Robert A. Good, in his own words, talks about science...
The Minnesota Scene
A Crucial Portal of Entry to Modern Cellular Immunology
My approach to research, teaching, care of patients and community service that is reflected in the accompanying portfolio evolved as a natural consequence of the influence of the outstanding teachers in the sciences-basic to medicine, clinical medicine and the mentors in clinical investigation by whom I was trained at the University of Minnesota Medical School and at the Rockefeller Institute for Medical Research (the latter became the Rockefeller University under the direction of Detlof Bronk approximately twenty years after I studied there).
I was the first to pursue combined PhD and MD curriculum at the University of Minnesota. The mentor for my PhD training and thesis, Berry Campbell, Professor of Anatomy and Neuroanatomy, was actually also a neurophysiologist. He taught me many things, but above all to have a healthy skepticism concerning evaluation and interpretation of my own observations and those of others. He was a brilliant young scholar trained at Johns Hopkins, Columbia University and at the Rockefeller Institute for Medical Research. He was sometimes, perhaps, a bit too skeptical about the contributions of others, but at the same time enthusiastic about potential yields from careful and critical laboratory research. He was a scientist capable of seeing far beyond the present, in light of his laboratory findings, especially when they were taken, together, with his interpretation of the existing literature. He had a wholesome respect and appreciation for the history in the fields in which he was a leading investigator.
Fred Kolouch was a young academic surgeon who, as a master degree student, concluded that he had discovered that plasma cells are the antibody-producing cells. He was far ahead of his time, but subsequent analysis of my own and those of Fragraeus in Sweden had proved him to be correct in his extrapolations of his findings which extended a faint trail he had recognized through the literature extending back to 1905 As he left immunology and hematology to pursue academic surgery, he intellectually willed to me his interest in lymphocytes and plasma cells after he had assured himself that I would pursue the trail he had uncovered. I proved true to Kolouch’s legacy, since I have investigated lymphocytes and plasma cells continuously and productively now for more than 50 years and have continued my investigations of these cells during the entire 10-year period of my professorship at USF.
When I began my research in immunology in 1944, we literally knew nothing of the cellular basis of immunity, little or nothing of the molecular basis of immunity and did not have an inkling of the functions of the major organs of the lymphoid system such as the thymus, Peyer’s patches, lymph nodes and spleen. With the legacy left to me by Kolouch, I have been able continuously to contribute new knowledge and understanding of lymphoid cells, their functions and their malignancies, and to develop as a consequence of these studies, an entire school of scientists each of whom have contributed through exciting discoveries to the understanding and analyses of the lymphoid systems and immunologic functions for more than 50 years. The surging knowledge derived from this line of research by members of our ‘school of immunology’, as well as that of an increasing army of immunologists of other derivations, has brought ever closer the realization of the promising ability to predict and control of the immune systems. Such analyses could only vaguely realized as a kind of promised land by Berry Campbell, Kolouch and me as we carried out our initial experiments and began to interpret nature’s incredible experiments concerning the lymphoid systems 53 years ago.
It was Irvine McQuarrie, a pediatrician from Johns Hopkins and, earlier, a PhD, MD from the University of California who, after futile efforts made by Von Pirquet and Schultz at Minnesota had established the University of Minnesota Pediatric department as a veritable breeding ground for development of leading pediatric scholars and academicians. By the time I studied with him, McQuarried had trained at least 25 men who had become professors and pediatric department chairmen throughout the United States. McQuarrie captured me for pediatrics while I was pursuing at once graduate studies in virology and immunology and a permissive honors medical curriculum toward an MD degree. He captured me especially with long conversations about the incredible contributions which might be made from studying the ‘Experiments of Nature’ in young children. McQuarrie was an effective people-watcher and his skill at selecting first the right people and then training them well in pediatrics contributed very much to his success as the leader of what became known as the ‘McQuarrie School of Pediatrics’ that had spread throughout the Central and Western United States. I was the last of McQuarrie’s boys, but had been well prepared by basic studies in anatomy, virology and pathology for a scientific career rather than a career as a medical administrative head a large pediatric department. However, it was through McQuarrie that I was taught the value of viewing medicine in the light of lessons to be learned, from study and analyses of the experiments of nature-often revealed by study of rarer forms of disease.
I ultimately traced the legacy given me by McQuarrie through the insightful contributions of Garrod (1924) and his ‘Inborn Errors of Metabolism’, through the teachings of William Osler to a beautiful letter written by William Harvey just six weeks before he died in 1657. Harvey wrote this letter to man he addressed as Jan Vlakfield, the distinguished physician at Haarlem. His letter contains the following lines:
‘It is even so. Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by the careful investigation of cases of rarer forms of disease. For it has been found in almost all things, that what they contain of useful or of applicable , is hardly perceived unless we are deprived of them, or they become deranged in some way. The case of the plasterer….Farewell, most learned sir, and whatever you do, still love’
This was the expression of the philosophy that had guided my Professor, McQuarrie, and that has also guided much of my most revealing research, especially that part which has been concerned learning about and understanding immunology from study of the patients with primary and secondary immunodeficiency diseases. It is this philosophy that I have been able to pass along to the most productive members of my ‘school of cellular and humoral immunology.’ William Harvey’s philosophy has been a beacon illuminating our way and permitting our making numerous contributions to understanding both cellular and humoral immunologic functions.
Thus, it has been for me so often the quiet moments of reflection over an actual clinical problem with a patient that led me to discover the two separate cellular components of immunity, make the initial discovery of the crucial role of the thymus in immunologic development, guided me to carry out with colleagues the first efforts to treat leukemia by bone marrow transplantation, to achieve the first successful cure of a fatal genetically determined disease- X-linked severe combined immunodeficiency-by bone marrow transplantation, and to achieve first successful treatment of an acquired disease, aplastic anemia, by bone marrow transplantation when the otherwise successful treatment of SCID had been complicated by the occurrence of aplastic anemia.
The joy that has repeatedly derived from successful treatment of numerous otherwise certainly fatal diseases which, at the same time, have contributed new fundamental information about how the immunity systems develop, how they are controlled and how the cell systems are integrated one with the other, has been beyond measure. Thus, it is our patients joining my distinguished teachers whom I have described above and with the questions raised by these patients’ illnesses in the clinic and their responses to novel treatments who have actually become the most important teachers of modern cellular and humoral immunology.
Having finished both PhD and MD degrees at Minnesota and learned lessons about how to ask questions and obtain answers both in the laboratories and at the bedside, I seized the opportunity to spend a year at the Rockefeller Institute for Medical Research. It was here that I came under the influence of Maclyn McCarty who showed me that frequent scientific publication was not essential to a life of discovery and analysis.
It was Maclyn McCarty, along with Oswald T. Avery and Colin McLeod who would, nearly 10 years between scientific publications, discovered that DNA contained the inheritable information that was responsible for transformation of pneumococci from one type to another (Griffiths, 1928). This seminal research, of course, anticipated by 20 years the revolutionary discoveries by Watson and Crick that the double helix of DNA contained all the genetic information. McCarty’s philosophy and worship of excellence and research work of only the highest quality that represented a pattern which I could encompass in my scientific philosophy, but not always reach in my work. While at the Rockefeller, I also worked in collaboration with several other outstanding scientists who reached the highest international stature. These included Henry Kunkel and Chandler (Al) Stetson. It was at the Rockefeller that Stetson introduced me to Lewis Thomas whose enthusiasm and sheer joy in scientific enquiry and in the ‘Lives of the Cell’ helped me very much to develop of my scientific approaches. McQuarrie and I were able to recruit Lewis Thomas to Minnesota. Four years later, when I was still only 32 years old, I was forced to decide whether I should become one of McQuarrie’s young pediatric department chairmen in the Pediatric Department at Minnesota on McQuarrie’s home turf or should follow Thomas’ footsteps and accept an American Legion Chair endowed as a Research Chair. It took me about 1/1,000,000 of a second to decide on the latter as being best for me. Thomas had developed in his laboratory a vigorous panel of young Turks all doing credible and in some cases, rather revolutionary, basic medical research when he was invited to leave Minnesota to accept a department chairmanship at New York University. I was given the choice of accepting the Pediatric Department Chairmanship with McQuarrie’s imminent retirement, or of following in Lewis Thomas’ footsteps as Research professor. However, having made the decision, I sought Thomas’ advice about how I should function in such a demanding research position made famous by its first occupant of the endowed chair I was to accept. I was to succeed the incomparable Lewis Thomas. Thomas, who was always writing something, saw how seriously I was taking this challenge, he put down his pen, looked me straight in the eye and said: “Bob, always have something-some research you are doing yourself from which you get your emotional kicks then you will always be able to help and effectively collaborate with the graduate students and fellows who gather around you and you will not get in their way when they don’t want or need you. Second, proceed to gather as much money for your and their research as you can and spend the money as fast as you can and somehow these two columns will come out even and you won’t have to become an administrator. Above all, stay out of ‘Washington’. Although I did not always follow this insightful advice perfectly, I did to a major degree. Thus, throughout my scientific life, I have been able to function as an effective, independent scientist and also to be a truly contributory scientific advisor, mentor and collaborator with my students and fellows at all levels rarely getting in the way or taking scientific credit that belonged to them.
For more than 20 years, I worked effectively in my endowed chair as professor of pediatrics and also microbiology and made many satisfying discoveries and analyses. I learned to teach my young associates and collaborators and learned also to pay attention to observations that do not fit the current scientific paradigms as a sure way to make real discoveries. To pursue the things that fit contributes beauty to science and are most satisfying to the investigator, but almost never lead to true discoveries. Creativity in science derives from careful analyses of observations and clinical presentations of findings that do not fit-that is where the real fun resides in science.
Finally, in my career in science and medicine, I accepted administration of a department of pathology. Here, I tried my hand at teaching what is known, as well as what is not known. I could do this, but always it was in teaching and considering what is not known where I had my fun. I also spent nearly 10 years trying to bring the forefront of discovery and critical analyses into a large Cancer Research Institute-Sloan Kettering Institute for Cancer Research in New York. This effort was successful, primarily in the areas where my group and I continued to carry out leading edge research in immunology and cellular engineering. However, from 9:00 a.m. to 5:00 p.m. administering a large scientific institute seemed primarily to pursue chronophagia. Although I continued to be a productive scientist, I was not a good administrator. I continued my productive scientific work by carrying out research between 5:00 and 9:00 a.m. and between 6:30 and 10:00 p.m. nearly every day whilst I was in New York.
Thus, after this I was able to accept, with enthusiasm, an appointment at USF which demanded a relatively small administrative activity and provided maximum time to develop one on one Socratic teaching, Socratic group teaching, vigorous research and carefully chosen service to both university and community. Over the 10-year period as physician-in-chief-,an honorific but responsible challenge, at All Children’s Hospital-I have been able to facilitate the development of a small community children’s hospital into a major licensed regional children’s hospital which can address in a highly professional manner, almost all of the medical and surgical problems faced by children. At All Children’s Hospital, I have been able to teach in a Socratic style, have been able to encourage and continue to develop scholars and scientists who are entering and being successful in academic pursuit. I have continued to educate and train many outstanding clinicians who are subspecializing in clinical immunology and allergy, and are able to care for children with rheumatologic diseases. During this period, I have always pursued research I have been doing myself so here again I might continue to facilitate maximally the growth and development of the members of my ‘school of immunology’ by helping each of the students at all levels, progress and develop maximally on their own terms.
Long ago, when I first began my research and with it development of my ‘school of cellular immunologists’. I used to worry very much about what I would do if a really brilliant student came to my laboratory, developed an interest in an important or critical area of research in immunology and then worked very hard with the best possible methods available and did not make a discovery or complete a revealing analysis. What should I do? Having spent 53 years now interacting with many, many such students, this dilemma has never had to be faced. The reason, I believe, is that there is still so much to be learned. What is known is like a crumb or tuft of dust in the corner of a huge auditorium. What is yet to be learned is like the entire remaining auditorium. Thus, by asking critical questions, accepting only definitive answers, everyone who puts mind and body to the task actually makes discoveries and therewith establish his or her own scientific uniqueness. So much for the ‘End of Science’. This requires from me only a modicum of support and ability regularly to encourage, encourage and encourage capacity appropriately to wait, wait, wait for the productive discoveries to mount. True students and developing scientists and scholars continue to need from established scientists and scholars their unqualified acceptance, constructive criticism, encouragement (in spades) and, only occasionally, actually a helping hand.
I am now well underway on my 75th trip around the sun. I remain and have been continuously funded from the National Institutes of Health. I have been so for more than 50 years and my funding now extends well beyond the turn of the century. These fundings have always been via competitive grants in aid from the National Institutes of Health as well as grants from local and other competitive national resources. The current medical students continue to be inducible to science and academic life-may be not quite as inducible as in years gone by. They need more encouragement, not less, and the graduate students continue regularly to be challenging and, occasionally, to be truly brilliant.
The combined teaching research and service opportunities for devoted faculty are no less challenging and fulfilling here at USF than they were a half century ago at Minnesota. I have been fortunate at USF to have minimal administrative distraction, time and support that permits me to continue to make discoveries about the immune systems, opportunity to teach in a Socratic way, and to teach, also, by example, and opportunity to recruit, foster and encourage promising young men and women to enter careers in medical science, or to pursue as subspecialists medical practice of the highest quality.