A Revolution in the Physiology
of the Living Cell


by
Gilbert N. Ling, Ph.D.

Damadian Foundation for Basic and Cancer Research
c/o Fonar Corporation, Melville, New York

KRIEGER PUBLISHING COMPANY
MALABAR, FLORIDA
1992
ISBN 0-89464-398-3

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A Short History and Acknowledgments

The completion of the present volume gives me an opportunity to say thanks to America in general and to some special individuals. For without their support, I certainly would not be doing what I am doing now: reporting the completion of a major scientific revolution in cell physiology, the foundation science of biology and medicine. A revolution of this scope and in such a central field of knowledge happens only at long-time intervals. And of course each revolution can happen just once. To play a part in the development and completion of this revolution is an honor and privilege of the highest kind indeed. To say thanks is not always an easy task. Because so many individuals and institutions have been involved in so many different ways and over such a long period of time; to recognize and thank each properly, a short history of the work is needed. This history began in China.

After my graduation from the National Central University in Chungking, I participated in a nationwide competitive examination and won the biology slot of what is known as the Boxer scholarshipsa historically important gift of America to China in the wake of the Boxer rebellion (endnote 1). By the time the result of this examination was announced, I had enrolled in the graduate school of the National Tsing Hua University in Kunming. My roommate there, C. N. Yangwho, with T. D. Lee, was to be awarded the Nobel prize for physics in 1957won the physics slot. Full of high hopes and wonderment, we Hew over the Himalayan "hump," and sailed from Calcutta. On a cold November afternoon in 1945, we first saw, through snow Hurries, New York City's looming majestic skyline.

With the encouragement of Prof. C. O-Yang, Head of the Department of Biology at the National Central University, I had taken many elective courses and read fairly extensively in order to prepare myself to study mechanistic biology (e.g., cell physiology). I came upon Ralph W. Gerard's monograph: "The Unresting Cells" (Harper, 1940). I admired the "holistic" approach in his concept of the living cell. After the announcement of the result of the Boxer examination, I approached Dr. Gerard and was accepted as his graduate student in the world-famous Department of Physiology at the University of Chicago. From the time I knocked on the door of his third-floor office in Abbott Hall until his untimely death in 1974, Dr. Gerard had been unfailingly an inspiring and caring teacher as well as a scientist of lofty stature and broad vision.

Shortly after my arrival in Chicago, I met Dr. Steven W, Kuffler, who later offered me my first job in his laboratory at the Wilmer Institute of Ophthalmology, Johns Hopkins Medical School in Baltimore. In his kindly and generous way, he gave me full freedom to pursue my own direction of research.

It was in the Welch librarynamed after Dr. Henry Welch who had played an important historical role in bringing American medicine and medical research to the forefront of the worldwhere I spent much time browsing and just thinking. It was in this library I first conceived of a radically new mechanism for a major mystery of the living phenomenon: the ability of living cells to selectively accumulate potassium ion over the highly similar sodium ion (see Section 6.2.4.). In Baltimore I had another piece of great fortune, i.e., meeting and later marrying the beautiful and talented concert-pianist, Shirley Wong.

By this time Dr. Gerard had moved his staff from the University of Chicago to the Neuropsychiatric Institute (NPI) of the University of Illinois Medical School, also located in Chicago. He offered me an opportunity to continue my research in the well-equipped laboratory which he had designed.

At NPI, I wound up the experiments proving beyond any doubt in my mind that there is not enough energy for frog muscle (and other living cells) to operate the postulated sodium pump (as part of the so-called membrane-pump theory). The sodium pump was postulated to explain the same phenomenon mentioned above: the selective accumulation of potassium over sodium ion in living cells. It was at NPI I began to lay the foundation of the new general theory of the living cell that I was to launch later.

After Dr. Gerard had accepted a new job elsewhere, I too accepted in 1957 a position at the newly inaugurated Department of Basic Research at the Eastern Pennsylvania Psychiatric Institute (EPPI) in Philadelphia. The enthusiasm of Dr. George Eisenmann had influenced my relinquishing my Associate Professorship at the University of Illinois and in saying goodbye once more to Chicago and to my able assistants: Arlene Schmolinski, Mary Carol Williams and Margaret Samuels.

In the environment provided by EPPI, at once carefree and intellectually exciting, I continued to develop (and test the predictions of) the new theory of the living cell, which was to be named the association-induction (AI) hypothesis. My research work progressed well with the able help of Leo Kushnir, Margaret Ochsenfeld, Marilyn Welsh, Jeanne Chen, Kathryn Kalis and Kay Slemmer.

Soon after my arrival at EPPI, I began to put down in writing A Physical Theory of the Living State. Even though I had the efficient secretarial assistance of Betty Jane Bruecker and later Shirley Ripka (I am indebted to both), the volume took almost five years to complete. However, before the book appeared in print, the atmosphere at EPPI abruptly changed. Eventually, I and most of the Senior Research Scientists of the Basic Research Department left EPPI. After that, the Department survived for a number of years until it was shut down permanently.

Shortly afterward, I met Pennsylvania Hospital's Frank Elliott, M. D., a brilliant neurologist with a dry sense of humor, a sharp wit and an amazing range of knowledge. We hit off famously from the very first meetingand have remained great friends ever since. Indeed, in recognition of his friendship and the key part he played in sheltering and helping the further development of the association-induction hypothesis, I dedicated my second book In Search of the Physical Basis of Life (Plenum, 1984) to him and to his always interesting, original, and charming wife, "Gee."

Through Frank Elliott's efforts, the John A Hartford Foundation (established by the A and P estate) provided the fund for constructing on the ground of the Pennsylvania Hospital, a new laboratory at the corner of 7th and Delancey streets in the Society Hill area of Philadelphia.

The Pennsylvania Hospital was the first hospital in this country, founded by Benjamin Franklin and Thomas Bond in 1751. Its amphitheater, still beautifully preserved, once witnessed routine operations without anesthesia and later, the eloquence of Joseph Lister advocating aseptic surgery.

When I joined the Pennsylvania Hospital it was just beginning a renaissance; outstanding research-minded scientist-physicians like Frank Elliott were enticed from all over the world. Led by the capable, and enterprising president, H. Robert Cathcart, the Pennsylvania Hospital saw rapid growth and modernization and in time became once again an outstanding hospital in the country. Illustrious and rich in history, prosperous and modern in its current fame, Pennsylvania Hospital was the home of the association-induction hypothesis for the next 27 years.

Soon after my arrival at the Pennsylvania Hospital, my first book, The Physical Theory of the Living State (Ling, 1962) was published by the Blaisdell Publishing Company, a branch of Random House. The new theory was intended to replace the membrane-pump theory, but it offers much more. Though diverse in coverage, the new theory tells a "whole story," built upon a set of self-consistent basic postulates. In this aspect, the AI hypothesis is totally different from the ad hoc membrane-pump theory.

However, the introduction of a new theory was only the beginning. It was during the ensuing 27 years at the Pennsylvania Hospital, that the theory was put to extensive worldwide tests; and confirmed: the purely scientific part of the revolution replacing the membrane-pump theory by the corresponding part of the AI hypothesis had been accomplished.

In this period of time, the financial support of our research came from four sources: the National Science Foundation, the John A. Hartford Foundation, the Office of Naval Research (ONR), and the National Institute of Health (NIH), with the lion's share coming from the last two institutions. For this support, I say thanks. However, I would like to recognize two outstanding scientist-administrators in particular: Dr. Arthur B. Callahan, Program Director of the Medical and Dental Branch, ONR and Dr. Stephen Schiaffino, Associate Director of the Division of Research Grant, NIH.

In my view, both Dr. Callahan and Dr. Schiaffino are capable scientists and thoroughly familiar with the past history of scientific progress (endnote 2), the innovative, iconoclastic nature of my work, and its potential value to the future of biomedical sciences. They also know that it would be grossly unfair, indeed extremely naive to ask those scientific peers, whose fundamental beliefs I have already proved wrong, to judge the merit or lack of it of my work.

Continually monitoring progress made by both sides, Dr. Callahan gave support for my work, as he knew well that virtually all of the U.S. research funds allotted to this general area of research, had been supporting work based on the conventional view.

Drawing a similar conclusion from his first-hand knowledge, Dr. Schiaffino introduced the ad hoc "Special Study Sections" comprising knowledgeable but neutral scientists. From experience, he also seemed to realize that it was imperative not to include in these Special Study Sections, any scientists who had subscribed to the membrane-pump theory exclusively and are thus by definition, my scientific enemies.

Suffice it to mention here that without the support of Drs. Callahan and Schiaffinooften at the risk of their own job security and chance of future promotionas well as the dedicated efforts of the many neutral and fair-minded scientists reviewing my research proposals over the years, the chance of continuing our work would have been nil.

As the AI hypothesis continued to develop, independent scientists began to test the predictions of the AI hypothesis on their own initiative, using among other methods, nuclear magnetic resonance (NMR) technology. Notable among those scientists, who on the basis of their own research came to confirm the AI hypothesis were Dr. Freeman Cope, Dr. Carlton Hazlewood and later Dr. Raymond Damadian. Damadian's discovery of the difference in NMR signals from the water in normal and those from cancer cells set the stage for his invention of the new diagnostic tool now known as magnetic resonance imaging or MRI mentioned earlier (see endnote 1 of Introduction).

For their important contribution in accomplishing much of the work described in this volume, I also acknowledge the skill and dedication of my research associates, in particular Margaret Ochsenfeld, Mildred Gale, Dobrilla Gabrillovich, Marsha Hurok, Patricia Shannon, Grace Bohr, Ellen Ferguson, Cheryl Walton, (the late) Sandy Will, Ann Sobel, Sigrid Jaweed, Kim Peterson, T. Jennine Bersinger, Marianne Tucker, Andrea Ostroski, Christine Vetter, Joanne Bowes, Mary Brady, Chris Murray, Dianne Graham, Dee Zodda, Ya-tsen Fu, Ze-ling Niu, Randy Murphy, John Greenplate, Christopher Reid, Mark Sellers as well as Emmar-Lee Jackson, and Melissa Antley. Thanks are also due to my able secretaries over the years: Diane Weinstein, Nina Primakov, Nancy Hunt, Janice Malseed, Marilyn De Feo, and Jean Brogan.

I thank also my postdoctoral students, Drs. Ignacio Reisin (from Buenos Aires), William Negendank, Wei-hsiao Hu (from the Chejiang Institute of Technology), and Zheng-lian Zhang (from the Beijing Institute of Biophysics), all having contributed very substantially to the success of the revolution.

I am also indebted to my many summer students. With few exceptions they have demonstrated extraordinary capability in absorbing new knowledge quickly and in successfully carrying out demanding experimental studies all within the spell of a summer vacation. They include Edward Rossomando, Harriet Wells, Victor Smollen, E. Denise Campbell, Susan Sneider, Young Kwon, John Baxter, Mark Whalen, Kathlenn Boyce, Mark Ling, Tim Ling, Ken Weiss, Jim Butler, Marion Kelley, Laurie Tomkins, David Blackman, Michael Balter, Davida Kohler, Robert Houle, Jim Wood, Alain D'Andrea, Margaret Stienman, Curtis Cooke, Michael Leitman, Andrew Fischer, Bing Hong Cheak, Howard Dubner, Gerri Magavaro, Andrew Rosen, Sharon Horowitz, Thea Kolebic, Jill Wright, Karen Holmes, Lisa DiSanto, Anna Marie Maguire, John O'Leary and others. Much of their work has either already been published or will be.

As mentioned above, under the protective wings of Drs. Callahan and Schiaffino our work was fairly judged periodically by neutral scientists who consistently recommended continued support. Unfortunately, Dr. Callahan and Schiaffino eventually left their posts. The new administrators held entirely different views in regard to my work. Thus the new Director of Division of Research Grants, Dr. Jerome Green and his subordinates believed strongly that no one applicant should be treated differently from all the others, and accordingly insisted that the new (in-name-only) Special Study Sections must include scientists from both sides. My repeated protests were to no avail. Strongly dominated by my scientific opponents in the panelwho have never openly defended their membrane-pump theory in public against my published refuting evidence, nor challenged in print the AI hypothesis and the confirmatory supportive evidence gathering in the literature for well over a quarter of a centurythe panel "massacred" all three renewal proposals and NIH withdrew all its support. In consequence, my laboratory was forced to close on October 31, 1988 at the height of its productivity.

Since the Pennsylvania Hospital had no resources to support my research, the termination of all my research grants spelled the end of my salary and my research. There was no time left to complete the writing of this volume, no time to obtain a publisher, and no time to write up and publish the large amount of data essential in rounding up the logic of the revolution. It then dawned on me that the revolution so near completion might yet be buried alive forever.

Then from Long Island, my friend, Raymond Damadian came to my rescue. Seven large trucks came to Philadelphia and moved my entire laboratory to Melville, New York. Along with me also came my long-time associate, Margaret Ochsenfeld, and an associate of more recent times, Zhen-dong Chen. I completed the writing of the present volume and eventually signed a contract with Krieger Publishing Company of Melbourne, Florida. The survival of the revolution was assured. In our new environment, my little team soon rose up to a new challenge: to continue basic and cancer research in directions which enhance the chance of the long-term financial success of our host corporation.

The survival of the revolution was assured, because once published, the book will be in safe keeping in many libraries throughout the world, awaiting those scientists, young and old, who understand the nobility, purity and goodness in searching for the truth, in caring for the happiness and suffering of other human beings, and treasure both objectives far above money, power, prestige and public acclaim.

In closing this brief account of the history of this revolution, I want to say thanks to five categories of people not already acknowledged above: my scientific friends; colleagues at the Fonar corporation; Pennsylvania Hospital administrators; my publisher and his staff; and my family.

I have dedicated this volume to my friend, Raymond Damadian and his gracious wife, Donna. The fact that he had made it possible for me to publish this volume and to survive as a working scientist adds yet another testimonial to his great friendship, his profound understanding of the role of correct basic knowledge to the development of beneficial practical applications, and his unshakable dedication to the common good of mankind.

The year 1973 not only saw the crisis in financial support for my laboratory, it also marked the beginning of increasing difficulties I encountered trying to publish my work in the scientific journals that had published my earlier work. It was Adam Lis and Diane Maclaughlin's introduction in 1969 of the journal Physiological Chemistry and Physics (PCP) that has made it possible to document the rapid progress we made in years following. Raymond Damadian (with Freeman Cope) acquired the journal in 1976 and again and again rescued it from bankruptcy before it was eventually on an even keel. This is an occasion for me to thank Adam Lis and Diane Mclaughlin for creating this journal and to point out how in yet another way Raymond Damadian contributed to the completion of this revolution and to the freedom of expression in biomedical sciences.

To the late Freeman Cope and to Carlton Hazlewood, I am deeply indebted for many reasons. As an example I may mention that without their introduction of NMR method to test my theory of cell water, Raymond Damadian might never have invented MRI. Without Raymond Damadian's invention of MRI, he might not have the necessary means to save my scientific life and the revolution.

How Carlton Hazlewood has maintained his scientific integrity and unswerving dedication to searching for truth in the trying environment he had to lace from day to day commands respect from all who study the history of this scientific revolution.

To my long-time friend from our student days, physicist C. N. Yang and his profound knowledge about physics I owe much for the theoretical development of the cooperative aspect of the association-induction hypothesis. I also thank George Karreman, Bud Rorschach, Jim Clegg, Ivan Cameron, Charles Trombitas for their contribution to this volume; Walter Drost-Hanson, Herbert R. Catchpole, Milton B. Engel, for their friendship and support as well as constructive criticisms over the years. In particular, I want to thank Gerald Pollack for the time and efforts he spent in trying to rescue my laboratory from closing, and his many constructive criticisms and valuable suggestions that became a part of the present volume.

After losing so many of my one-time young comrades-in-arms, the continued friendship and unswerving loyalty (to the highest ideal shared) of Ludwig Edelmann of Homburg, Germany and Miklos Kellermayer of Pecs, Hungary are treasured and acknowledged with both gratitude and admiration. For maintaining his scientific honesty, Ludwig Edelmann had not only lost his job, but also the chance of continuing the career as a biophysicist for which he had been trained. Yet he had the resilience, resourcefulness and scientific originality to maintain his status as a first rate scientist, only switching to a different tool of investigation: electron microscopy. As an electron-microscopist, he has continued to introduce new methods leading to the capture of the living state in thin cell sections (see chapters 3 and 4) and to the vindication of the validity of his earlier conclusion concerning the true nature of the living cell.

Miklos Kellermayer's ability in carrying on first-rate research under difficult conditions and his special talent in inspiring a large group of young Hungarian scientists to examine and test the association-induction hypothesis are both important and timely. For these young scientist may very well become the vanguards of the new generation of scientists to lead the future world of biology and medicine. With this thought in mind, and with a very warm heart and many thanks, I welcome the succession of young Hungarian scientists from Miklos Kellermaver's group in Pecs, who have been writing me, communicating with me on science and best of all, coming to visit me at Melville. They include Attila Misetta, Peter Bogner, Szabolcs Somoskeoy, Tamas Henics and Eszter Nagy.

Once more I want to thank Margaret Ochsenfeld for her life-long dedication to her research work which has contributed so much to the completion of this revolution; and for her newly acquired responsibility in taking care of the publication of PCP, now bearing the name, Physiological Chemistry Physics and Medial NMR. For his vital help in moving my old laboratory and transporting it to a new location and for cheerfully carrying on research with our still limited facilities I thank also Zhen-dong Chen, the third member of my present laboratory staff.

Since our arrival at Melville, I have enjoyed the friendship and ever cordial hospitality of just about every member of our new host, the Fonar Corporation. Specifically, I thank Luciano Bonani, Kurt Rehnan, Tim Damadian, Fred Peipman and their staff for many helps including the monumental task of moving my laboratory and equipment to its present location.

Of our friends at the Pennsylvania Hospital, 1 particularly want to acknowledge once moreas I did before with the publication of my second book, In Search of the Physical Basis of Life (Ling, 1984) the generous hospitality and efficient help from President H. Robert Cathcart, Vice President Harry Heston and all departments and their staff members. And with equal feeling, 1 acknowledge the occasional but as a rule timely financial assistance from the Hospital's General Research Support Fund.

I wish to express my appreciation to Robert Krieger of Krieger Publishing Company for publishing the present book. I say thanks to Marie Bowlcs, Krieger's production manager for her ever cheerful and efficient helpfulness; copy editor Miriam Champness for her meticulous, and thoughtful editing of the manuscript; Elaine Rudd for her constructive criticism and suggestions. This section will not be complete without my acknowledgement of J. Jarrett Engineering for the superb typesetting job it has done.

In my final acknowledgment, I want to remember with love, gratitude, (and infinite sadness), my ever-loving and scholarly father and mother (Mr. Yen-tze Ling and Mrs. Chi-lan Ho Ling) who gave me everything, but are no longer here to share with me this moment of triumph. I thank my brother (Morris Y. Ling) and his wife (Chuan-Yu Hua), for living by and passing on the family tradition of scholarship and excellence to their two children, my niece (Elizabeth) Ming-chu (Ling), and my nephew, (Robert) Ming-re, and for taking care of my ailing parents while I was far far away. I also want to thank my sister Nancy, Professor of microbiology at the University of California at Santa Barbara (and her three attractive and accomplished children, James, Jennifer and Jackie) for a life-long close friendship from our earliest days.

With gladness I express my deep gratitude to my wife, Shirley for sharing my life. Her love of, and talent for classic music have enriched and added a new dimension to my life. Her teaching skill, and managerial ability combine to create a home at once cultured, purposeful, affectionate and well-run, making it possible for me to be engaged full time in my scientific pursuits, and for us both to raise three wonderful children, Mark, Tim and Eva. All have been nothing but constant sources of parental joy and pride since their arrival. They as well as their respective spouses Jenny, Kirn and Neil have added to my life's journal, new frontiers of interest, abiding affection, and a great deal of happiness.

NOTES

1. In the year 1900, there was what has been known as the "Boxer Rebellion" in Beijing. In its aftermath, China paid indemnities to all eight nations involved. Japan used its indemnity money further to enhance its military power. America returned the money to found in Beijing the Tsing Hua University and an independent scholarship program. At two- or three-year intervals, some 20 "Boxer scholars" would be chosen in a nationwide, competitive examination open to all qualified college graduates. The winners, one in each field, would be given financial support to pursue graduate studies in the United Slates. Five groups of Boxer scholars had already successfully completed their much-coveted learning experience in America, when the Japanese invasion of China put an abrupt halt to the program.

Then in 1943 the program was activated once morefor the last time. for me, this resumption as well as its timing was a lucky break indeed: It was right after my graduation from the National Central University in Chungking, qualifying me for the competition. Good luck stayed with me and I won the biology slot.

2. Science progressed in the past not by a steady accumulation of knowledge, as had once erroneously been believed. Rather, steady accumulation of knowledge was inter-spersed by quantal jumps or revolutions. As result of each revolution, a set of long-held beliefs were replaced by a new constellation of ideas or what science historian Thomas Kuhn called "paradigm" (Kuhn, 1962).

Kuhn separated scientists into two kinds: normal scientists whose scientific efforts follow conventional paradigms, and revolutionary scientists who introduce new ones. Pointing out that Kuhn's nomenclature is appropriate only for bygone scientists, 1 suggested the designations for contemporary scientists: Type 2 scientists (who follow accepted scientific practices and beliefs and are exemplified byjonas Salk who developed the Salk vaccine) and Type 1 scientists (who go against conventional beliefs and practices and are exemplified by Louis Pasteur, who made the revolutionary discovery of bacterial and viral origin of diseases and vaccination) (Ling, Physiol. Chem. Phys. 10:95, 1978). Only when Type I science has been proven to be correct does it become revolutionary.

Both Type 1 and Type 2 scientists are necessary for the continued progress of science. Indeed, the discovery of Type 1 scientists provides the foundation for the Type 2 discovery of tomorrow. However, while Type 2 scientists strongly benefit from the Type 1 discovery of yesterday, Type 2 scientists and their contemporary Type 1 scientists are at odds and natural enemies.

At the end of the Second World War, the United States embarked on a new enterprise unknown before: large scale financial support of individual scientists for performing basic and practical research. This was an important and highly commendable undertaking. Unfortunately, the method chosen to award the money to some scientists while denying it to others was not carefully thought through. As a result, the system hastily put together, and called the peer-review system, is strongly biased in favor of research that follows traditional ways of thinking (Type 2), while giving no consideration at all to Type 1 science. This system must be overhauled as soon as possible so that it will promote both Type 1 and Type 2 sciences.

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"Gilbert Ling"