the chemical defense may be as little interrupted as possible the periods of sleep are light and short. During sleep the temperature falls because the brain is driving the mechanism less foreibly. АП of the brain does not sleep, however, nor do all the glands or involuntary muscles, hence the temperature remains above normal, although it usually falls below the daylevel.

Thirst.—When the biologie bipolar mechanism is excessively driven in a strong defense against foreign living and dead proteins, large quantities of water are used. The need of abundant water in the operation of a bipolar mechanism has been deseribed; that that need is magnified in the mechanism driven by infection, is obvious. This need is manifested by thirst. The Mechanism of Collapse and Death in Overwhelming Infections.—Gazing directly at the sun breaks down the photoelectro-chemical mechanism of sight. When the sensitive areas and nerves of the body are heavily traumatized or when the individual has been subjected to an overwhelming emotion, the internal lesions of the brain cells are so great that they cannot continue their normal function and become unable to transform potential energy into electric energy at a normal rate, so that the power to perform muscular work, mental work, and glandular work is lessened; the power to maintain the blood-pressure is diminished ; the power to produce the normal amount of body heat is lost, and the state called shock is produced. Since foreign proteins drive the brain cells just as they are driven by emotion or by physical injury it follows that an excessive foreign protein stimulation, such as results from perforation of the intestines, from the penetration of an abscess into a large absorbing cavity, from anaphylaxis, may drive the brain cells to their ultimate destruction—to death.

It is not surprising, then, that precisely the same principles of treatment apply to the shock of acute infection as to traumatic shock; that the same agents that aggravate shock, aggravate fevers, ie, injury, fear, worry, loss of sleep, ether and chloroform anesthesia, muscular exertion, ete. ; and on the other hand, that precisely the same principles of treatment are applicable to both the acute and the Em forms m nfect on, viz., rest, fluids, morphin, sleep.

Infection, like any other cause of exhaustion, may be г garded as an activation of the same bipolar mechanism ; causes an increased fabrication of electric energy; in each ease the fabrication of the electric energy is activated by 6 same organs; in each case, when the drive has been so inten or so prolonged as to produce a permanent change in the driving battery or in any of the activators, exhaustion follows. Anaphylaxis, with its momentous chemical blow, may be likened to a bolt of lightning striking an electric battery.

The suggested interpretation of this group of clinical phe | nomena which we have selected for discussion is sufficient to indicate the basis for our belief that all of the phenomena of life, normal and pathological, can be described in electrochemical terms—are the manifestations of the variations in the operation of one or another essential constituent part of a bipolar mechanism. It follows, logically, that the restoration of the organism, whatever the primary cause of its derangement, requires, in addition to the removal or adjustment of the primarily affected part, the same essential electro-chemical measures, the restoration of the primary batteries by water, the promotion of oxidation, rest and sleep.

SHERRINGTON. The Integrative Action of the Nervous System, New York, 1906, p. 17. Tue three outstanding facts about cancer are (1) that it originates only in the living; (2) that the cancer cells thrive at the expense of the cells of the tissues in which they develop; and (8) that the cancer cells have a much higher capacity for multiplication and growth than do normal living cells. The fundamental requirement in presenting any theory which may explain the nature of cancer, therefore, demands primarily that we discover whether normal cells and cancer cells are distinguished by any physical characteristics which may explain the superior ability of the cancer cell to multiply at the expense of other tissues in which it grows.

The best known example of growth energy is that initiated by fertilization in reproduction. The outstanding facts regarding fertilization which may throw light on the cancer problem are: 1. The spermatozoón has the properties of the nucleus of the ovum with which it unites. (Fig. 45.) 2. Тһе spermatozoón may be said to reinforce the nucleus and as a consequence, 3. The quiescent negative ovum flares up in active metabolism and growth and in consequence shows a striking change in its internal structure (Fig. 46); and it assumes electrical properties, i.e., electricity is a constant phenomenon from the moment of fertilization, so long as the life of the new individual lasts.

This comparison of the processes of the multiplication of cancer cells with that of fertilized cells is no new conception, the similarity of the nuclear changes having even led to the supposition by some that malignant processes actually were the result of some form of fertilization. Moreover, the сусће variations in the growth of tumors correspond to the cyclic changes in nuclear and mitotie activities which have been observed in protozoas. Fic. 45.—The metamorphosis of the nucleus of the spermatid into the head of the spermatozoón. Note the concentration of the nuclear material in the head of the spermatozoón. (From Jordan and Ferguson. Textbook of Histology. New York, 1916, p. 484.)

The whole histologic picture of malignancy indicates that it is primarily nuclear in origin as is suggested especially by the large nuclear plasma ratio which is maintained either by the size of a single nucleus or by multiple nuclei (Figs. 47 and 48), by nuclear hyperchromatism in the active stages and by the shrinkage of the nuclei in the degenerating or necrosed areas. Physical chemists (McClendon, Lillie, Loeb, ete.) have shown that fertilization of the ovum is attended by an increase in permeability; that the state of activity of cells, whether in the course of normal functioning or in multiplying, is attended

| Се) pue z, ‘dd 'бобт “етүЧәрецчд ‘АЗотоззин Jo xooqjxo[p ‘лайн ‘рортлест ‘цоя шолу) ‘потуе2тиахер Витмојјој sosuvyo те[п[үәәел}шт əy} JO иотуъјиәѕәлдәл orjeuroqog— 97r “DIT by an increase in permeability. On the basis, therefore, that the processes of cell division in cancer are analogous to the processes of cell division in fertilized cells we have applied certain biophysical methods of measurement to various types of tumors, both benign and malignant, and our results appear to

Fig. 47.—Spider cell with multiple nuclei from rhabdomyosarcoma. (From Ewing: Neoplastic Diseases. Philadelphia, 1922, p. 218.) indicate that the nature of cancer falls within the domain of the bipolar theory. Certain analogies between cancer and the pyogenic infections may aid in this interpretation. Cancer cells multiply, bacteria multiply, each finds restraint in certain tissues. Neither cancer nor pyogenic infection commonly attacks tissues of high oxidative capacity; thus neither cancer nor pyogenic infection primarily attacks the heart muscle, the voluntary muscles, the

cortex of the brain, the normal thyroid gland, the liver, the parenchyma of the kidney, the spleen, etc. No enzyme, no specifio chemieal property has been found to account for this fact. These are tissues of high chemical activities; these organs are homologous in structure and their cells are closely approximated and bathed in fluid; in other words, these organs are concentrated cell suspensions. Neither infection nor cancer attacks primarily the anatomically and physiologically intact surface layers of cells like the skin and mucous membranes, the latter in turn being an electrically charged cell suspension system. They attack these after the normal cells are disturbed. Our first generalization then is that cancer originates not in the midst of a cell suspension such as the cellular organs but

at the boundary points between highly cellular and less cellular structures. These less cellular struetures—subeutaneous, submucous—are successfully attacked by cancer or infection only when the cellular defense is broken down; in the case of a pyogenic invasion a single break in the line of defense may be sufficient for entrance; cancer depends rather upon the gradual lessening of the defense which results from the frequent breakslower cancer has passed this first line of defense, each follows the path of least resistance—namely, the lymphatic channels and the connective tissue, rather than attacking the solid cellular organs.

Another analogy between cancer and infection is found in the faet that each obeys laws of cell division and growth which apparently are the same as those which govern the cells of the host. Both cancer and infection are repulsed by vigorous metabolic activity within the defending structures; thus, as we have already noted, the heart muscle, the voluntary muscles, the normal thyroid, are relatively immune. То this fact, we may add the significant fact that bacteria do not attack the most active part of the cell itself; that is, the nucleus of the cell is highly immune to pyogenic invasion. To this statement it should be added that the cell nucleus and bacteria show a similar reaction to stains. Finally, unlike the normal cells of animals, cancer cells and bacteria have no specific function ; they possess growth energy only.

From this argument we conclude that the area of oxidating surface in the nucleus of a cell as compared with the area of oxidating surface in the cytoplasm is but another way of expressing the nuelear plasma relationship and signifies that the larger the nucleus in comparison with the cytoplasm the greater the energy potential of the cell. Thus, if two cells have ап identieal organization, an identical energy potential, then, with respect to each other in the competition for nutrition their chances are even, but if in one of two adjacent cells the size and organization of the nucleus are such as to give it a greater capacity for oxidation, hence a greater demand for nutrition,

then the cell of comparatively low oxidative capacity will suffer in the competition and will break down in starvation. As we have stated above, in cancer cells the nuclear plasma relation quantitatively resembles that of fertilized cells. Be- fore fertilization the ovum in itself is so lacking in organization and hence in oxidative capacity that there is apparently little or no difference in potential between its nucleus and its cytoplasm—it carries little or no electric charge, it is inactive, negative. But when the nucleus of the ovum is reinforced by the nucleus-like spermatozoón there is at once established a difference in energy potential within the cell, oxidation becomes rapid, nutrition is demanded, the size of the nucleus increases, mitosis is inaugurated, cell division occurs.

As we have stated, our interpretation of cancer assumes that the difference between the cancer cell and the neighboring cells of lower potential is analogous to the difference between the unfertilized and the fertilized ovum. The analogy ends, however, once the mechanism of cell division has been established, for cancer cells have little or no differentiation. If the foregoing biophysical interpretation is correct, then cancer tissue must meet the following biophysical requirements: (1) the cancer cells must have a high capacity for the storage of electric charges; and (2) the conductivity of cancer tissue must show specific variations from the conductivity of normal tissues. That is, if our assumption is correct, then the lipoid films of the cancer cells, of the normal cells and of the fertilized cells would take electric charges in a direct ratio to the combined surface area of their lipoid films. For instance, though in its external appearance a fertilized fish egg is apparently the same as an unfertilized egg, one would expect the former to show a higher capacity than the latter; one would expect that the capacity of cancer cells would be higher than that of normal cells; one would expect that radiation would lower the capacity of cells; one would expect to find a higher capacity in such cellular tissues as the brain, liver, muscles, adrenals, thyroid, spleen, pancreas, than in such indifferent tissues as connective tissue and fat.

Our first biophysical investigation of cancer consisted in a series of comparative measurements of the electric conductivity of normal and of pathological tissues (Appendix C). The clinical tissues measured included malignant and benign tumors Fic. 49.—Comparison of the electric conductivity of carcinoma of the breast with that of comparatively normal portions of the same gland (3 cases). of the breast and of the uterus, uleer and carcinoma of the stomach, carcinoma of the rectum, malignant and benign tumors of the mouth, jaws, and neck, X-ray burns and various types of goiters—hyperplasia, fetal adenoma, multiple adenoma, toxic

adenoma, exophthalmic goiter, simple colloid goiter. The following were the significant findings: 1. In all instances in which comparative measurements were made the conductivity of the malignant growth was higher than that of a normal portion of the same organ. (Figs. 49 and 50.) Fic. 50.—Comparison of the electric conductivity of neoplasms of the uterus with that of comparatively normal tissues of the same organ (3 cases). ђ 2. The outer growing parts of cancers showed a high соп- ductivity in contrast with the conductivity of the central nongrowing parts.

were found in the degenerating adenomata and the malignant thyroids; the conductivities of the hyperplastic thyroids were lower; and the conductivities of the colloid goiters were the lowest of any of the pathological tissues studied. (Fig. 51.) These measurements were made with an alternating current of 1000 cycles. This comparatively low frequency of current would probably find the path of lowest resistance, in large part, undoubtedly, through the intercellular tissues.

Extending this line of inquiry, the theoretical requirement that cancer tissue must have a high capacity for the storage of electric charges, was given to Dr. Fricke and Dr. Morse, of the Biophysical Department of the Cleveland Clinic Foundation for investigation. Dr. Fricke has derived a formula and devised an apparatus whereby frequencies ranging from 800 to 416 million or more cycles can be applied to the cells under investigation. The physical estimations of the capacity of normal tissue and of benign and malignant tumors thus far made are as follows:

Eighty specimens from 58 cases have been investigated, including 15 carcinomata of various types, 3 sarcomata, 3 benign tumors and 16 goiters of various types. In the arbitrary units employed normal tissues have ranged from 28.2 m. m. f. for fatty tissue, and 60 to 180 m. m. f. for connective tissue to 600 m. m. f. for the normal uterus. АП of the earcinomata have had a relatively high capacity ranging from 660 to 1920 m. m. f. in the actively growing portions of the growth. The degenerated portions of the growth have had a lower capacity and radiated tissues have been much lower, the tissue in one radiated case showing as low а capacity as 180 m. m. f. Thus far in every case studied the tissue in which the cancer had developed had a lower capacity than the cancer itself. This difference has been particularly marked in the ease of eareinomata of the breast in which the capacity of the adjacent glandular connective or fatty tissue has often been less than 1/10 that of the malignant tissue. Among the goiters colloid goiters have shown the highest capacity of any tissues studied, as much as 4560 m. m. f. in one case, the average being in the neighborhood of 2400. This finding is of prime significance in view of the fact that cancer of the thyroid never develops in a colloid goiter.

'вәп5вт} orjse[doou јо pue јешлоц јо Адтоваво отлдодје оца Jo иоѕтлейшоо —'66 ‘DI Adenomas and hyperplastic thyroids have, as a rule, had a low capacity for glandular tissue which in general seemed to show a somewhat higher capacity than other tissue. Connective tissue has usually a very low value, between one and three, and the capacity of fatty tissue may be as low as 28.2 m. m. f., while an aetive inflammatory process may show a capacity of 1200 m. m. f. (Fig. 52.) These measurements run parallel relatively to the conduetivity measurements previously made by Miss Hosmer and Miss Rowland.

The findings in these researches suggested that much of the story of cancer may ultimately be derived from conductivity and capacity measurements. These findings moreover are in accord with the histological picture presented by the microscope. The microscope indicates the general structure which in turn indicates the capacity of the cell for work, multiplication, function, ete. A further striking parallel between the cytologic picture and biophysical findings is found in the fact that cells which have been subjected to lethal X-ray or radium radiation show loss of differential stainability and in our laboratory Fricke and Morse have shown that heavily radiated tissue almost wholly loses its capacity. |

Armed with these physical facts, let us see to what extent some of the well-known facts regarding cancer may be harmonized. First of all, on the basis of electric potential, implying as it does oxidative capacity, if two cells are side by side competing for food, the one having the higher potential, such as the fertilized cell or the cancer cell, starves out, and if the higher potential—higher oxidative capacity—persists long enough, destroys the ordinary tissue. Among cells with equal capacity, such as those within the cancer itself or the daughter cells of the fertilized ovum, division oceurs evenly, no one starves another. This fact explains why cancer does not arise either primarily or secondarily in that fiery furnace, the heart muscle, or in other muscles, or in the cortex of the brain, or in the normal thyroid gland, ete. It also indicates why when from some cause the capacity of an epithelial cell resting on subeutaneous or submucous cells of low capacity has been increased until it is equal to the capacity resulting from fertilization, that cell will easily rob the neighboring inactive tissues of their

nutrition and will supplant them, just as the vigorous growing weed overgrows and supplants the highly differentiated less vigorous domestie crops. A consideration of the conditions under which cancer de- ` velops in the thyroid gland is illuminating. First, cancer almost never develops in the normal thyroid or in colloid goiters but over 90 per cent of cancers of the thyroid arise in the fetal adenomata. On the basis of our premise a physicist would have predicted that that would be the case, even though he knew nothing about the actual incidence of cancer in the thyroid gland; for, as has been stated above, the capacity measurements made by Fricke and Morse show that both colloid goiter and the normal gland have a higher capacity than cancer of the thyroid, while the capacity of fetal adenoma is lower than that of cancer.