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INTRODUCTION

In this volume I present the essence of a major revolution in cell physiology, the first since the cell was recognized as the basic unit of life a century and a half ago.

In A Physical Theory of the Living State (Ling 1962), I presented decisive experimental evidence against the conventional membrane-pump theory of the living cell, and introduced a new and much broader theory called the association-induction hypothesis. Results of worldwide testing of my work in the twenty-one years following were cast in historic and contemporary perspective and published by Plenum in a monograph entitled In Search of the Physical Basis of Life (Ling 1984). Now, after several more years of intensive research, the revolution is finally completed and a new paradigm is launched.

Like many paradigms introduced in the past, this one holds great promise. In its brief history, it has already given rise to one life-enhancing diagnostic tool, magnetic resonance imaging (MRI)[1].

Yet there has been strong resistance to the new concepts introduced. The extraordinary ferocity of this resistance may itself testify to the far-reaching importance of the present revolution. For, as pointed out by science historian I. B. Cohen, "Every... revolution in science has engendered an opposition among some scientists; the degree and extent of antagonism may even be taken as a measure of the profundity of the revolutionary changes ..." (Cohen 1985, 18).

For reasons to be described, it is important that the revolution and the new opportunities it has created be made known to as many relevant persons as possible, and as soon as possible: To teachers, researchers, students, scientist-administrators, and science publishers, among others. This is because a correct basic theory of cell physiology, besides its great intrinsic value in mankind's search for knowledge about ourselves and the world we live in, will also play a crucial role in the ultimate conquest of cancer, AIDS, and other incurable diseases.

In the United States alone, a thousand men, women, and children die of cancer every day. AIDS is another killer, and as of now there is no cure. Nor is there assurance that AIDS will be the only deadly virus to confront mankind in the future. Drugs, our ultimate line of defense against fatal as well as nonfatal diseases, are still in a primitive state of development. So far, no drug has been created through understanding; most, if not all, were discovered by accident or by trial and error. But trial and error offers little hope in accomplishing complex objectives soon.

A nation that has achieved the proverbially impossible task of landing a human being on the moon has proven much less successful in conquering cancer and many other incurable diseases. To understand the cause of this disparity, let us consider the following thought experiment.

Suppose with the aid of a time machine we could send a transistor radio to Queen Victoria of England. Enthralled with this magic box, she breaks it by accident. The Queen vows to have it repaired at any cost. Yet we can advise her that no matter how much money she spends and how many scientific geniuses she enlists in her efforts, the radio cannot be fixed. That is, not until the basic knowledge of physics has matured; a transistor radio can then be repaired easily. War on cancer and war on AIDS cannot succeed yet for the same reason that Queen Victoria cannot repair her radio. There is not yet enough basic knowledge — in this case, cell physiology.

In its broad definition, cell physiology can be somewhat arbitrarily divided into two components. Genetics deals with what August Weisman (1834—1914) called "germ plasm." Cell physiology proper deals primarily with what Weisman called "soma." Before its recent spectacular development, genetics had already undergone two major revolutions, in which Charles Darwin and Gregor Mendel, respectively, played key roles. Largescale federal research funding, beginning in the 1940s, then fueled dazzling progress. The deciphering of the genetic code testifies to the rapidity of progress guided by the correct theories. Yet the understanding of genetics alone is not enough; cell physiology proper must also be fully understood in order to provide the foundation for the conquest of cancers and other deadly diseases. The ultimate aim of cell physiology includes the understanding of the most basic mechanisms underlying all living phenomena at the molecular and submolecular level. Unfortunately, the version of cell physiology widely taught and subscribed to today has not reached the level of maturity genetics attained before the forties.

The hypothesis of the living cell widely taught as fact and explicitly serving as the foundation for most biomedical research, is called the membrane-pump theory. In this theory, interpretations of all the major physiological phenomena of the living cell are based on the assumption that the cell interior is in essence an aqueous solution of proteins, ions, and other small and large molecules. Postulated pumps in the cell membrane determine the chemical composition of the cell content at the expense of metabolic energy, by molecular mechanisms still unknown.

Theodor Schwann (1810-1882) founded the Cell Theory. Schwann argued then that all living cells and their nuclei are surrounded by a membrane, and that this membrane is prior in importance to its content. The content of the cellular cavity, i.e., of the interspace between the nuclear and cellular membranes was to Schwann typically a homogeneous, transparent liquid. In his view the cell membrane possessed "metabolic power" by which the membrane chemically altered the fluid substances adjacent to it — the Zeilenkeimstoff outside and the cell content (Inhalt) within (see Hall 1969, 2:194). Comparing the current textbook version of the basic theory of cell physiology with what Theodor Schwann propounded in 1839, one is left with the almost incredible conclusion that little change has been made in this subject since Schwann's time. Yet 148 years have gone by. To give us insight into just how long 148 years is, we need only recall that in 1900, physicists were not at all sure that atoms existed (Bronowski 1973, 351).

It is the purpose of this volume to document the full disproof of the membrane-pump theory and to document the verification of the association-induction hypothesis. It is only now that I can formally announce the completion of a revolution (in the area of cell physiology covered by the membrane-pump theory) because it is only now that all the requirements of a scientific revolution, listed in Chapter 12, have been met.

Why did it take 148 years to evolve a new paradigm? The purpose of cell physiology is not to discover new basic principles that govern the properties and behaviors of the entire universe. Rather, the purpose of cell physiology is to seek understanding of the unique set of natural phenomena we call "life" in terms of the principles of physics already understood from the study of the much simpler inanimate world. For this reason, the ideal time to study cell physiology would be after physics had solved all of the relevant problems. But as pointed out above, cell physiology was already old before physics had reached anywhere near its current state of maturity. As a result, correct early seminal ideas of cell physiology could not continue developing, and in time were checked and rejected, not because the ideas were wrong, but because the physics necessary for further development was not yet in existence.

The new theory of cell physiology, the association-induction hypothesis, traces its origin to the early perceptions of the gelatin-like properties of living matter, and of the unusual behaviors of water when associated withcertain biomacromolecules, and referred to as Schwellungswasser or "imbibition water" (see Chapter 1).

Carl Ludwig (1816—1895) is often regarded as the father of modern physiology. With von Helmholtz, du Bois-Reymond, and Brucke, Ludwig overthrew the old vitalistic concept of life phenomena and inaugurated the physico-chemical approach familiar today. Ludwig discovered in 1849 that dried pig bladders, when soaked in a solution of sodium sulfate, took up much more water proportionately than they did sodium sulfate. He remarked that "the smallest components of the (bladder) membrane have a pronounced affinity for water— whether it is chemical or adhesive will one day be told us by chemistry when it lifts itself out of its present theoretical misery" (Ludwig 1849).

Seventy years later, J. R. Katz quoted this passage from Ludwig under the section title "Carl Ludwig's Problem" in Katz's paper entitled "The Role of Swelling" (Katz 1919). Katz then commented that chemistry had indeed lifted itself out of its theoretical misery, citing the work of van't Hoff, Nernst, Ostwald, Arrhenius, Gibbs. Since Katz's optimistic remarks, another seventy years have gone by.

Ironically, the theoretical work of the scientists Katz so proudly cited did little to promote the further understanding of either the observations of Ludwig or those of Katz. Instead, these scientists played key roles in the promotion and eventual acceptance of the membrane-pump theory. According to this theory, the cell interior is considered a dilute solution; the strong interaction of water with the bulk of the dry matter of living cells, observed by Ludwig and studied by Katz, is considered of minor or no significance. Nor was this outcome surprising. The work of most of these noted scientists dealt primarily with the properties of dilute solutions and with physico-chemical manifestations associated with dilute solutions. Thus van't Hoff's law of osmosis, improperly applied, gave the initial impetus to the acceptance of the membrane theory (see Section 10.1); Arrhenius's theory of ionic dissociation, also improperly applied, became a major roadblock to the recognition of the role of ionic adsorption on proteins in cells (Section 4.2). The work of Ostwald and Nernst played key roles in the development of the earlier membrane theory of cellular electrical potentials (Section 11.1). It is only in the much more recent past that physicists have moved rapidly forward into an area of knowledge that is of direct relevance to the focal interests of Ludwig, of Katz, and of myself.

A branch of modern physics of great importance, statistical mechanics, was pioneered by the great physicist Ludwig Boltzmann. Statistical mechanics has provided the broad conceptual framework on which the association-induction hypothesis is built (Ling 1952, 1962). The great theory of Boltzmann and the theories of physicists de Boer, Zwikker, and Bradley, as well as the association-induction hypothesis, have provided answers to Ludwig's questions and given new insights into the importance of the work of J. R. Katz. (See Section 5.2.5.3, including endnote 5 of Chapter 3.)

It has become increasingly clear that the fundamental laws of physics, even since the maturation of the science, are often too "remote" to be directly applicable to cell physiology. To explain complex living phenomena, cell physiologists must spend lime developing and extending their specialized area of physics, and testing it out on inanimate models which are more complex than those physicists usually deal with — but far less complex, and thus more likely to provide unambiguous answers, than the living cells themselves.

History thus shows why a new paradigm of cell physiology could not have evolved earlier. History also shows us that, following a scientific revolution, only young and forward-looking scientists are able to fairly assess the value of and eventually inherit a new paradigm. Witness three of the world's greatest revolutionaries in their own words:

"I do not expect my ideas to be adopted all at once. The human mind gets creased into a way of seeing things. Those who have envisaged nature according to a certain point of view during much of their career, rise only with difficulty to new ideas. It is the passage of time, therefore, which must confirm or destroy the opinions I have presented. Meanwhile, I observe with great satisfaction that the young people are beginning to study the science without prejudice. ..." (Lavoisier, Reflections on Phlogiston)

"Although I am fully convinced of the truth of the views given in this volume... , I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine... but I look with confidence to the future,—to young and rising naturalists, who will be able to view both sides of the question with impartiality." (Darwin, Origin of Species)

"A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it." (Planck, Scientific Autobiography)

To facilitate familiarity with this new theory and its broad implication, I have composed this volume in a certain way.

(1) It is concise, yet it contains extensive references to the more comprehensive foundational work In Search of the Physical Basis of Life (Ling 1984), offering its readers easy access to rich historical and contemporary background materials. Familiarity with these background materials will in turn provide the kind of firsthand, authoritative knowledge that inspires the self-confidence and the intellectual independence for studying science without prejudice, and for further developing and exploiting a new paradigm.

(2) It deals with all basic aspects of cell physiology as a harmonious and integral whole. Once this self-consistent, theoretical basis is mastered, a young researcher may discover new orders and perspectives in what may seem mere mountains and mountains of scientific "news" of bygone days.

(3) Most important of all, the volume reveals what may be startling to some and yet should be reassuring to all: At the most fundamental level, life phenomena are in fact not only coherent but simple. This simplicity forecasts great opportunities for rapid progress, both in terms of true understanding of living phenomena and in terms of practical application of knowledge obtained. Indeed, the time might not be too distant when we can cure cancer and eliminate other fatal diseases just as easily and routinely as we can repair Queen Victoria's faulty transistor radio.

NOTES

1. MRI scanning, which allows continued quantitative investigation and monitoring of normal and diseased human body parts without surgery or x-ray irradiation, was invented by Dr. Raymond Damadian, holder of the patent (U.S. Patent 3,789,832), who wrote me on November 9, 1977: "On the morning of July 3, 1977, at 4:45 A. M... we achieved with great jubilation the world's first MRI image of the live human body. The achievement originated in the modern concepts of salt water biophysics [introduced by] your treatise, the association-induction hypothesis." The homemade MRI scanner on which the first MRI image of a live human body was made, named "Indomitable" (see Damadian et al. 1977, Kleinfield 1985) is now on exhibit in the Smithsonian Institution, Washington D.C. (Hall of Medical Science, National Museum of American History). Dr. Damadian was awarded the National Technological Award by President Ronald Reagan on July 15, 1988. He was inducted into the National Inventors Hall of Fame on February 12, 1989.

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