Life at the Cell and Below-Cell Level. The Hidden History of a Fundamental Revolution in Biology
"Dr. Ling is one of the most inventive biochemist I have ever met."
Crossword puzzle and fox hunt: two models for scientific research
Science resembles the solving of a crossword puzzle. An ordinary crossword puzzle can be done easily by one person. In solving the scientific puzzle of Nature, an inherent difficulty lies in its immense size. Inevitably, a division of labor is inaugurated and uncoordinated multiple starts are launched. Thus, with perfectly good intentions, fragmentation, the deadliest disease of science, was set in motion. And, for a science like cell physiology, there is a second pitfall.
In solving the cell-physiological puzzle, correct basic physico-chemical concepts rather than words are used to fill the blank spaces. Since these physico-chemical concepts were being discovered at the same time the cell-physiological research was on-going, the early cell physiologists were bound to make wrong entries because the right ones were not yet known. By the time the right physico-chemical ideas came along, wrong entries had already been written into textbooks and taught worldwide year after year to generation after generation of young people at their most impressionable age.
The crossword puzzle analogy emphasizes that there is only one unique solution for each man-made puzzle as well as for the puzzle of Nature. A fox hunt is a cogent model in another aspect. It underscores the critical need of a correct guiding theory. A guess (theory) must be made early on the general direction the fleeing fox has taken, before the chase can begin. Once that guess is correctly made, the rest of the hunt has a much greater chance to proceed fruitfully.
If not, the leader of the hunt must have the courage and wisdom to make changes promptly. Nonetheless, if the discovery of a wrong theory is made late in the game, changing direction is difficult.
The secret of past success in major directional changes
These great inborn difficulties notwithstanding, science has made major directional changes in the past. These changes are referred to as scientific revolutions. What was the secret of their success in the past? Before attempting to answer, let us not forget, successful or not, a scientific revolution has never been easy. For their roles in a scientific revolution, Bruno lost his life at the stake, Galileo was imprisoned for life and Semmelweis died in an insane asylum. Revolutionaries, who did live to see the success of their work, were found more often at the time of, or after, the Enlightenment movement of Western Europe.
Replacing a broadly accepted but wrong guiding theory in science with one closer to truth has been as a rule initiated by one (or a few) individuals). This is what I call Step 1 of a scientific revoluton.107 p 319 However, if science is to survive as a continuing cooperative effort, the new and closer-to-truth revolutionary theory must be accepted by the scientific community as a whole. This conversion of the scientific majority is what science historians call a scientific revolution, but which I believe is Step 2 of that process. (In an earlier writing, I called Step 1 a scientist's scientific revolution, and Step 2 an historian's scientific revolution.107 p 319) Step 2 is as a rule more difficult to accomplish than Step 1. Thus, the great physiologist-physicist, Hermann von Helmholtz expressed a similar view in his 1881 Faraday lecture: "...it is often less difficult for a man of original thought to discover new truth than to discover why other people do not understand and do not follow him."537 p 1
To illustrate how Step 2 of past scientific revolutions actually did get accomplished, I cite two specific examples.
(i) Joseph Priestley (1733-1804) was the Unitarian minister-scientist who, as mentioned earlier, discovered oxygen but believed it to be "dephlogisticated air." When Antoine Lavoisier argued that it was really oxygen, Priestley fought him tooth and nail—until he realized at last that Lavoisier was right. Then Priestley made a 180-degree turn and praised Lavoisier's "chemical revolution" with overflowing admiration and enthusiasm: "There have been few, if any, revolutions in science so great, so sudden and so general.... of what is now named the new system of chemistry."346 Rapid and broad acceptance of Lavoisier's new theory soon followed.
(ii) Michael Faraday (1791-1867) came from a poor family in London. He had no formal education. Yet he revolutionized the field of physics with his iconoclastic concepts of curved electric and magnetic lines of force and his field theory. He was almost entirely rejected by his peers. Some even suggested that "he ought to return to sixth form mathematics before venturing into the deep ocean of Laplacian physics."366 p 507 But there were also striking exceptions.
William Thompson (Lord Kelvin) and especially James Clerk Maxwell both recognized the importance of Faraday's revolutionary concepts. Later Maxwell was to introduce his own famous theory of light as electromagnetic waves, which marked one of the great forward leaps in physics. Yet through it all, Maxwell always insisted that the core of Maxwell's advanced field theory were the ideas Faraday expressed in his life's work.54 p 509, p 513 Thus Step 2 of another major scientific revolution was once more successfully carried out.
Eighty-nine years after Faraday's death, Albert Einstein—possibly the greatest scientist of all time—wrote: "For us, who took in Faraday's ideas so to speak with our mother's milk, it is hard to appreciate their greatness and audacity."365 p 101 And Faraday did all this "without the help of a single mathematical formula."537 p 1
The two sets of historical events cited above tell us that the secret of the successful scientific revolutions of the past lies in the deep belief in fair play or sportsmanship among the key participants in particular and, lesser though still importantly, the scientific community in general. One asks, "Is this secret formula so lofty that one cannot expect it from ordinary people?"
Not so at all. Indeed, every participant in a competitive sport accepts and lives by it without a second thought. It is true that occasionally one hears of someone in sports who used illegal drugs or even attempted to beat up a referee, but that is a rare exception. Almost all participants of competitive sports know how to win and how to lose. In this obedience to a widely accepted ethical rule of fair play, the very spirit of sports resides. This spirit is not inborn. It is taught from the day the child learns to play the game—by fathers, amateur coaches, etc., who love the game, understand it and teach its rules of fair play and sportsmanship, which make the game possible. But another factor in favor of fair play and sportsmanship in sports is that everyone can see and fully understand what is going on. After all, they are exhibitions.
I am sad to say that the same spirit, which is as vital to the health and survival of science as it is to competitive sport, has not done well in the field of cell physiology in the later half of the 20th century. The decay began slowly and almost imperceptibly after the introduction in the 1940's of large-scale government funding of scientific research. To determine who gets support and who is refused, the peer review system was born and universally adopted.348; 349
Public funding of research per se is a great blessing to science and scientists, including myself. Unfortunately, those chosen to serve on peer-review panels are—unlike most referees and umpires in competitive sports—themselves competitors for the money they control. All too frequently, they forget the vital role of fair play and sportsmanship in science and see an impending major scientific progress as a threat to their personal advantage and prestige and use the entrusted power to suppress it.247; 350 Unlike sports, these activities are as a rule not open to public view.
(Creating and putting into practice something better than the widely-practiced "peer review" system—so that truly innovative ideas are encouraged rather than suppressed—is a matter of great urgency. Until this reform is successfully carried out, the peer review system will remain a blemish on the wisdom and integrity of a great leading Nation like the United States, which rightfully would not tolerate infringement of freedom in far less important issues.)
In his "History of Physiology," Karl E. Rothschuh pointed out that with the increase in practicing physiologists, the number of scientific journals have risen to such an extent that "Physiology has even ceased to be one whole and distinct teaching subject, a fact which virtually spells the end of the discipline as a certified field of scientific endeavor."352 p 349
This comment was made by Rothschuh years ago on what is known as organ physiology, e.g., renal physiology, digestive physiology, etc. But cell physiology has fared no better. It too has split into biochemistry, biophysics, pharmacology, cell biology, molecular biology, mathematic biology, etc., etc. Indeed, things have gotten much worse with the universal adoption of the peer review system, which further exacerbates fragmentation.
A verified unifying theory to put Humpty-Dumpty together again
"The eternal mystery of the world is its comprehensibility" (Immanuel Kant). To begin with, simple and coherent things are easier to understand (and to remember.) Thus the comprehensibility of Nature may be tied to its underlying simplicity and coherence, which are couched in such admonitions as that of Occam's razor, "What can be done with fewer is done in vain with more."
However, a fragmented approach is like "viewing the sky from the bottom of a well" (Chinese proverb). As such, it hides from view Nature's innate simplicity, coherence and comprehensibility. The question is: How can we heal this fragmentation? My answer is: Begin with a unifying theory.
Early on, I pointed out why the membrane theory at one time appeared to be a unifying theory (Chapter 4). Unfortunately, as more and more new facts came to light, they left no doubt that the membrane theory is not headed in the right direction. Then alternative theories based on the concept that cells are solid and made of protoplasm were introduced. Unfortunately, the protoplasm-oriented cell physiologists did not produce a unifying theory. The time was not yet right.
Not only were the essential basic physico-chemical sciences themselves still in their early development or not yet in existence (Chapter 7), powerful new scientific tools like radioactive tracer technology, which have played key roles in critically testing the alternative theories, were still to come. Nor did these investigators enjoy the benefits of public financial support, which was not in place until the end of World War II in the United States, for example.
All these had undergone profound changes when I came on the scene as I have pointed out repeatedly in the text of this volume. Whether or not the AI Hypothesis will remain the one and only unifying theory, as I believe it will, is a judgment that can be made only in the future. Notwithstanding, there is no denial that the AI Hypothesis is the first-in-history physico-chemical theory of life at the cell and below-cell level. And this whole volume testifies to how it agrees with the experimental studies designed to test its validity.
Let us begin with what a teacher does not want. No teacher worthy of that title wants knowingly to teach or present a wrong theory as truth—nor teach only (beautifully-illustrated) trivia.
However, a great teacher does more than just not doing wrong or meaningless things. He or she can expose the students to the right underlying rules of fair play and sportsmanship in the same way that loving fathers and volunteer coaches teach youthful sand-lot baseball players. And in the process, inspire in a few students an abiding love for the subject taught, and prepare him or her for a career in the service of all mankind that is always interesting and unswervingly relevant. To discover what specific tool may help our teachers to fulfill this critical role, let us return to the life of Michael Faraday once again.
At the age of fourteen, Michael Faraday was an apprentice to a small bookbinding business. He could easily have continued with what he had learned as an apprentice and spent the rest of his life as a journeyman bookbinder. But that was not to be. What then inspired this young bookbinder's apprentice to dream of a career of a modern Galileo or Isaac Newton? From what I could gather, his dream—where it all began—started with two articles on the history of science.
As young Faraday was glueing together the pages of a set of the Encyclopedia Britannica, something in the printed pages caught his eyes. It was an article entitled, "History of Electricity" written by a Mr. James Tytler. Tytler, in turn, took most of his material from Joseph Priestley's book, "The History and Current Status of Electricity."379 Faraday was so excited by what he read that he began to conduct experiments on the mantle-piece of his employer's shop. His scientific equipments were fashioned out of two glass bottles, which he bought from an old rag shop for six pence and one penny respectively. Soon he was defending his own theory of electricity among a gathering of young friends intent on "improving their minds." Unfortunately, as his love for science grew more and more fervent, the prospect of becoming a professional scientist, or even just continuing as an amateur scientist, became less and less bright. His apprenticeship was drawing to a close. He felt hopeless and depressed.
Then suddenly and unexpectedly came a lucky break. The janitor of the Royal Institution—home of such illustrious scientists like Sir Humphrey
Davy—was fired for engaging in a brawl. And young Michael Faraday was hired to replace him. This was how Faraday began his life career as one of the greatest scientists in history.
At the beginning, he was mostly engaged in helping Davy and others. But before long, he was on his own. Despite its lofty-sounding name, the Royal Institution had no regular income. Faraday, like the other members, had to earn his expenses. One way on which he relied was giving public lectures on scientific subjects. He took great pains to learn how to be an effective speaker and in the end, became good at it. On one occasion, his lecture was so engaging that school children gave up their Christmas parties to hear his talk, which bore the title: "The Chemical History of the Candle."
So it seems that in the early intellectual environment of Michael Faraday, narratives on history of one sort or another kept on popping up. Is there something special about history that reaches out to the young mind? If so, it would not be surprising. The English word, history, is synonymous with the word, story. When one reads to a child, be it Winnie the Pooh or Peter Rabbit, it is always a story or history. A story or history is always "moving" and coherent. It tells of experiences with which the listener is familiar, including a reassuring happy ending.
With these examples in the background, one can see why cell physiology has been losing ground steadily (to such a degree that knowledgeable scientists began to believe that (all) science is approaching an end). Being fragmented and, in my view, wrongly-headed, the conventional cell physiology has no story to tell and, of course, is truly at an end. With no story to tell, students and teachers would be hard put to develop a genuine interest in it—as Faraday himself and his young audience did on a Christmas Day long long ago. But all this is changed now.
The AI Hypothesis has made cell physiology truly coherent for the first time. Convinced that the best way to bring future generations of the likes of Michael Faraday into the field of cell physiology is to tell them its story or history, I gradually convinced myself of the need for a book like this one, which too is a story and bears that magic word in its subtitle.
While teachers and their students are an important segment of the audience I am trying to reach, they are not the exclusive audience I am looking for—as I have briefly mentioned in the Preface. Others I am trying to reach include all kinds of scientists, especially those close to biology and medicine, who want to update their basic knowledge; molecular biologists seeking the link between genetics and cell and subcellular physiology; physicists looking for new fertile terrains to apply their talents and knowledge; researchers in medicine and in pharmacological companies searching for new ways to cure diseases and invent drugs; school-board members eager to offer the right and up-to-date guidelines for school curriculum they supervise; science reporters and editors who may open the eyes and minds of an even larger body of intellectually adventurous book readers. True, teachers and their wards hold the key to reverse the senseless unending teaching of meaningless long-ago-disproved ideas. But we need the help of everyone to accomplish the momentous task lying ahead.
Fifty-five years have gone by since Vannevar Bush wrote his report to President Franklin D. Roosevelt, bearing the title: "Science, The Endless Frontier."400 Those, who have read only Horgan's "End of Science" (see Preface), may be misled into thinking that Bush was wrong and that science does not offer an endless frontier. Those who have gone through the present volume, may realize how right Vannevar Bush was and still is. And in all probability will continue to be.
As an illustration, the invention of MRI shows not only that cell physiological science is burgeoning, it also shows how physics is as alive as ever, because, among other reasons, advanced cell physiology is physics. And then, advanced physics is also advanced cell physiology. For after all, it is the cell physiological activities of the trillions of brain cells in men and women who call themselves physicists that have created physics.
It would be wonderful if I could present a list of all the exciting avenues open to cell physiological research in the future. But as space is limited, I must satisfy myself with just two.
First is a reminder that many of the seemingly dead-end scientific accomplishments now gathering dust in some unreachable storage libraries—and sooner or later in danger of becoming parts of some garbage dump—be they biochemistry, or biophysics or molecular biology etc., etc. will become alive again, when viewed in the new light of the unifying AI Hypothesis. Better still, in them will be found truths that show conflicts, real or apparent, with the predictions of the AI Hypothesis. They will be the spring-board for the continued growth in future cell physiological science.
Second is one specific direction that answers the question with which I began this story: How to develop an inexhaustible arsenal of weapons against cancer, AIDS and other deadly diseases, which are the true enemies of our species? These weapons are in the form of drugs. Unlike the kind we have, they will be rationally designed and thus on target and without untoward side effects. And they can be cheap.
It is truly astonishing to listen to political debates on how to stave off the impending bankruptcy of the Medicare/Medicaid programs as the US population ages and more and more people consume larger and larger quantities of prescription drugs. For this to happen in as wealthy a country as the US tells just how extremely inefficient and expensive it is to obtain useful and safe drugs through random trial and error—as it is being done now, a process which also leaves patients of AIDS in poor countries around the world to die like abandoned cats and dogs.
What chance is there for improvements if we just do more of the same—along the line of the membrane-pump theory? Indeed, the theoretical mechanism of drug action now being taught in textbooks remains not much more than the same old lock-and-key model. The conventional concept of drug action begins and ends with receptor-site fitting. The fitting drug does not do anything. Because there is nothing proposed to respond to drugs other than site-fitting, one cannot go very far—indeed anywhere at all—on such a dead-end road.
In contrast, the AI Hypothesis in its very name, association and induction, has already spelled out the basic mechanism of drug action. It is an electronic one, a direction more specifically explained in Chapters 14 and 15. Thus, based on the theoretically derived relationship between the c-value and the rank order of selectivity of K+, Na+ and other alkali metal ions (and other criteria) and the c-value analogue and the rank order of selectivity between helical structure and water polarization-orientation, one can already determine experimentally whether a specific drug or other cardinal adsorbent functions as an electron-withdrawing cardinal adsorbent or EWC or an electron-donating cardinal adsorbent or EDC. This is a big step forward. Nothing like this has ever occurred before.
In addition, this type of experimentation carried out has already begun to produce new, valuable information from a variety of intact living cells, normal as well as cancerous. Among the cardinal adsorbents—which include all drugs—the most important is ATP. And from our studies of its influence on different physiological manifestations in living cells, we reached the conclusion that ATP is an EWC. Ouabain, in contrast, is an EDC. Why ATP is an EWC and why ouabain is an EDC are questions that will challenge the best of the coming generations of new biologists, chemists and physicists, but especially those who have mastered the essence of all three fields of science. And hopefully this volume may stimulate the training of scientists of this kind. But all that is for the future. For the moment, we return once more to something at our current rather primitive level of progress.
As pointed out repeatedly, a crucial step in verifying a cell physiological theory is the invention or discovery of an inanimate model. An inanimate model shares major attributes with living cells, but one upon which it is much simpler and easier to test the theory. In almost all the subsidiary theories of the AI Hypothesis, one or more suitable inanimate model(s) was found by 1992—with one important exception.
That exception is an inanimate model showing how drugs and other cardinal adsorbents at minute concentrations can induce an across-the-board change of the c-value of a large number of β- and γ-carboxyl groups, and that with their c-value change, the theoretically predicted change in the relative adsorptive preferences for K+, Na+, for example, can follow.
It is thus with great pride and joy that I, together with my associate, Dr. Zhen-dong Chen (as well as Margaret Ochsenfeld), can now make the preliminary announcement that a few of these inanimate models have been found and the essence of the changes predicted by the AI Hypothesis tentatively confirmed. Having said that, I must add that the demonstrated changes are very small though statistically significant. They are, after all, models and not the real thing.
Not the least earnest message, which we want to share with the next generation of cell physiologists and their teachers, is about our experience as what I shall call less-than-popular scientists—though even now we have more facilities than Faraday had to make do with in his time. All these experiences suggest that if you always do your best with whatever you may have, you will be at a better starting position for a scientific career than Michael Faraday was when he learned with unspeakable joy that he was appointed the "fag and scrub" man of the Royal Institution.