Chapter 8 - The Key to U.S. Research
Alfred T. Sapse, M.D., assistant professor, department of immunology, UCLA, and director of the Laboratory of Eye Research, Cedars-Sinai Medical Research Institute, had a strange obsession which troubled him particularly in his spare moments—of which there were relatively few. He kept thinking about what he had seen and experienced many years before as a young doctor in Romania--—Dr .Aslan's GH3 treatment, which had helped those old people so much.
He had read the papers about it, pro and con, but he knew that GH3 worked because he had seen it work, and there is nothing like firsthand observation. All the papers in the literature could not alter the truth of what he had seen.
His obsession was why and how GH3 was effective. If he could know the answers to why and how, he might be able to--—well, maybe help in some way to get it medically tested in the United States.
He had a few clues: several reports in the American studies (Bucci-Saunders, Gordon Abrams in particular) had suggested that procaine was an MAO-inhibitor. Research went back to 1940, when Dr. F. J. Philpot discovered that procaine was an MAO-inhibitor in the test tube (in vitro); but at that time no one knew the significance of MAO inhibition, nor could they know that the inhibition had to be reversible so that the vital enzyme MAO could still play its important role in the subtle chemistry of the body's metabolism—without destroying the hormones such as noradrenaline, which were also necessary to the body's normal functioning.
The exact amount of all the hormones, enzymes, vitamins and other substances functioning in the right place at the right time was the key to the balance of the human body. And balance (or homeostasis) of the body—if it could be maintained at optimum efficiency—would be the answer to aging or any other ailment afflicting the human body and mind.
Every researcher agrees—no matter how violent his disagreement about the cause of dysfunction—that if homeostasis (balance) could be maintained, the body would survive as long as the balance did: in other words, indefinitely. It would be the age-old dream come true.
Immortality. Was it possible? Probably not through any one process, yet this was the most important clue thus far, at least translated into practical, human terms. But Sapse was not thinking of anything than "Why does GH3 work?" That was the first step.
He had access to UCLA s giant computer, one of the best in the world. As Dr. Sapse told me later: "If it hadn t been for Medlar [the computerl, this might never have happened. Medlar is so incredible and so accurate and fast that you almost have the answer before you ask the question."
He fed Medlar information culled from all the world literature on GH3, in addition to his own theoretical formulations. Night after night, Sapse and Medlar worked together in a sort of mystical union, such as a man may have with a completely cooperative, thoroughly competent partner.
The question between man and machine was: How can a single drug do so many things to so many people? Is there any drug in the world that can do this?
With a pulse of 120 and sweat glistening on his forehead, on a fateful day in May 1971, Dr. Sapse approached Medlar with a perfcrated card. The card contained four letters.
The moment of truth had arrived. What would Medlar say to the five-word question? Would the answer be a blank, or would it be an answer such as "Sorry, but insufficient data"?
The computer ate the question and then, somewhat like the oracle at Delphi in ancient Greece, the giant machine opened a ridiculously small slot, and the answer fell down in the tray. It contained four letters! Suddenly the mystery surrounding Gerovital H3's 20-year-old controversial history was partly solved.
Conceivably a major breakthrough in the fight against aging had taken place. The four letters on the cornputer card were MAOI.
Since we have previously explained what MAOI means (monoamine oxidase inhibitor), we need not recount the technicalities. The researcher was stunned almost like Socrates when he received his three answers from the Delphic oracle.
Realizing this, the professor did an incre4ible thing. He startled his colleagues by announcing that he would devote most of his time toward research and promotion of GH3—a substance that almost none of them had heard of—and if they had, It was unfavorable, most of them adhering to the AMA line.
He resigned his position at UCLA after a soul-searching period during which his colleagues warned him that he was ruining his career and following a disastrous course.
Dr. Sapse had no money saved and no backing. He took the gamble of win-or-lose, because of his obsessive belief that GH3 would succeed and he would succeed with it.
Sapse invited his friend Manfred Mosk to form a company to have GH3 tested in the United States. As a company, it was probably the most risky ever created. The company was started with $1000 capitalization, only on the evidence which Dr. Sapse had amassed, which amounted to the fact that GH3 worked, and that he would like to see it tested in the United States under FDA auspices, because he believed if it got a thorough testing, the government would approve its licensing here.
The next act of our drama took place in Dr. Sapse s apartment. Among those present were Manfred Mosk, Jean Doran, Dr. Sapse, and Dr. David M. MacFarlane. Manfred Mosk, an investment banker, specialized in the economics of the drug industry; Jean Doran, a good friend of Dr. Sapse, was former director of a chemical factory in Romania; Dr. MacFarlane was an assistant professor in the department of pharmacology at the University of Southern California (USC), Los Angeles. He was introduced to Dr. Sapse after he (Sapse) had asked friends at USC to recommend a young dynamic scientist who specialized In the pharmacology of monoamine oxidase.
At the meeting, Dr. Sapse asked Dr. MacFarlane to test Gerovital H3 to see if it was indeed an MAO inhibitor.
Dr. MacFarlane was intrigued by the MAO-inhibition hypothesis. He was eager to explore it. He left with a sample of Gerovital H3, promising that be would call as soon as possible, regardless of whether or not he had found something of interest
When he left, a lot of fingers were crossed.
About a week later, at three o'clock in the morning, the telephone rang at Dr. Sapse s apartment. Dr. MacParlane was at the other end of the line: "Dr. Sapse, I have some good news for you! You have a winner on your hands! Gerovital H3 is indeed an MAO-inhibitor—that is for sure—but I am intrigued by several features of Gerovital H3 that I had not found or known when using other drugs of this type. It will take me time to evaluate this, but I will."
Dr. MacFarlane kept his promise. In the months to come, he was the first to discover and report to the scientific press that Gerovital H3 is a weak, reversible, fully competitive monoamine oxidase inhibitor, qualities that make Gerovital H3 a unique drug of its type.
Now one of the most remarkable episodes in the history of GH3 occurred. When Dr. Sapse was convinced that he had the rationale of GH3, he telephoned his friend Mosk. It happened that Mosk was in Paris at the time. He had just returned from seeing a play, and business was not uppermost in his mind.
However, the insistent ringing of the phone forced him to answer. It was his friend Sapse, in Los Angeles. "You must go to Romania and get the contract for our company's distribution of GH3 in the United States," Sapse told him. "And do it as fast as you can. We now know the rationale behind GH3, and there s no time to lose making the tests."
Somehow he convinced Mosk to go immediately, which he did.
Now Mosk, although born in Romania, had lived in the United States so long that he had no contacts in the country of his birth. However, being intelligent and a capable business negotiator, he took the simplistic approach—unthinkable in modem-day diplomacy or business, which decrees you have to have an "In" and a prearranged order of protocol to achieve results. Perhaps so, usually. But not in the case of Mosk and GH3.
Mosk went straight to the proper authorities, told them his purpose, negotiated, and waited while they checked out his and Sapse's credentials. This took two weeks. And then an agency of the Romanian government negotiated with him a contract stating that his company, Rom-Amer, would have sole importing and distribution rights to GH3 in the United States for ten years; also the right to deal with the FDA, the United States governmental arm for drug approval.
As Dr. Sapse told me later: "It was a brilliant piece of negotiation by Mosk. For years GH3 had been under a vast cloud of suspicion, so finally when the Romanian authorities got a proper offer, they gave a proper answer. They want to see GH3 accepted, because the United States is still the leader of the world, no matter what others say."
When Mosk returned, he was able to capitalize the company for about a million dollars on the basis of the contract between Romania and Rom-Amer, and list it on the stock market. Our purpose here is not to emphasize the business side of GH3 but to dwell on the scientific. Yet the business side is so fascinating that it would be impossible to leave it out if we're being objective, and also since it plays such an integral part in relation to whether the United States ever gets GH3 or not. It's somewhat amazing to me,—a scientific, objective writer—that certain persons seem to feel that all talk of finances and business should be ignored in a book dealing with a medical treatment. Yet as almost everyone knows, it takes money to research any drug, and living in our so-called capitalistic society, everybody has to pay the rent and taxes—for research as well as for keeping the roof from leaking.
The New York Times and the Wall Street Journal will undoubtedly relate in great detail the story of Gerovital H3's financing in the United States when GH3 is approved.
A most challenging situation still lay ahead for Sapse and Mosk. They had to confront the Federal Food and Drug Administration, which was notorious for its opposition to foreign-produced drugs. Procaine hydrochloride (novocaine), which as we know is the primary ingredient of GH3, has been used by the medical and dental professions in the United States for the past seventy years as a safe, effective drug. It is safer than aspirin, which is now known to cause internal bleeding, and has been used for about the same seventy years with no knowledge of its pharmacologic action, only its empiric (practical) action.
However, Sapse and Mosk, armed with their MAO-inhibitor knowledge and their Romanian contract, approached the FDA, and finally got an appointment.
What they encountered at FDA headquarters amazed them. The officials of the FDA were receptive to Dr. Sapse's approach to GH3, particularly as it related to the aging-depression syndrome.
Necessarily, GH3 would have to go through all the steps required by law and FDA regulations, RomAmer would have to follow the necessary procedures in order to gain United States acceptance.
The test should be based solely on one factor which should be relatively easy to demonstrate: the effect of GH3 on old-age depression. There are millions of old, depressed people for whom there is no adequate and safe treatment without undesirable side effects. It would be of the greatest value if such a drug were available, particularly a low-cost drug—which GH3 obviously is.
At this point, it might be appropriate to quote the FDA's definition of depression. The following is contained in the FDA s most recent guidelines (June 1974):
Patients with a depressive syndrome usually manifest depressed mood ~(as described below) plus a significant number (4-5) of associated symptoms.
1. Depressed mood characterized by any of the following: sad, low, blue, despondent, hopeless, gloomy
2. Anhedonia--—inability to experience pleasure
3. Poor appetite or weight loss
4. Sleep difficulty (insomnia or hypersomnia)
5. Loss of energy; fatigue; lethargy
8. Decrease in libido
9. Loss of interest in work and usual activities
10. Feelings of self-reproach or guilt
11. Diminished ability to think or concentrate, such as slowed thinking or mixed-up thoughts
12. Thoughts of death and/or suicide attempts
13. Feelings of helplessness and hopelessness
14. Anxiety or tension
15. Bodily complaints
Three phases of testing would be necessary. Phase I is testing on patients already under psychiatric care, to determine safety and efficacy in the dosage prescribed by the Asian method. These patients would be withdrawn from other drugs, if any.
Phase II consists of double-blind studies In which GH3 would be tested against a placebo (a harmless yet inert substance such as saline water) under identical circumstances. The experiment would be devised so that the ampules would be identical in appearance; neither doctor nor patient would know what was being injected. In fact, no human being would know, because a third scientist working with a computer, independent of the testing group, would establish a code number for each ampule. The code would be sealed and broken only when the experiment was over. Then, and only then, would it be determined which patients received GH3 and which received the placebo. Meanwhile each patient would receive a battery of just about all the physical and mental tests known to medical science, before, during and after the experiment.
There could be no quarreling with the results of such a double-blind computerized test, which would be the crux of the whole experiment.
Phase III, the last hurdle for the experimental drug, consists of GH3's being tested by twenty to thirty psychiatrists throughout the country, each working with thirty to forty patients. This would ensure GH3's safety (and confirm its efficacy) on a relatively large scale, including ascertaining the degree of allergic responses among the population.
The reason for phase three is that mass testing should be done for every new drug, since some have been found to be dangerous en masse; few can forget the specter of thalidomide, which maimed hundreds of unborn children in a certain period of their mother's pregnancy. (However, for every thalidomide, there are hundreds of potentially excellent drugs which go unmarketed because of the too stringent laws passed in the wake of the thalidomide hysteria; this Is the opinion of many scientists, including many at the FDA, but that is another story beyond the scope of our inquiry in this book. We mention it only to show that a new drug, to be approved in this country, has to undergo years of testing at costs prohibitive except to a very few giant pharmaceutical houses, and even they can market but a fraction of the drugs they develop.) Surely there must be a "middle ground" between safe and dangerous. Take penicillin as an example. Penicillin would probably never pass today s laws because it is dangerous to a few, yet it has saved countless millions and opened the door to a wonderful new era in medicine. Aspirin, too, might not pass the present FDA tests for safety.
GH3 is fortunate in that it has already passed the animal and human safety tests (which are formidable hurdles) partly by virtue of novocaine's seventy-year history of use on millions of persons. All that remains is proof of efficacy and specific performance, in the United States under FDA supervision. Proof of efficacy we consider has now been established, as we shall see later.
At any rate Dr. Sapse, who had been told about the tough attitude the FDA takes toward new proposals--particularly coming from relatively unknown sources--related to me how he came out of the meeting "sailing in the clouds" because, while the FDA was objective, the representatives displayed a sincere and helpful interest in GH3. We must give the FDA credit (or at least their scientists dealing with Sapse) for reconizing the need for a drug that would be of benefit to man, and instead of throwing roadblocks in the way, which they could have done easily, helping him form the experimental design of the forthcoming research.
Back in Los Angeles, the teammates, Sapse and Mosk pondered over who should direct the overall Gerovital H3 program.
Now let's go back a few months. Sapse is in the office of William 0. Clark, Ph.D., director of Psychopharmacological Research Laboratories, Veterans Administration Hospital, Sepulveda, California, who has just published a book, Principles of Psychopharmacology, edited in collaboration with Drs. Keith S. Ditman and J. del Giudice, a monumental collection of articles by the most eminent U.S. scientists who have studied the drugs of the mind.
When asked by Sapse who were the outstanding men in geriatric research, Dr. Clark opened the book at the chapter "Psychopharmacology of Geriatrics," an article written by two doctors. One of them was Nathan S. Kline, M.D.
Dr. Clark observed, "Kline is one of the best, if not the best. Incidentally, he talks about procaine as being a possible monoamine inhibitor!" ‘Dr. Clark continued, "I would also like to recommend two of my best associates, Sidney Cohen, M.D., professor of psychiatry at UCLA, and Keith S. Ditman, M.D., director of the Vista Hill Foundation."
Sapse thanked him for his time and advice, and left. Dr. Clark continued to oversee the efforts of Dr. Sapse. His advice would be of immeasurable help in the months to come.
Back at UCLA, Sapse plunged into the study of Dr. Nathan S. Kline, the man and his work. The first book to read was The Hundred Most Influential People in the World Today, by Donald Robinson (New York: Putnam, 1970). Dr. Kline was the first scientist to receive two Albert Lasker awards, among a multiplicity of other honors. He was the first doctor to introduce tranquilizers to the Western world; the first to experiment with Rauwolfla serpentina, an old "snakeroot" remedy from India for relieving tension and high blood pressure. Used successfully in the East for at least two thousand years, it had been ignored by Western medicine as being in the realm of folklore and therefore not worthy of serious consideration. Shades of foxglove (digitalis), cinchona bark (quinine), buttercups (colchicine), and recently, acupuncture--—all of them were unworthy of consideration by Western science until successful treatments finally forced their recognition.
Dr. Kline, being a man of vast erudition and a freethinking rebel as well, in spite of his orthodox medical schooling (there are still a few around), was impressed with what he saw and read about the Indian drug. He decided to test it on hundreds of patients at Rockwell State Hospital (New York), where he was research director. He was warned by his friends and by medical authorities that by even testing this "snakeroot" substance he stood in grave danger of losing his job and with it his career. "Why in hell should you test this damn stuff? You know it doesn't work. It's just witch-doctor mumbo-jumbo," was the essence of his friend's warnings.
But Nathan Kline, being composed of stubborn genes and with his DNA-RNA delivering correct messages to his brain cells—and with perhaps a trace of extrasensory perception (intuition)—all of which seems to blend with genius—decided to carry through with the experiment. In simpler Words, he was saying: "It's worth a try. And what is science for—except trying to find the facts?"
The experiment was a success. Disturbed people in hospitals were calmed and achieved varying degrees of what society calls reality. They could now be talked to and further treated, and more important, a large proportion could be released.
The rest is history. Heretofore there had been no hope or help for the mentally ill, who occupied at least half the hospital beds in the country. Now, with rauwolfia (and the subsequent improvements in drugs that followed), the hospitals were rapidly emptied of the mentally ill, who now could be reached. Not all, but it was a major breakthrough, and it saved untold millions of persons from a lifetime doomed to insanity.
No wonder Kline was now honored and respected. He had won his gamble with destiny. He went on to more achievements, more experiments, but none have yet eclipsed his great triumph over mental illness.
Sapse telephoned Kline and asked to see him about GH3. "But why do you want to see me about this?" Kline asked. Sapse: "I would like you to be scientific director of GH3 research." Kline: ‘I'm very busy in many projects; why should I get involved in this?" Sapse: "Because the FDA has given us the approval for the experiment, primarily based on the fact that (GH3 is a safe MAO-inhibitor, beyond any doubt now." Kline: "In that case, come immediately. A safe MAO-inhibitor is what we need now desperately."
And thus Nathan Kline became scientific director of Rom-Amer and organized the testing of the drug. The event was widely noted in the various media. Kline was cited by Mike Wallace on CBS's 60 Minutes and in Newsweek and Time—as well as by this writer as getting the toughest, best researchers available for the testings.
He did get them. He got, for example, William W. K. Zung at Duke University, one of the most prestigious researcher-psychiatrists in the world, the developer of the universally used Zung test for depression.
Kline set up Phases I and II of the experiment. Dr. Sidney Cohen, former director of the Division of Narcotic Addiction and Drug Abuse of the National Institute of Mental Health and a clinical professor of psychiatry at UCLA, would direct and institute the double-blind studies. Along with his associate, Dr. Keith S. Ditman, psychiatrist in private practice in Beverly Hills, California, and medical director and vice-president of the Vista Hill Foundation in San Diego, they would institute a part of Phase I. I interviewed many of their patients, which will be reported later.
We have only given the laboratory work a cursory mention, but the whole experiment was geared for "over proof," not to be confused with overkill in the military sense. In medicine or science, it is best to have every possible kind of evidence. The FDA did not demand animal evidence for GH3, but it was provided anyway by the most brilliant researchers at several great universities. And out of that research came forth clues and evidence which are so fantastic, yet conclusive, that without absolute proof no one would believe them.
For example, sickle-cell anemia. Who would have thought that GH3 would be demonstrated as having a potential in the treatment of that dread disease and other blood diseases? Yet it did, as we shall see later.
(See Appendix 11.)
Having set up the scientific design for the project, Dr. Kline has stepped aside from the project, waiting for the final results to come in. We will examine the evidence in the next chapters.