Innovation, Renovation, and Practicality
An autobiography
Clement Ching-Shaw Hsu, M.D.
December 2003
[In 2003, Dr. Tsai Wen-Chen (蔡文城), the author of many microbiology textbooks in Chinese language, invited scores of elder scholars in the field of microbiology in Taiwan to write autobiographical articles that would be useful and inspirational for the younger generations in the trade. They would be published as a monograph. Eighteen people submitted as requested. They were organized and edited by a senior editor for theUnited Daily Newspaper, Mr. Liu Jun-gu (劉峻谷). I was told at a gathering in 2005 prior to publication of the book that the content of my paper was considered by Mr. Liu to be most appropriate for students and was sent to all other contributors to follow. Therefore, this article was read by 18 people at least!]
I was born in the year 1937 in Taiwan when the Sino-Japanese war erupted. Taiwan was then a colony of Japan. My father graduated from Waseda University in Tokyo. My mother was the eldest daughter of poet Chen Shu-gu who was an active member of the Taiwan Cultural Association in its heyday, and was later voted as one of the 88 prominent Taiwanese who made significant contributions to the land. Our house was filled with books. There were many biographies of great people written by the Japanese authors that encouraged young children and adolescents to seek excellence in their lives. Since my childhood, I have had many opportunities to appreciate the backgrounds and upbringings of people who have accomplished great deeds, and through this have learned the keys to success. Noteworthy was that there was a Japanese translation of “Romance of Three Kingdoms”, the classic Chinese novel that describes intrigues and tactics among the feudal countries during 1st to 2nd century in China. I have become an avid reader of the novel repeatedly since I was 10 years old. For a person born as an introvert, these books cultivated my ability to reflect on myself and engage in deep thought.
The first person that greatly impressed me was Dr. Noguchi Hideyo, who was highly propagandized by the Japanese government during the World War II. Noguchi came from a very poor family but he studied hard and received many awards from countries around the world for his research accomplishments in medicine. I later learned that he went to Rockefeller University in New York and was the one who discovered the causative agent of general paresis being the syphilis spirochetes. I also found later that his accomplishments were not as great as I once thought. There were many others whose works also inspired my desire and ability to think. The most important amongst them was the book, “Introduction to Psychoanalysis”, by Dr. Sigmund Freud. He deeply explored, inferred, and analyzed the existence of the “subconscious” through hypnosis. His work and deductive analysis greatly influenced me. The value that Dr. Hu Shi placed on “Science” and “Democracy,” and the indomitable spirit of Dr. Sun Yat-sen all influenced my philosophy and outlook on life.
From these readings, I became convinced since my youth that people do not need titles, official positions, or high and mighty backgrounds. If one works hard and dedicates himself to new ideas, discoveries, or inventions, he can be successful. At the same time, I aspired to follow the line of medical research and be known in the world. Prior to my graduation from the Medical College of National Taiwan University in 1963, I went to the Public Health Teaching and Demonstration Center headed by Dr. Hsu Zi-chiu, who later became the Head of the Department of Health. There, I conducted experiments on the viability of the Vibrio cholera in the Tam-shui River water. I carried out detailed investigation of clinical data of patients with viral hepatitis as my graduation thesis. Not surprisingly, these work failed to yield useful results. During one winter vacation, I had an opportunity to work at the U.S. Naval Medical Research Unit II next door to the National Taiwan University Hospital. There I worked in the laboratory of Dr. Wang San-ping, who became famous for discovering Chlamydia pneumoniae and the development of the microagglutination test for the detection of the bacteria. At that time, I saw that a good environment is a prerequisite to perform first-rate research; one should always be innovative and attempt things that were never done before. And for that purpose, one should be equipped with new technology and facilities. I learned that new ideas or the innovations must eventually be useful to mankind. Practicality has been the objective of my research since. I also felt then that there were more developmental opportunities in the domains of virology and biochemistry. Actually, I realized later that any intelligent person who is hard working, observant, and creative could be successfully in any field and in any career.
After my arrival in the United States in 1965, I went to work first at two reputable teaching hospitals. At Jersey City Medical Center, I received strict training during my medical internship, and at Montefiore Hospital Medical Center in Bronx, New York, I did my first year of residency. During this time, a person who profoundly influenced me was my senior resident, Dr. Bob Sidel, who directly supervised and trained me for three months. He was originally a doctorate student and had already completed his second year residency at Boston City Hospital (BCH). He did such an outstanding job at the BCH that he was invited by the head of JCMC’s Internal Medicine Department, Dr. Jehger (the one who discovered Peutz-Jehger syndrome) to join the program. Dr. Sidel again served his second year residency at JCMC for the supervision of medical interns. (In the U.S., it is what you do that counts and not the official title.) Dr. Sidel gave me the most rigorous clinical training and fostered in me a strong sense of responsibility. In order to provide patients a swift and appropriate management, the physician should put the patient’s welfare as the first priority, and must work tirelessly and without complaints. Dr. Sidel was such a passionate and sincere person, that he became a role model for me as a physician. My first attending physician at that time at JCMC was an African-American hematologist, Dr. Luis Sullivan, who later became the Surgeon General of the United States. Dr. Liu Rong-jia, who was my five-years senior at NTUMC, followed Dr. Sullivan in his research on hematology after completion of training in internal medicine at the JCMC with honor. When I met with Dr. Sullivan two years later at Boston City Hospital, he again was the attending physician on the medical ward where I was in charge.
In the first year of residency, in preparation for the journal club, I presented an excellent review article on delayed hypersensitivity by Dr. Jonathan Uhr. In that paper he discussed the latest discoveries related to lymphocytes. It was in 1959 researchers had discovered that lymphocytes, cells of unknown function that appears in “chronic diseases”, could be stimulated into actively dividing lymphoblasts (blast transformation). It was also learned soon that these cells might play a major role in delayed hypersensitivity and cellular immunity. The discovery proved to be the most stunning development in immunology and was elected one of the ten most important discoveries in medicine during the 1960s.
When I was the senior assistant medical resident at Boston City Hospital (BCH) from 1967-68, the attending physician of the medical ward was Dr. Sidney Cooperband, who was conducting experiments on lymphocyte cultures. In his mailbox, he would receive one or two reprint requests on his paper on lymphocytes everyday. He was apparently one of the most highly regarded lymphocyte researchers at the time. At my request, he took me in to his lab. Employing off hours, evenings, weekends, and vacations, I used surgically removed tumor tissue homogenates to stimulate the lymphocytes obtained from the same patient in test tubes. In those days, the research methods of lymphocyte cultures were crude and the result I obtained was only marginal. But the report, published in 1971, received more than six hundred reprint requests from around the world. It was cited sixteen times in the following years. The paper received attention because this type of experiment was what many researchers in the world were thinking of conducting. Though I was the first author and the one who conducted the experiments, it was Dr. Cooperband who provided the idea and refined the paper.
Another experience I treasure in working at BCH was the chance to meet with many prominent physicians and scholars. Amongst them were the former chiefs of internal medicine, Dr. Franz J. Ingelfinger who accepted my admission application, and his successor, Dr. Arnold Relman. Both were among the most influential clinical scholars at that time and both served as the chief editor of the New England Journal of Medicine (NEJM). Prior to Dr. Relman’s acceptance of the chief editorship, for about half a year, I was required to report to him weekly on my nightly duties and the details of patients’ conditions during the previous evening. He was one of the most respected physician scholars who’s opinions played pivotal role in medical field. During the morning reports, he would even inspect my attire, and adjust my tie and belt.
I later realized that in my entire life I had the most pleasant working experience while in Boston. I could not describe why so for a long time. Recently I was talking to a professor from Yale University, who said that in Boston, every scholar you talk to does not make you feel that he is superior to you. I finally found my answer in this statement. He hit the nail on the head.
In 1968, I left Boston and went to the Section of Liver Diseases and Nutrition at the New Jersey College of Medicine and Dentistry. It was mainly because the head of the section, Dr. Carrol Leevy, would let me set up my own laboratory for lymphocyte cultures. It gave me an opportunity to engage in exploratory research on the relationship between liver disease and lymphocytes. At that time, a medical student reported that the sera of cancer and uremic state inhibited the blast transformation of lymphocytes. We already knew that these two diseases are associated with immunodeficiency. Therefore this report provoked my supposition that in biliary obstruction, the bile acids accumulated in the serum might also cause the inhibition of lymphocyte reactions. It has been my habit that when I tested one hypothesis, I would spend much time testing various other possibilities at the same time. I did not find the hyperbilirubinemic sera inhibited the lymphocytes but I noted that in patients with liver cirrhosis, their sera would inhibit the blast transformation. When I published these results in 1971, it was the very first paper that confirmed the presence of a relationship between liver disease and lymphocytes. It was probably also due to the clear description of my method that this result has repeatedly been verified by other laboratories and has been cited over one hundred times and for more than twenty years.
In 1969, I went to work in Dr. Elliot Osserman’s Immunology Laboratory at the Institute of Cancer Research at Columbia University. I wanted to understand immunology in-depth, and to continue with further research on lymphocytes. Dr. Osserman was the one who discovered that lysozymes was present in the urine of monocytic leukemia patients in huge amount and could be purified in gram quantities. He was a highly respected scholar. He followed a principle that if one could not be absolutely certain of the results and the study being done comprehensively, one should not publish the data. He believed that when a report is published, it should be a classic. He would not allow his research fellows to publish for two or three years. However, once they published, they would be considered authorities on those subjects. I again set up the equipment of lymphocyte culture in the laboratory. While I was looking into possibilities of why cirrhotic’s serum would suppress lymphocyte reactivity, I found that that the purified bovine fetal protein, fetuin, could stimulate human lymphocytes. Two years later, I demonstrated that the fetuin could also stimulate bovine lymphocytes. Different from previously known lymphocyte stimulants, phytohemagglutinin and pokeweed mitogen of plant origin, fetal protein is present in human and animal fetus. It is the animal protein stimulant coexisting in the body with immune cells. Moreover, during pregnancy, when the father’s foreign tissue antigen in the fetus can be accepted into the mother’s uterus (that is, when the immune function can sustain great changes) its serum level will increase markedly. If the fetuin could have the capability to stimulate lymphocytes in test tubes, its biological function could be related to the regulation of immune cells. This was a tempting assumption. Five or six years later, I mentioned this finding to Dr. Anthony Fauci who was visiting Northwestern University. He also found this subject interesting. However, though there were more than one hundred reprint requests, the report was almost never cited. At the Institute of Cancer Research, I also wrote with a young surgeon, Dr. Paul Logerfo as the coauthor, an article on the relationship between the degree of lymphocyte inhibitory activity and the carcinoembryonic antigen (CEA) concentration in lung cancer patient’s serum. This article was cited more than fifty times.
After one year at the Institute of Cancer Research, I went to work in Dr. Kurt Hirschhorn’s lymphocyte laboratory at Mount Sinai Hospital in New York City. Dr. Hirschhorn was the person who first demonstrated the relationship between lymphocyte blast transformation and the antigenic stimulation. I continued the research on blood serum and its effect on inhibiting lymphocytes. I also discovered that fetuin contained a minor component with different antigenicity and isoelectric point. Because of my studies on fetuin, I was invited to chair a session in a seminar, Protides of the Biological Fluids, held yearly in Belgium in 1976. However, this paper on the fetuin was almost never cited. It was only mentioned in reports by a European scholar who discovered that the human fetal protein also contained a small amount of another fetal protein with different characteristics.
During these two years, my income was very low. In order to support the family, I had to work part time at small hospitals at night. During the day, I conducted research in the laboratory. I seldom slept at home. I only owned one car that I shared with my wife. We lived in hardship, and had to let my dear wife Yui-li take my two children to Taipei for six months so I could fully concentrate on my work in the U.S.
In 1972, I was formally employed at the Section of Infectious Diseases at Northwestern University in Chicago. I was hired owing to the foresight of the section chief, Dr. Philip Paterson, who anticipated links between lymphocytes and clinical infectious diseases and wanted to hire a lymphocyte specialist to join his staff. Dr. Paterson had become well known for using animal experiments to verify that lymphocytes, and not serum, must be used to transmit the multiple sclerosis in animal (experimental autoallergic encephalomyelitis) from one animal to another. He was an extremely good writer and a perfectionist. He often returned from a short trip and was greeted by more than ten submitted papers from various journals for him to review. I gained the most from his meticulous training in writing and reviewing papers. Over the next one or two years, I had to pass the written test and the oral exam for the Board of Internal Medicine. I also had to study hard in clinical infectious diseases and to conduct daily rounds on patients with a fellow. I was also required to write a first rate research grant proposal. My mother passed away about that time, when my income was very meager. My life was miserable. The stress was so great that persistent arrhythmia developed and continued for more than half a year. Fortunately, my research capability was taken note of and I felt respected at the Medical School.
Soon after I started to work at Northwestern University, Dr. Patterson suggested that I should pay more attention to new research. He suggested that I set up the method to identify B-lymphocyte marker (i.e., surface immunoglobulin staining) and the method of calculating T-lymphocyte by E-rosette formation. Calculating B-and T-lymphocytes was the new trend and was catching people’s attention. At the time, there was a student in the MD and Ph.D. program, Gerri Marti, at Northwestern University, who loved research and frequently came to visit my laboratory. When he saw I was starting the T- and B-cell marker studies, he brought me the blood sample of a lymphosarcoma cell leukemia patient, EP, from haematologist Dr. James Hart’s clinic. This particular patient always had 300,000 to 500,000/mm3 leukemic lymphocytes in the circulation. At that time, the understanding of leukemic lymphocyte surface marker was that it was B-lympocyte in origin and it had surface immunoglobulins (SIg). SIg comprised of IgM and IgD only. And for each clone of B-cell, there can only be either kappa or lambda light chain. There were three case reports of T-cell leukemia.
EP’s blood test results indicated that over 70% of the leukemic lymphocytes were E-rosette-forming T-cells, but 20% of SIg-positive B-cells with brightly staining IgM was also detected. At first, I thought we had only discovered the fourth case of T-cell leukemia and it was not worth spending time to write about it. However, with more careful thought, I began to wonder why there were SIg-positive cells. Because nearly all lymphocytes in the EP’s blood were neoplastic lymphocytes, it was possible that the two clones of lymphocytes, T- and B-cells, had simultaneously transformed into cancer cells. But it could also be due to the attachment of putative antibodies to leukemia antigens to the neoplastic T-cell surfaces. If it was the former, due to its origin being from the same cancer cell clone, that SIg must all be with either the kappa or the lambda light chain. If it was due to the attached anti-leukemic cell antibody, the kappa and lambda light chains should be detectable on the cell surface.
A month later, when EP returned to Dr. Hart’s clinic, Gerri brought another tube of EP’s cells to my laboratory. In the repeat examinations (T-cell marker positive cells were still very high at 90%,), I not only discovered that SIg was only formed by the lambda light chain but also that there was an increase of the SIg-positive cells to 50%. This development surprised us. For the subsequent seven months, we followed up on EP’s blood cell components monthly. As a result, we discovered that within 2-3 months, EP’s leukemic cells had all turned into cancer cells with both T and B characteristics! (Moreover, all the immunologlobulin isotypes, IgD, IgA, and IgE became all detectable on the same cell.)
The above discovery could have a great impact at a time when it was believed that T- and B-cells were separate cells. With Dr. Paterson’s guidance on how to succinctly and clearly describe these series of changes in fifteen minutes, and even adding a twist from the famous Shakespearean quote, (“To B or not to B, that is the question,”) I presented a paper at the FASEB meeting at Atlantic City in 1974. The presentation was a total success with prolonged applause from the audience. Dr. Paterson proudly introduced me to the chairman of the American Association of Immunologists, “This is the man who put the distinction between T and B into question”. Not only did the immunologists in Chicago knew about this successful presentation, the co-author who used SIg and anti-T-cell antibody prepared in his own laboratory to affirm the characteristics of EP cells, Dr. Ralph Williams, even congratulated me from New Mexico by phone on the success of my presentation. In an international conference one month later, one Polish scholar told me, “You are very famous, at least in my country”. Later when I was visiting Dr. Osserman, who did not have a good impression of my lymphocyte research, he said, “You are ahead of your peers!” When I was applying for other positions and had to submit my resume, I asked Dr. Relman to write me a recommendation letter. He wrote to me, “I did not know you are doing so well!” I will never forget the satisfaction of having achieved some distinction and received such encouraging compliments.
This discovery was the peak of my research career. In 1976, when I obtained my American citizenship, I was one of the more than twenty people presented with the Outstanding New Citizens of the Year award from the Chicago Metropolitan Area Citizenship Council. From then on, if I were not confident of receiving a good response, I would rather not make a presentation. And I would make thorough preparations for all my speeches since then. It appeared that Dr. Osserman’s principle on excellence finally grew on me.
Later I observed that B-cell surface could simultaneously carry the endogenous isotypes other than IgM and IgD. This phenomenon could be clearly seen in patients with thyrotoxicosis. This is certainly an important observation. However, due to the lack of access to such patients, I was unable to continue this research, which required a large amount of patients’ blood.
Soon after the report of these sequential changes in T- and B-cell markers, I brought EP’s cells and generated rabbit antiserum, which could detect the B-cells. This discovery perked my interest in anti-leukemia antigen. Based on the method of the British researcher, Dr. Melvin Greave, I successfully produced rabbit antibody to acute lymphocytic leukemia-associated antigen (ALLA.) For this work, I was able to obtain a research contract from the National Cancer Institute (NCI) in 1980. There were only four weeks between the notice of the contract and the deadline for this contract application. There were thirteen applicants and only four or five could win the contract. Dr. Nathan Berlin, the former director of the Clinical Research Center of NCI, told me that receiving contract was more difficult than receiving grants, and added emphatically, “It is an honor!”
However, I realized that my time for research was nearing an end. I needed to catch up to the new technology of monoclonal antibody and flow cytometer for further studies. In conducting in-depth research, it requires other knowledge. I realized that the laboratory research of clinicians could be quite limited in depth. At the same time, my wife lost all her hearing due to nerve degeneration within a few months period and my two children’s education demanded a higher stipend. Our financial situation did not allow me to ignore the income any further. This was the time when I finally saw the importance of having sufficient revenue. Although research and publishing new data is very gratifying, one has to be responsible for the care of one’s family. Therefore, I turned my attention to the clinical work at hospitals where my new supervisor of the Section of Infectious Diseases sent me. Actually in 1981, the appearance of AIDS assured the importance of lymphocytes in infectious diseases. However, the section head gradually took over the laboratory for his use. I formally retreated from the experimental work. Later, the AIDS Center of Northwestern University used the lymphocyte laboratory and the technician that I initiated and trained, as its main resource.
(continued to part 2 of 2:
Innovation, Renovation, and Practicality--a 2003 autobiography (part 2 of 2)
)
沒有留言:
張貼留言