Frederick Chapman Robbins Born: 25 August 1916, Auburn, AL, USA Died: 4 August 2003, Cleveland, OH, USA

Affiliation at the time of the award: Western Reserve University, Cleveland, OH, USA Prize motivation: "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue Frederick Chapman Robbins was born in Auburn, Alabama, on August 25, 1916. He is the son of William J. Robbins, a plant physiologist, who became Director of the New York Botanical Gardens, and Christine, ne Chapman. Frederick C. Robbins was one of the most distinguished medical scientists and educators of our times. Beginning while a medical student and continuing after military service during the Second World War, he worked in the Boston virology laboratory of John Enders, together with his friend and classmate Thomas Weller. The work of this team led to the cultivation of the poliovirus and paved the way for the subsequent development of polio vaccines. Indeed, the fundamental techniques developed for this accomplishment made possible the cultivation of the viruses causing such other illnesses as measles and the subsequent development of vaccines protecting against these diseases. The recent cultivation of the coronavirus causing Sars used these techniques. The poliovirus work was recognised by the award to the three investigators of the Nobel Prize in Medicine or Physiology in 1954. His undergraduate university education was at the University of Missouri, from which he received the Bachelor of Arts degree in 1936. He began his medical education at Missouri, but transferred to Harvard University after two years, receiving the Doctor of Medicine degree in 1940. He then began hospital training at Boston Children's Hospital, a Harvard affiliate, but his training there was interrupted by entry into the US Army Medical Corps in 1942. During military service he was assigned to the Fifteenth Medical General Laboratory as Chief of the Virus and Rickettsial Disease Section, and in this capacity served in the United States, North Africa, and Italy. Most of his work during this period consisted of

investigations on infectious hepatitis, typhus fever and Q fever, and supervision of a diagnostic virus laboratory. He has also studied the immunology of mumps. In 1945 he received the Bronze Star for Distinguished Service and at the time of discharge from the Army in 1946 held the rank of Major. Returning to civilian life, Robbins resumed his training at The Children's Hospital Medical Center and completed this in January 1948. From 1948 to 1950 he held a Senior Fellowship in Virus Diseases of the National Research Council and worked with Dr. John F. Enders in the Research Division of Infectious Diseases, The Children's Hospital Medical Center. During this time he was a member of the Faculty of the Harvard Medical School. While he was working with Enders, Robbins chiefly studied the cultivation of poliomyelitis virus in tissue culture and the application of this technique. He also investigated the viruses of mumps, herpes simplex and vaccinia. After working initially on mumps and enteric viruses, Robbins and Weller took up Enders's suggestion to try growing poliovirus using the techniques they had developed. Success came quickly. So closely did John Enders and his two research fellows work together that it is difficult to sort out the separate contributions of the individual team members. However, Robbins was the lead author on the paper describing the cytopathic effect that allowed recognition of viral growth in the cultures of monkey kidney cells; it was probably his observation. It was in the laboratory that Fred Robbins met and fell in love with Alice Havemeyer Northrup. The daughter of John Northrup, a Nobel laureate in Chemistry, she was working as a technician in the lab. They were married in 1948 and have two daughters, Alice Christine and Louise Enders. While in Boston, he was appointed Associate in Pediatrics on the Faculty of the Harvard Medical School, Associate in the Research Division of Infectious Diseases, and Associate Physician and Associate Director of the Isolation Service at The Children's Hospital Medical Center, and also Research Fellow in Pediatrics at The Boston Lying-in Hospital and Assistant to the Children's Medical Service, Massachusetts General Hospital.1

In May, 1952, he moved to Cleveland, Ohio, where he had been appointed Professor of Pediatrics at Western Reserve University School of Medicine and Director of the Department of Pediatrics and Contagious Diseases, Cleveland Metropolitan General Hospital, the position which he at present occupies At that time the Western Reserve University School of Medicine was embarking on a major curriculum reform that led to the abandonment of traditional discipline-based courses and institution of interdisciplinary committee teaching. Robbins enthusiastically supported the innovations and served as chairman of the school's Committee on Medical Education from 1958 to 1962. He is an associate member of the Commission on Viral Diseases of the Armed Forces Epidemiological Board, United States Department of Defense, of the Board of Scientific Counselors of the Division of Biologics Standards, Public Health Service, United States Department of Health, Education and Welfare, of the Physician's Council, the Scientific Research Advisory Board of the National Association for Retarded Children; he is also Chairman of District V of the Committee on Medical Education of the American Academy of Pediatrics, and of the Awards Committee of this Academy, and served on the Public Health Council of the Ohio State Department of Health. He is also a consultant to the Infectious Diseases and Tropical Medicine Training Grant Award Committee of the National Institute of Allergy and Infectious Diseases, and to the Oregon Primate Research Center. He continued his virology research in his hospital laboratory, which served as a reference laboratory during a number of vaccine trials and in which were trained many individuals who went on to major academic and pharmaceutical positions. In 1955, John Carroll University of Cleveland conferred upon him the honorary degree of Doctor of Science, and in 1958, the University of Missouri, his alma mater, did the same. In 1961 he was elected President of the Society for Pediatric Research, and in 1962 a member of the American Academy of Arts and Sciences. In 1966 Fred Robbins was named Dean of the Case Western Reserve University School of Medicine. At that time, the dean's office was located in a small house near the medical

school and adjacent university hospitals. But much of Robbins's business was not transacted there. Quiet and modest, yet friendly and outgoing, he was more likely to collar a professor or student in a corridor than in his office. His deanship years saw an expansion of the school of medicine and a continuing effort at curriculum reform and revitalisation. In 1980, Robbins resigned his deanship to assume the presidency of the Institute of Medicine of the National Academy of Sciences. Chartered by the United States Congress but not a governmental agency, the academy draws together scientists who consider issues of national import and plays a major role in shaping public policy. In 1985 he retired from the Institute of Medicine and returned to Case Western Reserve University as a distinguished University Professor Emeritus. "Emeritus" is an academic euphemism for retired, but to Fred Robbins it meant nothing of the sort. He maintained an office in the medical school "C" near the main entrance where he could easily confront his colleagues in corridor C; he was on the scene every day. He served on many national and international bodies including several with the Pan American Health Organization. In 1990 he became Chairman of the PAHO International Commission for the Certification of Poliomyelitis Eradication in the Americas. Unlike the smallpox virus, which is transmitted aerially and causes the only other disease to have been eradicated, poliovirus is excreted into the environment, and it was not sufficient for health officials simply to interrupt transmission by quarantining cases. Thus, in addition to establishing reporting criteria and immunisation goals, the commission had to develop criteria for monitoring viral excretion. In 1996, coincident with Robbins's 80th birthday, the commission he chaired certified the eradication of poliomyelitis from the Americas. The programme has now been expanded globally, and total eradication is likely to be achieved within the next few years. Mass immunisations using vaccines produced in cultures of the type developed by Enders, Robbins and Weller have made this possible.

As the 20th century approached its end, Aids became the viral disease at centre-stage, and Robbins became increasingly concerned about this new plague. In 1987 the United States National Institutes of Health announced a competition for awards under a new programme to establish international collaborations for Aids research. Robbins saw the announcement and recruited three of his faculty colleagues to join him in traveling to Kampala, Uganda. Thus was born a multidisciplinary collaboration between Case Western Reserve University and Makerere University in Kampala that continues to the present, now much expanded, focusing on Aids and tuberculosis. The collaboration uses offices at Mulago Hospital that were formerly used by the British Medical Research Council for its studies of the treatment of tuberculosis. Robbins made many trips to Uganda, and both in Cleveland and in Kampala his leadership was continually felt. In 1990 Robbins convinced the Case Western Reserve School of Medicine to establish a Center for Adolescent Health, and in 1992 he became the Director. The activities of this centre focus primarily upon the under-served adolescent children of Cleveland's innercity neighbourhoods. In addition to the Nobel Prize, Robbins received many honours, awards and honorary degrees, including the first Mead Johnson Award in 1953, the Kimble Methodology Research Award in 1954, the Ohio Governor's Award in 1971, the Abraham Flexner Award of the American Association of Medical Colleges in 1987, and the Benjamin Franklin Medal of the American Philosophical Society in 1999. At Case Western Reserve University the east wing of the medical school was named the Frederick C. Robbins Building in 2002. The Frederick C. Robbins Professorship in Child and Adolescent Health was endowed by gifts from his friends in 2002, and the Frederick C. Robbins Traveling Fellowship for medical students pursuing international electives in 2000. Fred Robbins was a kind and modest person, an inspiring leader, a person whose sharp mind never ceased generating ideas; a wise mentor, a revered teacher and a friend of and advocate for the children of the world. "Come ye, let us go up to the mountain . . . and he

will teach us his ways and we will walk in his paths" (Isaiah ii,3). Robbins stood at the top of his mountain; he never failed to teach us or lead us in his paths. Honors & Awards Award for Distinguished Achievement (Modern Medicine), 1963 Honorary Degree, Doctor of Laws, University of New Mexico, 1968 Medical Mutual Honor Award, 1969 Ohio Governor's Award, 1971 Honorary Fellow, All-India Institute of Medical Sciences, 1977 Honorary Fellow, National Academy of Medical Sciences (India), 1977 Honorary Degree, Doctor of Science, University of North Carolina, 1979 Honorary Degree, Doctor of Science, Tufts University, 1983 Honorary Degree, Doctor of Science, Medical College of Ohio, 1983 Honorary Degree, Doctor of Science, Albert Einstein College of Medicine, 1984 Honorary Degree, Doctor of Science, Medical College of Wisconsin, 1984 Honorary Degree, Doctor of Medical Science, The Medical College of Pennsylvania, 1984 Honorary Degree, Doctor of Laws, University of Alabama, Birmingham, 1985 Abraham Flexner Award of AAMC for Distinguished Service to Medical Education, 1987 Judge Baker Children's Center Camille Cosby World of Children Award, 1988 NASA Public Service Award, 1989 Ohio Science and Technology Hall of Fame, 1992 Case Western Reserve University Medical Alumni Assoication Board of Trustees Award, 1993

Honorary Degree, Doctor of Science, honoris causa, Case Western Reserve University, May 24, 1992 Frank and Dorothy Humel Hovorka Prize, Case Western Reserve University, May 22, 1994 Honorary Degree, Doctor of Science, Kirksville College of Osteopathic Medicine, Kirksville, Missouri, June 7, 1998 Benjamin Franklin Medal, American Philosophical Society, Philadelphia, PA, April 22, 1999 Award Ceremony Speech Presentation Speech by Professor S. Gard, member of the Staff of Professors of the Royal Caroline Institute Your Majesties, Your Royal Highnesses, Ladies and Gentlemen. The principles of cultivation of bacteria were laid down in the late 1870's by Robert Koch. Since that time the bacteriologists could study systematically the diseases caused by bacteria, isolate the causative agents in pure culture and make themselves familiar with their nature. With the aid of the culture technique they were able to trace the routes, along which infection is transmitted, to detect carriers and other sources of infection thereby making a rational combat of epidemics feasible. They could produce therapeutic sera and prophylactic vaccines. Finally, the culture technique was instrumental in the discoveries of the modern wonder drugs, sulfa, penicillin, streptomycin, etc.

The 75 year old fight against the bacterial diseases has been successful. Although not completely eradicated, plague, cholera, typhoid, diphteria, and sepsis have ceased to be a threat to mankind. Tuberculosis seems to be under control. The trends are clearly reflected in the vital statistics. Since the turn of the century the rate of mortality from bacterial infections in this country has been reduced by more than 90%.

Turning to the virus diseases we meet an entirely different picture. It is true that smallpox is brought under control thanks to the efficient vaccine that Nature itself has provided. Yellow fever was checked by means of mosquito control and with the aid of Theiler's vaccine, an achievement awarded the 1951 Nobel Prize. The spread of epidemic typhus can be prevented by the use of DDT - a feat likewise awarded a Nobel Prize - and the disease itself successfully treated with antibiotics. In all the others, however, our art fails us. Worst of all, many virus diseases are on the increase, a tendency particularly evident in poliomyelitis. After having been practically unknown at the turn of the century, poliomyelitis in this country is now responsible for almost one fifth of all deaths from acute infections. Similarly epidemic jaundice seems to increase; it presented serious problems particularly during the last World War. Many more examples could be mentioned.

It is not difficult to find the reason why the virologists have failed where the bacteriologists were so successful. They have been severely handicapped by the difficulties connected with the cultivation of viruses. Unlike bacteria and other microorganisms, virus is incapable of multiplying in artificial life less culture media. In the test tube it appears as an inert chemical substance; only in the interior of a living cell its hidden forces are liberated. Here, it turns the more active and incites a process which may, sometimes within a few minutes, lead to cell destruction and the production of hundreds of new virus particles.

At first the virologist had to resort entirely to animal experiments, hoping that inoculation of the test material would produce a typical disease. Instead of studying the virus itself he must be content to observe the animal's reaction to infection and try to deduce therefrom some information on the properties and the nature of viruses. This indirect method is more labor and time consuming, more expensive and above all less easily interpreted than the bacteriological culture technique. It is hardly possible to use it on such a scale a needed for the control of epidemics. Furthermore, the laboratory animals often fail us, as

many viruses have so completely specialized on the human race that they do not attack any other living beings. Experiments on human volunteers, sometimes resorted to in such cases are hardly advisable.

Then, in 1949 there appeared from a Boston research team a paper, modest in size and wording but with a sensational content. John Enders, director of the Children's Hospital's Research Laboratory and his associates Thomas Weller and Frederick Robbins reported the successful cultivation of the poliomyelitis virus in test-tube cultures of human tissues. A new epoch in the history of virus research had started.

The art of growing animal tissues isolated from the organism was learned already in the first decade of this century. The metazoan cell may be regarded as a micro-organism, more highly specialized than free-living bacteria, that is true, for its existence dependent upon the symbiosis with its fellow cells in the organism, and yet capable of leading its own life if only it is offered a suitable medium. Therefore, the principles of tissue culture are largely the same as those applied in cultivation of bacteria. The greatest difficulty encountered by Carrel, a French-American to whom the development of the technic should be credited, was prevention of contamination of the cultures by micro-organisms, which multiply rapidly thereby destroying the tissue. To meet this end Carrel introduced a complicated ritual. Tissue culture developed almost into tissue cult, a mystery the secret rites of which were revealed only to a narrow circle of inaugurates with Carrel as their high priest.

Already at an early stage the virologists sensed that tissue culture might prove a valuable tool, but the technical difficulties discouraged them. Not until 1925 Parker and Nye were able to present conclusive evidence that a virus could multiply in tissue cultures. The year 1928 is also worth remembering in the present connection. Then, the Maitlands, in Manchester, introduced a considerably simplified technique by which cells could be made to retain their viability for a short period of time and to exert a certain activity,

although growth was inconsiderable. However, a virus capable of rapid multiplication might find sufficiently favorable conditions to permit by this technique its maintenance and to a certain extent its study without resort to laboratory animals. The Maitland technique has found application for certain practical purposes. It was, for instance, instrumental in the development of Theiler's yellow fever vaccine. It is not equivalent to the bacteriological culture methods, however. Thus, it cannot be used for isolation of a virus from a test material.

Enders' interest in tissue-culture methods dates back to around 1940. He was convinced that the Maitland cultures were but an unsatisfactory ersatz, not answering the requirements of the exacting viruses, and for this reason found a return to the more intricate Carrel technique inevitable. In the 1940's together with Weller and a few other associates he studied the viruses of vaccinia, influenza and mumps, thereby gathering valuable experience.

At last, time was ripe for experiments on the poliomyelitis virus. The prospect of a favorable result could not be considered particularly bright. Other scientists had previously attacked the problem with very moderate success. It was generally held that the final word had already been said by Sabin and Olitsky who in 1936 tried to grow the virus in Maitland cultures of various tissues from chick embryos, mice, monkeys, and human embryos. Their results remained completely negative except in cultures of human embryonic brain tissue in which the virus at least seemed to maintain its activity. These findings were taken as a definitive confirmation of the accepted concept of the virus as a strictly neurotropic agent, i.e. capable of multiplying in nerve cells exclusively. Accordingly, the hopes of a practicable method for the cultivation of the poliomyelitis virus were temporarily shelved. Of all tissues, nerve tissue is the most specialized, the most exacting and consequently the most difficult to cultivate. As, at that, there seemed to be no alternative to the use of human brain tissue, the general resignation is easily understood.

In the 1940's the belief in the neurotropism of the virus began to falter, however, and Enders, Weller and Robbins decided to repeat Sabin and Olitsky's experiment with an improved technique. In their first experiments they used human embryonic tissue. To the great surprise of everybody except perhaps the experimenters themselves they registered a hit in their first attempt. The virus grew not only in brain tissue but equally well in cells derived from skin, muscle, and intestines. Furthermore, in connection with the multiplication of the virus, typical changes appeared in the cellular structure, finally leading to complete destruction, easily recognizable under the microscope. This observation furnished a convenient method of reading the results. Furthermore, immune serum was found to inhibit specifically the virus multiplication, the technique therefore being applicable also in immunity tests. Subsequently, Enders, Weller and Robbins found that tissues secured from operations on children as well as adults could be used to advantage; all tissues except bone and cartilage seemed to be equally suitable. Finally they tried to isolate the virus from various specimens directly in tissue cultures. This was likewise achieved. In the latter observation probably the greatest practical importance of their discoveries is to be found. The virologists finally had a tool in the same classes the culture technique of the bacteriologists.

These discoveries incited a restless activity in the virus laboratories the world over. The tissue-culture technique was rapidly made one of the standard methods of medical virus research, among which it now holds an undisputed first place. So far it has been applied primarily in the study of poliomyelitis. It has been tested and excellently held its own in all possible connections, as a diagnostic tool of clinicians and epidemiologists, in vaccine production and for purely theoretical purposes. Its field of application is not limited to poliomyelitis research, however. The use of cultures of human tissues has permitted attacks on many virus problems previously out of reach because of the lack of susceptible laboratory animals. Already at an early stage Enders, Weller and Robbins discovered agents representing a previously unknown group of viruses. Other scientists have

systematically pursued this line and the answer to the question of the causes of a number of common-coldlike diseases now seems to be at hand. Weller has succeeded in cultivating the agents causing varicella and herpes zoster, Enders that of measles, viruses previously almost inaccessible for study. The method has also been successfully applied to several problems in the field of veterinary medicine.

We now possess essentially improved technical facilities for the combat of viral diseases. We should be aware, however, of not claiming any victories in advance. It took 75 years to achieve those results in the field of bacteriology to which we now point with pride. Much effort and a considerable time will be required for equivalent achievements in the fight against the virus diseases. However, thanks to Enders, Weller and Robbins' discovery we may look with confidence to the future.

Dr. John Enders, Dr. Frederick Robbins, Dr. Thomas Weller. Karolinska Institutet has decided to award you jointly the Nobel Prize for your discovery of the capacity of the poliomyelitis virus to grow in test-tube cultures of various tissues. Your observations have found immediate practical application on vitally important medical problems, and it has made accessible new fields in the realm of theoretical virus research.

By giving the virologists a practicable method for the isolation and study of viruses you relieved them of a handicap, burdening them from the birth of their science and placed them for the first time on an even footing with other microbe hunters. We may now look with confidence to the future and may justifiably expect equally spectacular achievements in the fight against virus diseases as were already accomplished on the bacteriological battlefield.

The electronics, radioactive isotopes, and complicated biochemistry of our age has threatened to turn medical science into something dangerously resembling technology. Now and again we need to be reminded of its fundamental biological elements. Against

this background we express our admiration of the biological common sense, characterizing your approach to important medical problems, and of the wonderful simplicity of the solutions you have presented. It is my privilege and pleasant duty on behalf of Karolinska Institutet to extend to you our sincere felicitations.

Dr. Enders, Dr. Robbins, Dr. Weller. May I now request you to receive your Nobel Prize from the hands of His Majesty the King.