Translated by Stanley Cua, PhD, from the book "CDA-II, The Smart Cancer Drug" by Dr. Ming C. Liau, 1999 originally in Chinese
DETERMINATION TO FIND A CURE FOR CANCER
From the time I was born in 1935, until 1962 when I went to graduate school in America, I had been living in Taiwan. During this period of time, there were two wars, one the second world war and the other against Chinese communists. My life was very unstable and was almost always in poverty. I had to study very hard so that I could go abroad for higher education , which was the dream of every young adult of my time. At that time the person who influenced me most was Dr. Yugawa Hideki of Japan, a Nobel prize laureate, who said that he was not born a genius, but that his hard working was many more times that of others. His words adhered permanently in my mind and has become my lifetime principle.
Because of my hard work in school, I was honored the second highest in the entire school when I graduated from high school. I was also honored the second highest place in the entire Taiwan University in my first year at the university. Taiwan University was the best university in Taiwan, and the students were among the best in the country. For me to be in the second place, I must have been studying extremely hard.
When I was still young, I saw the agony and suffering of a relative who died of cancer, and had a strong adverse feeling against cancer. On the other hand, I didn't feel bad when I saw another relative died of stroke at about the same time. I promised myself to do my best to eradicate cancer when I grew up, and I have since then direct my study towards this goal.
I selected Pharmacy as my major study in Taiwan University. Antibiotics were at its best at that time. Antibiotic drugs were the drugs of choice because they were very selective in eliminating the bacteria in the host. They killed the bacteria with only minor side reactions. On the other hand, chemotherapeutic drugs for cancer killed the cancer cells as well as the normal cells indiscriminately and had many side effects. Selectivity is a very important requirement of an effective drug. Drug without selectivity such as chemotherapeutic drugs for cancer is not a good drug. But unlike bacteria cells and human cells which are very different, to find a drug that can distinguish cancer cells from normal cells in one's own body is not easy because cancer cells differs only slightly from normal cells. Nevertheless, the drug that can distinguish cancer cells from normal cells must be found. From the first time I encountered Pharmacy, I already had a feeling that the fundamental difference between cancer cells and normal cells must be found, else we would never develop an effective drug for cancer.
What is the fundamental difference between cancer cells and normal cells ? This question has always been in my mind, and it has steered the direction of my research. After graduating from college, I continued to do research in the field of biochemistry at Taiwan University, because biochemistry is the branch of science that is most related to finding the difference between cancer cells and normal cells. I worked under Professors Shu Chian Tian and Tong Ee Tze on the unique composition of cancer cells and the anticancer components of Abrus precartrins, I began to learn cancer disease. After I finished my degree in Biochemistry Department, Professor Shu started and headed the Taipei Medical College. I lectured in that Medical College for a year before applying for higher education abroad. Professor Shu encouraged me to pursue study abroad and hoped that I would come back to teach in the Medical College. I never expected that I would stay in the United States for 32 years before returning to Taiwan, and by that time Professor Shu had already passed away. I missed him so much.
Before 1962, master degree was the highest educational degree in Taiwan. To pursue higher degree would have to go abroad. I applied to Professor Harris Busch of the Baylor College of Medicine in Texas, and was accepted with scholarship. The economy of the United States in the early 1960s was very prosperous, and it was easy to get scholarship in graduate school. I arrived in the United States in the autumn of 1962 to start the research career I had always dreamed of. In Taiwan, I could only obtain the knowledge of research facilities in textbooks. In America, they were all around the university's science and technology departments. I was immediately totally absorbed in the research environment. It was the era of rapid development of molecular biology. I had a thirst for new knowledge, and was frequently working day and night in my laboratory. Searching for new discovery became my only enjoyment. My research topic was the separation and structural composition of nucleoli. In less than 6 months I already had a publishable paper. Professor Busch had many interests, he was interested in anything related to the nucleus of living cells. There were many people working for him. With more than 500 papers published up to 1989, he could be the most prolific producer of scientific papers in America. He particularly emphasized efficiency in work, "the faster the better" was his motto. Publishing scientific papers and excellent skill in oral communications made him very influential in American Cancer Society. He was once the president of the Society.
I didn't stay long in Professor Busch's laboratory. When I first joined him, he was the chairman of both Biochemistry Department and Pharmacology Department. After six months, the school invited a new head for the Biochemistry Department. The new department head gave me two choices: either to change my major to pharmacology or stay in biochemistry but choose a new adviser. I had more interest in biochemistry and decided to choose a new adviser in Biochemistry Department. My decision made Professor Busch unhappy, which had bad consequence in my future career. My new adviser, Dr. Robert B. Hurlbert, and Professor Busch both came from University of Wisconsin under Professor Van R. Potter. Professor Potter was an authority in biochemistry. Although I didn't study or work under him, his thinking had influenced me deeply. He believed that the disruption of cell differentiation is the main problem of cancer. I completely agreed with his belief. My new adviser, Dr. Hurlbert and my previous adviser, Professor Busch were two different personalities. Dr. Hurlbert was more conservative and persistent. He worked out pyrimidine pathway as a graduate student at a time when the metabolism of glucose and energy conversion were the main stream, and he continued this line of research in his career. Professor Busch was more flexible. He followed the current trend in his research direction. My personality was closer to Dr. Hurlbert, and that was one of the reasons I chose him as my adviser. I like to work under Dr. Hurlbert because he didn't insist on his students to follow his footstep. This gave me the freedom to follow my own interest and belief in my research work. Otherwise, I would have been like all others trying to look for the impossible answer in the wrong direction by following the footstep of the adviser.
Strong ability to synthesize ribosome is a characteristic property of cancer cells. The formation of ribosome is a required step in cell replication. I liked to know if there is any difference in the synthesis of ribosome between cancer and normal cells. My research in Dr. Hurlbert's laboratory was directed towards the study of RNA synthesis in isolated nuclei and nucleoli of cancer and normal cells. I also tried to find out the regulatory factors in the synthesis of RNA and the purification of its synthesizing enzymes. Everything went very smoothly, and I completed my PhD degree in three years. However, I was disappointed with the results, because the enzyme that synthesizes RNA was not a factor in cancer growth.
After I received my PhD degree in 1966, I went to Philadelphia Cancer Research Institute to continue for my post doctorate research under Dr. Robert P. Perry. The size of the research institute was small (less than 100 staffs), but the research staffs were among the top-notch quality. Two were Nobel prize winners, and seven were members of the National Academy of Science, and Dr. Perry was one of them. The northeast of the United States had been the center of scientific development. Communication of new information was extremely fast. It was no wonder the center of new scientific discoveries. Dr. Perry had multitude of different research interests, sometimes in ribosome, sometimes in messenger ribonucleic acid, sometimes in methylation of nucleic acid, and sometimes in other unrelated topics such as the regulation of the formation of antibody, but his research topic was always at the forth front of science. He was an unpredictable type of scientific genius. When I joined him, he was concentrating on the regulation of ribosome formation. I worked in this area for two years, basically the work was pure science research, because Dr. Perry was not eagle to find the solution to cancer. Nevertheless, I learned the importance of the methylation of nucleic acid, and I directed my energy and attention in that area.
I DISCOVERED THE FUNDAMENTAL PROBLEM OF CANCER
I accepted the position of Assistant Professor at the University of Texas M. D. Anderson Hospital and Tumor Institue in 1968. I could then do independent research and pursue my dream of finding a cure to cancer. M. D. Anderson was the largest cancer research institute in America. Texans liked to be big, and its cencer research facility had also to be the biggest. At that time applying for the research funding was not easy because of the huge expenses in Vietnam war. I only got a nominal funding from the American Cancer society. In 1971, President Nixon announced the war on cancer, research funding became very much abundant and available. I got research grants both from National Cancer Institute and Welch Foundation.
I continued to make new discoveries, and the results were published in the most authoritative publications. 1968 to 1980 were my best years. I proved that methyltransferase was the most sensitive factor in the regulation of the ribosome formation. I also discovered that methylation process was accomplished by a complex from three enzymes, namely, methionine adenosyltransferase (MAT), methyltransferase (MT), and S-adenosylhomocysteine hydrolase (SAHH). The regulatory function of this complex is very different between cancer cells and normal cells. The activity of this complex in normal cells is completely dependent on external factor, which is growth factor. When the external growth factor is present, the complex is very active and the cells replicate; when growth factor is absent, the complex becomes inactive and the cells are diverted into differentiation pathway. On the other hand cancer cells produce their own internal "growth factor" as a specific protein factor that sustains the high activity of the complex, which enables the cells to continuously replicate and blocks terminal differentiation. The alteration of this complex by the specific protein factor produced in cancer cells is the central problem of cancer.
The value of Km of normal MAT is significantly different from that of altered MAT, hence it is easy to detect the altered MAT by simply measuring the Km value. All of the cancer tissues that I had analyzed had mutated MAT. Apparently the alteration of the aboved-mentioned ternary enzyme complex was the common denominator in cancer. The MAT was never found abnormal in normal cells, even those that had fast replication rate. It could therefore be concluded that the abnormal ternary enzyme complex was a characteristic property of cancer cells. This was exactly what I had been looking for. I always believed that if we cannot find the basic difference between cancer and normal cells, we can never solve cancer problem. I originally assumed that this basic difference should be a factor that could broadly affect the metabolism of the cells. The factor responsible for the abnormality of MAT affects all other methylation processes. This factor fits nicely into my assumption. Methylation regulates the formation of ribosome, which is a necessary modification for the function of mRNA and tRNA, and a very important factor in the regulation of gene expression. I believed that I had found the key to the basic cause of cancer. But to convince others of the theory that I had developed in 1980 was very difficult, because the methylation of DNA was not clear at that time. The ability of methyl radical to affect the expression of some genes was only slowly appreciated after 1985.
After knowing the cause, it was much easier to find the solution. I discovered after treating liver cancer cells with poly(I)(C) the altered ternary complex was first normalized, and after a while, the formation of nucleic acid and protein was reduced, and finally the cells stop to replicate. This was my discovery in 1975. The inhibition of cell replication by Poly(I)(C) was identical in principle to the induction of terminal differentiation of cancer cells by interferon or retinoic acid. Therefore in 1975 I already established prototype of differentiation therapy, although the terminology of differentiation therapy was not known yet at that time. I believed that the induction of differentiation by these agents was mediated through oligoisoadenylate in normalizing the ternary enzyme complex. In other words, oligoisoadenylate and CDA-II has the same effect. Oligoisoadenylate is a very special compound of adenylic acids, made up of three adenylic acids. The altered ternary enzyme complex in cancer cells are especially sensitive to this type of compounds. On the other hand, the normal ternary enzyme complex is not affected. Hence this type of compounds has selectivity in the inhibition of cancer. Theoretically I had discovered that the inhibitors of abnormal cancer methylation enzymes could selectively inhibit cancer, but before I could find a cell differentiation agent that could be tested clinically, I had to stop my research work, because my funding was cut off.
Mid l970s were the period of most abundant funding in cancer research. My research work was very innovative and important, and my publications were numerous, why was my funding cut off? It was because of one of my publications that contradicted the view of both my doctorate advisor, Professor Harris Busch, and my post doctorate advisor, Dr.Robert Perry. Before l975, there was a controversy in the relative positions of the smaller and larger rRNA genes. Some researchers believed the larger gene to be in the front (i.e., ribonucleic acid 5' side), Professor Busch was one of them. I had a very good way of finding out the correct positions in this controversy. The distribution of methyl groups in these two rRNA is quite different, and thus can be used to distinguish these two rRNA sequences. I introduced radioactive methyl groups into newly formed nascent chains, and then separate them into two parts according to their chain length, and finally analyzed the distribution of methyl groups in these two parts. My finding was that the smaller gene was in the front and the larger gene in the rear position, which was the opposite of Dr. Busch's result. At about the same time, Dr. Perry published a paper that was also the opposite of my finding. I published a paper with a conclusion simultaneously contradicting two of my advisers, which was an unforgivable sin. My renewal application of American Cancer society grant in l975 was cut off, because the review panel concluded that I was creating controvery. God knows that I was trying to reconcile, not to create, a controversy that had already existed. Three years later, my research funded by National Cancer Institute was also cut off. This research was about methylation enzymes that had nothing to do with the controversy. In addition, Dr. Perry has published another paper correcting his own mistake, but it was to no avail. I was never able to get another research grant again. Although I still had the support of the Welch foundation, I was fired nonetheless. At the year of my highest creativity, l980, I left M.D. Anderson Hospital & Tumor Institute, terminating my l2 years of assistant and associate professorship. My dream of finding a cure for cancer also vanished.
God had not let me down, I soon found a new job at the Burzynski Research Institute as the chairman of the biochemistry department. The Institute was founded by Dr. Burzynski, who was 8 years younger than I was. He immigrated into America in l970 and worked as an assistant professor at Baylar College of Medicine. He later founded the Burzynski Research institute in l978. Originally he was in the research of peptides in the blood, and later found that these peptides had anti-cancer properties, and was since then involved in anti-cancer research. Urine has similar anti-cancer peptides, he then extracted these peptides from the urine and called them "antineoplastons". He used antineoplastons to treat cancer patients and obtained unusually good responses. He became known for his success in treating cancer patients with antineoplastons. When I joined him in the latter part of l980, it was one of his best years. A large group of cancer patients heard about him and came to be treated, nobody including FDA interfered with his work. Not too long after I joined him, the media was very interesed in his unorthodox approach to cancer. NBC broadcasted nationwide an interview with him. He was young and successful at that moment and made some remarks that criticized and antagonized the medical establishments. From then on, we had basketful of troubles and never lived a peaceful day again. FDA was always at our back requiring all sorts of documentations. I had to spend 4 years to organize all the paper work to satisfy the requirements, such as manufacturing process and quality control of antineoplastons. Court cases began to appear. There was at least one big case every 3 years that could destroy him and his research. The case in l997 was the biggest of all, with 75 counts that could send him to jail for 99 years. Actually his license could be revoked and his cancer treatment terminated even with only one count. Why would the government, especially FDA, want him to be in jail was beyond comprehension. But Dr. Burzynski was very lucky, he never lost a single case. It was probably not just luck, but his success in the treatment that saved so many cancer patients who were all behind him and rallying in front of the court house in all those cases. If not for those cancer patients he saved, he would have been annihilated long time ago.
I was with Burzynski for l4 years, most of the time we were struggling just to be alive. When I first joined him, his financial situation was very good, he bought a lot of laboratory equipment and instruments to let me do the research. But later, his financial resources were depleted. There was one time he even borrowed $5,000 from me to meet the emergency. I could not do much in research under that kind of condition. His financial difficult started to improve after l985, I was then able to spend more time in research. I then discovered that his antineoplastons could solve altered ternary methylation enzymes I discovered. How could this be so coincidental? I began to believe that I was sent by the God to solve the cancer problem, because these anti-cancer agents were given to us at birth from our God. I started to rekindle the fire of discovering cancer cure inside me, and went back to my busy research.
I concentrated all of my energy into the search for the anti-cancer agents in the urine, from separation and purification to the theory of their anti-cancer action. I discovered that the urine contained three major anti-cancer agents: cell differentiation inducing agents, cell differentiation helper inducing agents, and an anti-cachexia agent. Cachexia is caused by infection resulting in the over-excretion of low molecular weight metabolites in the urine. Low molecular weight metabolites in the urine contain the anti-cancer agents. Chronic infection can usually lead to cancer because of the presence of cachectin that depletes the anti-cancer agents in the urine. These three anti-cancer agents in the urine work synergistically against cancer, which results in the most effective inhibition of cancer. At this time, the function of the DNA methylation was already recognized, and the inability of the stem cells or cancer cells to express differentiation related genes was due to the presence of methyl groups in the promoter of these genes. Therefore for these genes to express, it must go through the synthesis of hypomethylated DNA. The altered ternary methylation enzymes in the cancer cells are too active, which is the reason that cancer cells can not undergo differentiation. If cancer cells are treated with the anti-cancer agents of the urine, the altered ternary methylation enzymes will be inhibited,and the cancer cells can go through the synthesis of hypomethylated DNA to trigger differentiation to reach a state that cancer cells are no longer capable of dividing. I finally completed my fundamental theory of cell differentiation therapy. I also established the hypothesis of chemical surveillance in our body, explaining why we all have anti-cancer agents in our body, and yet some can still get cancer. These theoretical bases could explain the logics of using the urine extract in cancer treatment, but they never had the opportunity to be recognized in the United States. The U.S. medical authority never gave me a chance to publish my discovery and theory. I was deeply fraustrated. Even until now 4 years after dissociation from Burzynski Research Institute in l994, my paper and thesis in these areas that involved only synthetic compounds, which had nothing to do with the urine, were all rejected by the medical publishers in the U.S. The antagonism of the U.S. medical authority towards me is really deep-rooted.
In l993, the oncologist of Chang Gung Hospital in Taiwan, Dr. Gi Ming Lai, went to America to see me through the introduction of a relative. He had a very important cancer patient who had tried every chemotherapeutic drug without success, and had to turn to alternative therapy. This was a typical example, a very important cancer patient, going through the best chemotherapy with very good initial response, sometimes to the point of complete remission, but later the drug-resistant cancer cells appear and no chemotherapeutic drug can stop the progression, even the alternative therapy. Patients who reached this stage could not be saved. However, I could help other patients who had not reached this stage. He detected that I was not happy with my life in the United States, and invited me to go to Taiwan to start a new life. Dr. Lai was the first orthodox-trained physician I had encountered who was not against unorthodox treatment. If there were more oncologists like him, cancer problem might have already been solved. I was very fraustrated at that time, so I accepted his invitation and returned to Taiwan next year. Dr. Lai introduced me to an early investor in China, Mr. Hoger Y. S. Chang and an enterpreneur Mr. Ringo M. L. Chang. Later these two enterpreneurs together with me and some of their friends incorporated a new "Everlife Pharmaceutical Corporatioon".Mr. Hoger Chang and I went to Hefei, Anhui province in China, to build the factory. There was no relative and friend to keep us company in that isolated place, and we had to endure the hardship and loneliness day after day. Quite often, the pictures that came to my mind were the Su Wu tending the sheeps after he was captured by the nomad in China, our ancestors in Taiwan exploring the wilderness, and Deng Xia Ping pacing in his backyard when he was ousted by Mao Ze Tong. I started to train my endurance, jogging 3 kilometers everyday. All these sufferings were for the objective of "removing the suffering of patients from cancer disease, and building a better tomorrow". That was my ideal, and also the ideal of Everlife Pharmaceutical Corporation.
I redesigned the manufacturing process, and my good friend from America, Dr, Shih San Lee came to help me. In the September of l995, the first batch of cell differentiation agent, CDA-II, was produced. We immediately requested Dr. Xu Bo Shou of Anhui Medical University to conduct a clinical trial to observe if there was any toxicity or side effect. Previous pre-clinical studies have been conducted and have shown the drug to be quite safe. It should not have side effect. Clinical trials verified that there was no toxicity, but had a mild side effect of blood vein irritation during the injection. Fortunately among the cancer patients in the initial clinical trials, two had very good responses, one was a non-Hodgkin's lymphoma patient who had regressed for 3 years without recurrence. The other was a lung cancer patient treated in combination with radiation therapy, who had also regressed for 3 years without recurrence. The initial clinical trials in Anhui Medical University established the safety and efficacy of CDA-II.
Our general manager, Mr. Hoger Y. S.Chang, although a lay person in cancer field, studied very hard and collected many information concerning urine therapy against cancer. We then found Dr. K. Sano in Japan using urine therapy to treat cancer patients with good results. I thought of cooperating with him, and went to Japan in March of l966 to talk with him. Two months later in May, we invited him and another very famous urine therapist in Japan, Dr. Ryoichi Nakao, to come to Taiwan to conduct seminars in urine therapy. It was a very successful event, and we continued to cooperate closely. Dr. Sano was a genius in the use of CDA-II. He combined it with vitamins Bl7 and C, which he used previously in combination with his urine therapy, and the results were extremely good. Without question, CDA-II was a good anti-cancer agent. In only 4 short years, we have attained the success of today. The full support of our board chairman, Mr. Ringo M. L. Chang, was the most important factor. He only wanted to do something good for the people, and had put in more investment than anticipated. Without him our dream could not have come true.
Above translation has been read and corrected by Dr. Liau (Stanley)