Chapter-01-Laboratory-Animal-Medicine-Historical-Perspectives_2015_Laboratory-Animal-Medicine-Third-Edition-.pdf

C H A P T E R 1 Laboratory Animal Medicine: Historical Perspectives James G. Fox, DVM, MS, DACLAMa and B. Taylor Bennett, DVM, PhDb a Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA b Management Consultant, Hinsdale, IL, USA O U T L I N E I. Introductio...

C H A P T E R 1 Laboratory Animal Medicine: Historical Perspectives James G. Fox, DVM, MS, DACLAMa and B. Taylor Bennett, DVM, PhDb a Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA b Management Consultant, Hinsdale, IL, USA O U T L I N E I. Introduction II. Origins of Animal Experimentation III. Early Veterinarians in Laboratory Animal Science and Medicine IV. The Organizations of Laboratory Animal Science A. Background B. The National Society for Medical Research C. The American Association for Laboratory Animal Science D. The Institute for Laboratory Animal Research E. The American College of Laboratory Animal Medicine F. The American Society of Laboratory Animal Practitioners G. The Association of Primate Veterinarians H. The International Association of Colleges of Laboratory Animal Medicine 1 V. Education and Training in Laboratory Animal Medicine 2 VI. ACLAM-Sponsored Texts 5 14 15 16 16 17 19 VIII. Regulation of Animal Research in the United Kingdom and Canada 19 IX. Commercial and Academic Breeding of Rodents 20 X. Conclusion 20 Acknowledgment 20 References 20 17 I. INTRODUCTION gaining new biological knowledge or solving specific medical, veterinary medical, dental, or biological problems. Most commonly, such experimentation is carried out by or under the direction of persons holding research or professional degrees. Laboratory animal care is the application of veterinary medicine and animal science to the acquisition Five key terms identify the fields or activities that relate to the care and use of animals in research, education, and testing. Animal experimentation refers to the scientific study of animals, usually in a laboratory, for the purpose of Laboratory Animal Medicine, Third Edition DOI: http://dx.doi.org/10.1016/B978-0-12-409527-4.00001-8 18 VII. Impact of Laws, Regulations, and Guidelines on Laboratory Animal Medicine 10 10 11 17 1 2015 Elsevier Inc. All rights reserved. © 2012 2 1. Laboratory Animal Medicine: Historical Perspectives of laboratory animals and to their management, nutrition, breeding, and diseases. The term also relates to the care that is provided to animals as an aid in managing pain and distress. Laboratory animal care is usually provided in scientific institutions under veterinary supervision or guidance. Laboratory animal medicine is recognized by the American Veterinary Medical Association as the specialty field within veterinary medicine that is concerned with the diagnosis, treatment, and prevention of diseases in animals used as subjects in biomedical activities. Laboratory animal medicine also encompasses the methods of minimizing and preventing pain or distress in research animals and identifying complicating factors in animal research. Comparative medicine is “the study of the nature, cause and cure of abnormal structure and function in people, animals and plants for the eventual application to and benefit of all living things” (Bustad et al., 1976). Laboratory animal science is the body of scientific and technical information, knowledge, and skills that bears on both laboratory animal care and laboratory animal medicine and that is roughly analogous to animal science in the agricultural sector. Laboratory animal medicine has grown rapidly because of its inherent scientific importance and because good science and the public interest require the best possible care for laboratory animals. In this chapter, we trace briefly the historical evolution of laboratory animal medicine and consider its relationship to other areas of biology and medicine. II. ORIGINS OF ANIMAL EXPERIMENTATION The earliest references to animal experimentation are to be found in the writings of Greek philosopherphysicians of the fourth and third centuries bc. Aristotle (384–322 bc), characterized as the founder of biology, was the first to conduct dissections that revealed internal differences among animals (Wood, 1931). Erasistratus (304–250 bc) was probably the first to perform experiments on living animals, as we understand them today. He established in pigs that the trachea was an air tube and the lungs were pneumatic organs (Fisher, 1881). Later, Galen (ad 130–200) performed anatomical dissections of pigs, monkeys, and many other species (Cohen and Drabkin, 1948; Cohen, 1959a). He justified experimentation as a long, arduous path to the truth, believing that uncontrolled assertion that was not based on experimentation could not lead to scientific progress. Dogma replaced experimentation in the dark centuries following Galen’s lifetime. Whereas anatomical dissection of dead animals and people had been among the earliest types of experimentation, in medieval times this practice was prohibited by ecclesiastical authorities who wanted to prevent acquisition of knowledge about the natural world that could be considered blasphemous. Not until the 1500s was there a reawakening of interest in science. Andreas Vesalius (1514–1564), the founder of modern anatomy, used dogs and pigs in public anatomical demonstrations (Saunders and O’Malley, 1950) (Fig. 1.1). This vivisection led to great leaps in the understanding of anatomy’s correspondence with physiology. In 1628, Sir William Harvey published his great work on the movement of the heart and blood in animals (Harvey, 2001; Singer, 1957). By the early 1700s, Stephen Hales, an English clergyman, reported the first measurement of blood pressure, using as his subject a horse “fourteen hands high, and about fourteen years of age, [and with] a fistula on her withers” (Hoff et al., 1965) (Fig. 1.2). During the 1800s, France became a primary center of experimental biology and medicine. Scientists, such as François Magendie (1783–1855) and Claude Bernard (1813–1878) (Fig. 1.3) in experimental physiology and Louis Pasteur (1822–1895) in microbiology, contributed enormously to the validation of the scientific method, which included the use of animals. Bernard (1865) commented: … it is proper to choose certain animals which offer favorable anatomical arrangements or special susceptibility to certain influences. For each kind of investigation we shall be careful to point out the proper choice of animals. This is so important that the solution of a physiological or pathological problem often depends solely on the appropriate choice of the animal for the experiment so as to make the result clear and searching. FIGURE 1.1 Illustration by Andreas Vesalius. Pig tied to dissection board for the administration of vivisections. From Saunders and O’Malley, 1950. LABORATORY ANIMAL MEDICINE II. Origins of Animal Experimentation FIGURE 1.2 Title page from “Statical Essays” (Hales, 1740). LABORATORY ANIMAL MEDICINE 3 4 1. Laboratory Animal Medicine: Historical Perspectives FIGURE 1.3 Claude Bernard, often referred to as the founder of FIGURE 1.4 Dr. Cooper Curtice. Curtice contributed importantly experimental medicine, developed and described highly sophisticated methods of animal research in his laboratory in Paris. Photograph from Garrison (1929). to the demonstration that arthropods can act as carriers of mammalian diseases. Courtesy of The Nation’s Business. Pasteur studied infectious diseases in a variety of animals, such as silkworms (pebrine), dogs (rabies), and sheep (anthrax). Pebrine (pepper) was an economically important disease of silkworms in France when silk was a major fabric; Pasteur and others demonstrated the parasite that caused the disease (Duclaux, 1920). As pathogenic organisms were identified that could be related to specific human diseases, their animal disease counterparts also were studied. Pasteur and others perceived that the study of animal diseases benefited animals and enhanced the understanding of human diseases and pathology. The extraordinary power of the experimental approach, including experiments on animals, led to what has been called the Golden Age of scientific medicine. Despite advances in physiological and bacteriological understanding, criticisms of the use of animals in science began, particularly in England (Loew, 1982). The first Society for the Prevention of Cruelty to Animals (SPCA) was established in England, followed in the 1860s by an American SPCA in New York, a Philadelphia SPCA, and a Massachusetts SPCA. Objections to the use of animals in science were part of the concerns of these societies, particularly because Darwin’s findings on evolution made differences between animals and humans less sure in many persons’ minds (Loew, 1982). Most American and Canadian scientists, physicians, and veterinarians soon applied emerging scientific concepts in their research. D.E. Salmon, recipient of the first D.V.M. degree awarded in the United States (by Cornell University in 1879), studied bacterial diseases, and the genus Salmonella, a ubiquitous human and animal pathogen, was named for him. Cooper Curtice (Fig. 1.4), Theobald Smith, and others first demonstrated the role of arthropod victors in disease transmission in their studies of bovine Texas fever (Schwabe, 1978). The first paper published at the then fledgling Johns Hopkins Hospital and School of Medicine was by the physician William H. Welch, for whom Clostridium welchii was named, and was entitled “Preliminary Report of Investigations Concerning the Causation of Hog Cholera” (Welch, 1889). Thus, it became evident that the study of the naturally occurring diseases of animals could illuminate principles applicable to both animals and mankind, and lead to improved understanding of biology in general. John Call Dalton, M.D. (1825–1889), an American physiologist, spent a year in Bernard’s laboratory in Paris around 1850. He was highly impressed with Bernard’s instructional methods, which included demonstrations of important physiological principles in living animals. Subsequently, Dr. Dalton included such demonstrations in his teaching at the College of Physicians and Surgeons in New York City (Mitchell, 1895), the forerunner of the animal labs in which generations of students in biology and medicine were once trained. When Alexis Carrel received the Nobel Prize in 1912, the citation stated in part: “… you have … LABORATORY ANIMAL MEDICINE III. Early Veterinarians in Laboratory Animal Science and Medicine 5 proved once again that the development of an applied science of surgery follows the lessons learned from animal experimentation” (Malinin, 1979). Thus, starting in ancient times and continuing to the present day, animal experimentation has been one of the fundamental approaches of the scientific method in biological and medical research and education. III. EARLY VETERINARIANS IN LABORATORY ANIMAL SCIENCE AND MEDICINE On September 15, 1915, Dr. Simon D. Brimhall (1863–1941; V.M.D., University of Pennsylvania, 1889) (Fig. 1.5) joined the staff of the Mayo Clinic in Rochester, Minnesota, the first veterinarian to fill a position in laboratory animal medicine at an American medical research institution (Cohen, 1959b; Physicians of the Mayo Clinic and the Mayo Foundation, 1937). No such field was recognized at the time, of course; but Dr. Brimhall’s activities – management of the animal facilities, development of animal breeding colonies, investigation of laboratory animal diseases (Brimhall and Mann, 1917; Brimhall and Hardenbergh, 1922), and participation in collaborative and independent research (Brimhall et al., 1919–1920) – were the prototype of the present role of laboratory animal veterinarians in scientific institutions throughout the world. The decision to employ a veterinarian at the Mayo Clinic in 1915 appears to have resulted from a unique juxtaposition of institutional needs and personalities. Although the Mayo Clinic was already world renowned, organized research was in only a rudimentary stage of development. Around 1910, an unsuccessful effort was made to convert an old barn, belonging to the chief of surgical pathology, Dr. Louis B. Wilson, for animal experimentation (Braasch, 1969). Then, in 1914, with Dr. William J. Mayo’s active encouragement, the Division of Experimental Surgery and Pathology was created, the first real research laboratory at the clinic. Dr. Frank C. Mann, a young medical scientist from Indiana, was invited to head the division, with the primary assignment of developing a first-class animal research laboratory. Dr. Brimhall’s employment followed within a year and was accompanied by the planning and ultimate construction of new animal facilities (Figs 1.6 and 1.7). Christopher Graham, M.D., then head of the Division of Medicine, greatly influenced the decision to employ Dr. Brimhall. Perhaps the fact that Dr. Graham was also a veterinarian (V.M.D., University of Pennsylvania, 1892) provided insights into the contributions that veterinary medicine could make to experimental surgery and pathology. Certainly, the concept of mutual support among the professions was not at FIGURE 1.5 Simon D. Brimhall, V.M.D., the first veterinarian in laboratory animal medicine at an American medical research institution, worked at the Mayo Clinic from 1915 to 1922. Courtesy of University of Minnesota Press and Dr. Paul E. Zollman. that time widely held; there was, in fact, relatively little interprofessional communication between medicine and veterinary medicine. Dr. Brimhall retired in 1922 and was succeeded by Dr. John G. Hardenbergh (1892–1963; V.M.D., University of Pennsylvania, 1916). During his 5-year tenure at the Mayo Clinic, Dr. Hardenbergh was an active clinical investigator (Hardenbergh, 1926–1927) as well as animal facility manager. In a stout defense of animal experimentation, he also demonstrated the communication skills in the public arena that were to serve him well later in his career (1941–1958) as executive secretary of the American Veterinary Medical Association (Hardenbergh, 1923). Dr. Carl F. Schlotthauer (1893–1959; D.V.M., St. Joseph Veterinary College, 1923), who had joined the Mayo Clinic staff in 1924 as assistant in veterinary medicine, succeeded Dr. Hardenbergh in 1927. By this time, the Mayo Foundation was functioning as the graduate medical education and research arm of the Mayo Clinic and had become formally affiliated with the University of Minnesota. Dr. Schlotthauer ultimately became head of the Section of Veterinary Medicine at the Mayo Foundation (1952) and professor of veterinary medicine at the University of Minnesota Graduate School (1945). Thus, he was the first veterinarian to attain a full professorship for laboratory animal medicine-related academic activities. He vigorously opposed antivivisectionist LABORATORY ANIMAL MEDICINE 6 1. Laboratory Animal Medicine: Historical Perspectives FIGURE 1.6 Dog breeding facility, Institute of Experimental Medicine, Mayo Clinic, constructed in the mid-1920s. Courtesy of Dr. Paul E. Zollman. FIGURE 1.7 Interior of guinea pig breeding house, Institute of Experimental Medicine, Mayo Clinic, constructed in the early 1920s. Courtesy of Dr. Paul E. Zollman. attacks on animal research. He was a leader in the statewide campaign that led to adoption of the Minnesota pound law in 1950, i.e., a law authorizing the requisitioning for research and education by approved scientific institutions of impounded, but unclaimed dogs and cats. Dr. Schlotthauer believed that open and honest communication between medical scientists and humane society workers could lead to better public understanding and support of animal research. Consequently, he was also active in humane society activities, serving for many years on the board of directors of the Minnesota Society for the Prevention of Cruelty to Animals. He also was an important figure in the early years of the American Association for Laboratory Animal Science (AALAS). He was a founding member of its board of directors and presented a paper on animal procurement at its first meeting in 1950 (Schlotthauer, 1950). Although other veterinarians also held appointments at the Mayo Foundation between 1915 and 1950, Drs. Brimhall, Hardenbergh, and Schlotthauer were the ones most closely associated with activities that today are identified with laboratory animal medicine. LABORATORY ANIMAL MEDICINE III. Early Veterinarians in Laboratory Animal Science and Medicine It is noteworthy that the Mayo Clinic/Foundation has maintained a program in animal medicine continuously for more than 95 years, having initiated it long before most medical research institutions were prepared even to consider the possible value of adding veterinarians to their professional staff (P.E. Zollman, personal communication, 1982). Dr. Karl F. Meyer (1884–1974; D.V.M., University of Zurich, 1924; M.D. [honorary], College of Medical Evangelists, 1936) was an internationally known epidemiologist, bacteriologist, and pathologist. Dr. Meyer was intensely interested in matters related to laboratory animals for most of his professional life. He was the author of an early review of laboratory animal diseases (Meyer, 1928), one of the first publications of its kind in the United States. He was a unique personality (vigorous, dynamic, active); a world traveler on missions related to international health; and a scientist who engendered in his students respect, admiration, love, and fear in varying proportions. Together with his longtime associate Bernice Eddy (Ph.D.), a bacteriologist, Dr. Meyer developed a model animal facility at the George Williams Hooper Foundation at the University of California, San Francisco, during a 30-year tenure as director (1924–1954). Dr. Meyer was often away from the laboratory, and it fell to Dr. Eddy to supervise the animal facility, which she did with great skill and dedication. Dr. Meyer foresaw the need for and was an early advocate of the participation of veterinarians in the operation of institutional laboratory animal colonies (Meyer, 1958). He figured importantly in the planning that led the University of California to create the position of statewide veterinarian in 1953, which subsequently was superseded by the appointment of veterinarians at each of the university’s major campuses. Among his many honors, Dr. Meyer received the Charles A. Griffin Award of AALAS in 1959. Dr. Charles A. Griffin (1889–1955; D.V.M., Cornell University, 1913) was a bacteriologist at the New York State Board of Health, Division of Laboratories, Albany, New York, from 1919 to 1954. Dr. Griffin pioneered the concept of the development of disease-free animal colonies long before gnotobiotic technology had evolved (Brewer, 1980). In the 1940s, he utilized progeny testing to establish a rabbit colony free of pasteurellosis. Additionally, he showed that Salmonella spp. could be transmitted in meat meal (Griffin, 1952). This led feed manufacturers to improve the processing of laboratory animal diets so as to eliminate Salmonella contamination. The Charles A. Griffin Award of AALAS was established and named in Dr. Griffin’s honor (Table 1.1). He received the award posthumously in 1955, the first recipient of this prestigious award. The Griffin Laboratory at the New York State Board of Health central facility in Albany, New York, also is named in his honor. 7 Dr. Nathan R. Brewer (1904–2009; D.V.M., Michigan State University, 1937; Ph.D., University of Chicago, 1936) headed the laboratory animal facilities at the University of Chicago from 1945 until his retirement in 1969 (Fig. 1.8). Dr. Brewer’s interest in laboratory animals began in the mid-1920s, when he started veterinary school, and continued during his graduate student years in the Department of Physiology at the University of Chicago. Around 1935, Professors Anton J. Carlson (Ingle, 1979) and A.B. Luckhardt first approached Dr. Brewer about managing the University of Chicago animal facilities. They saw merit in the concept of a veterinarian, well grounded in the scientific method, as animal facility manager. They believed this arrangement would contribute to public confidence in the care and treatment of animals in research, and would help to turn aside antivivisection activists. However, many investigators at the university feared that a veterinarian would dictate the conditions of care and use of animals, and they opposed the creation of this position. It was not until 1945 that this opposition was overcome, and Dr. Brewer became supervisor of the Central Animal Quarters. Laboratory animal medicine began its modern evolution in the following years. Dr. Brewer’s role was seminal – as a founder of the American Association for Laboratory Animal Science, as the first president of the AALAS (1950–1955), and as a father figure for the then youthful group of veterinarians that had been employed by other medical schools and medical research institutions in the Chicago area between 1945 and 1949. Dr. Brewer received the AALAS Griffin Award in 1962. After his retirement in 1969, he remained active and attended local and national AALAS meetings up until his death at the age of 104. To honor his contributions to the field, the AALAS instituted an annual award in 1994, the Nathan Brewer Scientific Achievement Award. In 2005, at the age of 100, the American College of Laboratory Animal Medicine (ACLAM) presented him with a lifetime achievement award, which subsequently became the ACLAM’s Nathan R. Brewer Career Achievement Award in 2006. Dr. Bennett Cohen (1925–1990; D.V.M., Cornell University Veterinary School, 1949; Ph.D., Northwestern Medical School, 1953) was the director of the vivarium at the University of California Medical School in Los Angeles (Fig. 1.9). He was subsequently recruited to the University of Michigan where he founded the Unit for Laboratory Animal Medicine at the University of Michigan and was its director for 23 years. He obtained the rank of Professor of Laboratory Animal Medicine in 1968. Dr. Cohen was a pioneer and visionary in the field of laboratory animal science for over 40 years. His career of caring for animals used in medical research began at Northwestern University in 1949. A year later, he and veterinary colleagues in the Chicago area founded LABORATORY ANIMAL MEDICINE 8 1. Laboratory Animal Medicine: Historical Perspectives TABLE 1.1 Charles A. Griffin Award Recipients TABLE 1.1 Charles A. Griffin Award Recipients Year Recipient Year Recipient 1956 Charles A. Griffin 1986 Gerald L. Van Hoosier 1957 James A. Reyniers 1987 Orland A. Soave 1958 John B. Nelson 1988 Pravin N. Bhatt 1959 Robert D. Henthorne 1960 Nathan R. Brewer 1989 Dennis M. Stark 1961 Karl Frederich Meyer 1990 Steven H. Weisbroth 1962 George D. Snell 1991 Steven P. Pakes 1963 C.N. Wentworth Cumming 1992 J. Derrell Clark 1964 Phillip C. Trexler 1993 Robert O. Jacoby 1965 W.T.S. Thorp 1994 Harry Rozmiarek 1966 Bennett J. Cohen 1995 Leo A. Whitehair 1967 James R.M. Innes 1996 Henry Baker 1968 Robert J. Flynn 1997 Joseph E. Wagner 1969 Melvin M. Rabstein 1998 Thomas E. Hamm 1970 Willard H. Eyestone 1999 Steele F. Mattingly 1971 William I. Gay 2000 Charles A. Montgomery 1972 Lisbeth M. Kraft 2001 Ronald McLaughlin 1973 L.R. Christensen 2002 Jack R. Hessler 1974 George R. Collins 2003 Clarence Reeder and Joseph Mayo 1975 Eleanore E. Storrs 2004 James E. Corbin 1976 Henry L. Foster 2005 Jerry Fineg 1977 Thomas B. Clarkson 2006 Alvin Moreland 1978 Wilhelmina F. Dunning 2007 Not presented 1979 John C. Parker 2008 James G. Fox 1980 Charles W. McPherson 2009 Richard C. Simmonds 1981 Daniel H. Ringler 2010 William White 1982 Charles C. Hunter 2011 Fred Quimby 1983 Jules S. Cass 2012 Marilyn J. Brown 1984 James R. Ganaway 2013 Steven L. Leary 1985 Patrick J. Manning 2014 Mark A. Suckow the Animal Care Panel (ACP), which later became the AALAS. He served as the Association’s first secretary, as a member of the board of trustees, and later as president. Three years later, he and a few colleagues saw the need to establish standards of training and experience for veterinarians engaged in laboratory animal medicine. They convinced the American Veterinary Medical Association to accept the veterinary specialty of laboratory animal medicine and establish a specialty certification board. This became the ACLAM. In 2013, there were over 900 board-certified veterinarians in the United States. In 1963, Dr. Cohen chaired the National Academy of Sciences committee that wrote the first edition of the document that later became The Guide for Care and Use of Laboratory Animals. Since then, hundreds of thousands of copies have been distributed, and it has been accepted as a primary reference on laboratory animal care and use. The National Institutes of Health (NIH) now requires that awardee institutions comply with the provisions of the Guide. Dr. Cohen was the recipient of all of the major national and international awards in laboratory animal LABORATORY ANIMAL MEDICINE III. Early Veterinarians in Laboratory Animal Science and Medicine 9 FIGURE 1.9 Dr. Bennett Cohen, a pioneer and visionary in the field of laboratory animal science. FIGURE 1.8 Dr. Nathan R. Brewer, director of the Central Animal Quarters at the University of Chicago (1945–1969) and first president of the American Association for Laboratory Animal Science. Photograph taken in the late 1940s. Courtesy of Dr. N. R. Brewer. science. In 1966, he received the Griffin Award from the American Association for Laboratory Animal Science. This, the association’s highest award, was presented for “Outstanding Accomplishments in the Improvement of Care and Quality of Laboratory Animals.” In 1980, he received the Charles River Prize, the highest award of the American Veterinary Medical Association. The inscription reads, “You have been a moving force in laboratory animal science and a major figure in the founding of national organizations that have brought strength, cohesion and credibility to the field.” In 1990, the Governing Board of the International Council for Laboratory Animal Science (ICLAS) presented Dr. Cohen with the Council’s highest award, the Muhlbock Award, for his work in establishing high standards of laboratory animal care and use worldwide. In 1991, the Association for Assessment and Accre­ ditation of Laboratory Animal Care International bestowed an award in Dr. Cohen’s name, the Bennett J. Cohen Educational Leadership Award. This award recognizes individuals whose activities and attitudes promote the understanding of biomedical research, science education, and public and animal health. Dr. Cohen also established a national reputation in the field of gerontology. He originated health standards for aging animals and undertook long-term studies of rodent diseases of aging. At the University of Michigan, he established the Core Facility for Aged Rodents (CFAR) in the Institute of Gerontology and the Gerontology Research and Training Center. The CFAR provided aged rodents for study by scientists campus-wide. An additional and lasting legacy of Cohen’s impact on laboratory animal medicine is the stellar record he achieved in training future generations of specialists in the field. He trained numerous postdoctoral veterinary fellows from 1959 to 1985. Dr. Cohen was originally awarded the NIH training grant while at University of California, Los Angeles (UCLA) in 1960 and transferred the training grant to Ann Arbor when he relocated to the University of Michigan in 1962. It remains recognized internationally for its record of excellence. Dr. Thomas Clarkson (D.V.M., University of Georgia, 1954) was employed in the pharmaceutical industry for 3 years. He was then recruited to the Wake Forest School of Medicine, then known as Bowman Gray. At Bowman Gray, he directed the vivarium and was an assistant professor of Experimental Medicine (Fig. 1.10). He was promoted to associate professor in 1960 and full professor in 1967. He was chairman of the Department of Comparative Medicine from 1967 to 1979. Over the course of Dr. Clarkson’s 55-year remarkable career as a pioneer in comparative medicine and women’s health, Clarkson’s research with nonhuman primates moved through a broad range of topics: the effects of cholesterol on atherosclerosis; the effects of social behavior on primate health, especially the influence of stress as a contributor to heart disease; and the study of heart disease in postmenopausal female monkeys. The breadth of Dr. Clarkson’s investigations of the relationship among diet, body fat distribution, social factors and hormones on the chronic diseases affecting LABORATORY ANIMAL MEDICINE 10 1. Laboratory Animal Medicine: Historical Perspectives IV. THE ORGANIZATIONS OF LABORATORY ANIMAL SCIENCE A. Background FIGURE 1.10 Dr. Thomas Clarkson, a pioneer in comparative medicine and women’s health. older women is remarkable and a significant legacy to biomedical science. Dr. Clarkson has served on numerous editorial boards and advisory committees for academia and government. He is the recipient of numerous awards, including the Griffin Award of the American Association for Laboratory Animal Science, the Charles River Prize of the American Veterinary Medical Association, the Albert B. Sabin Heroes of Science Award, and the American College of Laboratory Animal Medicine Mentor Award. Of special note, Dr. Clarkson is one among a few veterinarians who have been elected to the Institute of Medicine of the National Academies of Science. Dr. Clarkson believed that teaching was central to the mission of academia, and he put the same record of leadership into training others as he did his own research. Importantly, he played a pivotal role in promoting and spearheading formal guidelines for training veterinarians for careers in laboratory animal medicine and biomedical research (Clarkson, 1961b, 1965, 1967). The training program he founded in comparative medicine marked its 53rd consecutive year of NIH funding in 2012, making it the longest continuously supported training program in the nation. Other personalities that played important roles in the early history of laboratory animal science and medicine have been characterized and their roles assessed by Brewer (1980). Organizations are important in scientific life as a means of implementing the content and activities of the fields they represent. Present-day students of laboratory animal science are confronted with a confusing array of organizational acronyms: AAALAC International, AALAS, ACLAM, ASLAP, APV CALAS, ILAR, ICLAS, NABR, FBR, and so on. It is instructive to examine why organizations such as these came into being and to evaluate their impact on laboratory animal science. Consider the environment for research in biology and medicine in the United States around 1945. A new national policy was just being initiated to provide increased federal support of science. The use of laboratory animals began to expand rapidly as the funding of medical and biological research increased, and a host of problems as well as challenges accompanied this development. The knowledge base regarding the care and diseases of laboratory animals was small. Published information was scattered and sparse. Few veterinarians were devoting themselves to laboratory animal care, which was not yet recognized as a special field. In many institutions, animal facilities and administrative arrangements for operating them were poor. Institutions were ill prepared to accommodate increasingly large animal colonies. Simultaneously, medical scientists were under increasingly vigorous attack from antivivisectionists whose objective was to stop or limit animal research. It became essential for scientists both to confront their persistent critics and to face up to the problems they knew existed. The Chicago area was a hotbed of antivivisection activity in 1945 (Fig. 1.11). The National Antivivisection Society, based in Chicago, was distributing its literature widely and working for legislative abolition of animal research in Illinois and elsewhere. Orphans of the Storm, a humane society with a strong antivivisection outlook, was headed by its founder, Irene Castle McLaughlin, a famous dancer of the World War I era. Mrs. McLaughlin had been appointed to the Animal Advisory Committee of the Arvey Ordinance. The ordinance permitted the medical schools in Chicago to obtain unclaimed dogs and cats from the public pound. On one occasion, during an inspection of the animal facilities at Northwestern University Medical School, Mrs. McLaughlin deliberately removed a dog from its cage because she felt that the animal was not receiving adequate treatment. She planned to take the dog to her shelter in Winnetka. Dr. Andrew C. Ivy, then professor and chairman of the Department of Physiology, and Dr. J. Roscoe Miller, then dean of the Medical School, were notified. They intercepted Mrs. McLaughlin and the dog at the entrance LABORATORY ANIMAL MEDICINE IV. The Organizations of Laboratory Animal science 11 FIGURE 1.12 Dr. Anton J. Carlson, professor of physiology at the University of Chicago and first president of the National Society for Medical Research. Courtesy of the University of Chicago Archives and Dr. N. R. Brewer. B. The National Society for Medical Research FIGURE 1.11 Cover page of antivivisection brochure, late 1940s. of the Medical School. At this point, Mrs. McLaughlin made a citizen’s arrest of Dr. Ivy and Dean Miller, and the protagonists proceeded to the Chicago Avenue police station. The dog was returned to the Medical School, and the arrests subsequently were nullified. However, the incident was given wide publicity in the media, especially in the Chicago Herald-Examiner, reflecting the antivivisection sentiments of publisher William Randolph Hearst and Mr. Hearst’s close friends, Mrs. McLaughlin, and actress Marion Davies. This incident illustrates the flavor of the relationships between animal research scientists and their critics in the mid- and late 1940s. Without realizing it, Mrs. McLaughlin had alerted the scientific community to the significant and determined opposition it faced. An organized response was a clear necessity. The National Society for Medical Research (NSMR) was created in 1946 by the Association of American Medical Colleges (AAMC) and about 100 supporting groups (Grafton, 1980). The AAMC had become concerned that progress in medical science could be jeopardized if antivivisectionists were successful in their numerous campaigns to prohibit or restrict animal experimentation. It was deemed essential to establish a separate organization to counter these antiscience activities and, especially, to promote better public understanding of the needs and accomplishments of animal experimentation. Public support of animal research depended upon such understanding. NSMR headquarters were established in Chicago, and Dr. Anton J. Carlson was elected the organization’s first president (Fig. 1.12). From its inception, the NSMR contributed importantly to campaigns conducted at the state, city, and county levels to win public support for the use of public pounds as a source of unclaimed dogs and cats for research (Fig. 1.13). Antivivisection efforts to restrict or prohibit animal experimentation were fought successfully in several states. The NSMR also developed educational material about animal research and distributed it throughout the country. In the late 1940s, the NSMR provided legal counsel to several Chicago-area research scientists who had been attacked by the Hearst LABORATORY ANIMAL MEDICINE 12 1. Laboratory Animal Medicine: Historical Perspectives FIGURE 1.13 Inside cover and page 1 of NSMR Bulletin, May–June 1949, reporting a national opinion poll on favorable public attitudes toward animal research. newspapers. Dr. Nathan Brewer was among this group. Libel suits were filed and dragged on for several years, until shortly before William Randolph Hearst’s death in 1951. The suits were concluded in favor of the scientists but without significant monetary settlement. The Hearst publications agreed to stop publishing statements tending to damage the reputations of scientists involved in animal research. The suits and Mr. Hearst’s death brought to an end the extremist approach of the Hearst publications to the vivisection–antivivisection issue. In 1952, a cause célèbre developed within the American Physiological Society (APS) that also involved other constituent societies of the Federation of American Societies for Experimental Biology (FASEB) and the NSMR. Robert Gesell, M.D., professor and chairman of the Department of Physiology at the University of Michigan from 1923 to 1954 (Fig. 1.14), made the following statement at the APS business meeting on April 15: The National Society for Medical Research would have us believe that there is an important issue in vivisection versus antivivisection. To a physiologist there can be no issue on vivisection per se. The real and urgent issue is humanity versus inhumanity in the use of experimental animals. But the NSMR attaches a stigma of antivivisection to any semblance of humanity. Antivivisection is their indispensable bogie which must be kept before the public at any cost. It is their only avenue towards unlimited procurement of animals for unlimited and uncontrollable experimentation. The NSMR has had but one idea since its organization, namely, to provide an inexhaustible number of animals to an ever growing crowd of career scientists with but little biological background and scant interest in the future of man. Consider what we are doing in the name of science, and the issue will be clear. We are drowning and suffocating unanesthetized animals – in the name of science. We are determining the amount of abuse that life will endure in unanesthetized animals – in the name of science. LABORATORY ANIMAL MEDICINE IV. The Organizations of Laboratory Animal science 13 Dr. Gesell asked that his statement be made part of the minutes. Vigorous discussion followed. Dr. Ralph Gerard, APS president, explained that it was not APS policy to include all statements by APS members in the minutes. Finally, a motion by Dr. Maurice Visscher, then professor and chairman of the Department of Physiology at the University of Minnesota (later, president of NSMR), was adopted, to be included in the minutes, “that Dr. Gesell had made a statement concerning animal experimentation which criticized physiologists and the NSMR and that the statement had been challenged” (APS minutes, April 15, 1952). At a second business meeting, on April 17, 1952, the APS adopted the following formal response: FIGURE 1.14 Dr. Robert Gesell, professor and chairman, 1923– 1954, Department of Physiology, University of Michigan. Dr. Gesell’s statement at the APS business meeting in 1952 became a cause célèbre. Photograph taken in the late 1930s. Courtesy of the Bentley Historical Library, University of Michigan. We are producing frustration ulcers in experimental animals under shocking conditions – in the name of science. We are observing animals for weeks, months, or even years under infamous conditions – in the name of science. Yet it is the National Society for Medical Research and its New York satellite that are providing the means to these ends. And how is it being accomplished? By undermining one of the finest organizations of our country, THE AMERICAN HUMANE SOCIETY. With the aid of the halo supplied by the faith of the American people in medical science, the NSMR converts sanctuaries of mercy into animal pounds at the beck and call of experimental laboratories regardless of how the animals are to be used. What a travesty of humanity! This may well prove to be the blackest in the history of medical science. Dr. Gesell had supported the formation of NSMR but subsequently took issue with Dr. Carlson on NSMR involvement in pound legislation. He also was dissatisfied with what he perceived to be a lack of interest by NSMR in promulgating more detailed humane criteria for the care and use of animals than existed at that time. He knew of the formation of the AALAS in 1950 and of the assistance that NSMR provided to AALAS in its formative years. This did not soften his view that NSMR was not constructively dealing with the issue of humane use of animals in research. The American Physiological Society reaffirms its sincere belief that the moral justification for humane animal experimentation, for the purpose of furthering biological and medical knowledge, in the interest of both human and animal welfare, is completely established. The American Physiological Society rejects the sweeping allegations made by Dr. Gesell in a recent business meeting. The American Physiological Society rejects unequivocally the inference that its members are insensitive to the moral responsibilities which they have in protecting the welfare of man and animals. The American Physiological Society expresses the hope that in the future all of its members will act in unison in promoting conditions facilitating humane animal experimentation. Despite efforts by Dr. Gesell to prevent and suppress use of his statement by antivivisection groups, it was distributed widely by these groups in their campaigns for legislative restriction of animal research. After all, it reflected the views of a respected American physiologist. The APS response was not similarly distributed by these groups. Dr. Carlson prepared a lengthy and thoughtful rebuttal of the Gesell statement for members of FASEB, but it too had only a limited distribution (A.J. Carlson, letter to FASEB members, September 17, 1952). After Dr. Gesell’s death in 1954, his daughter, Christine Stevens, a founder and the president since 1950 of the Animal Welfare Institute, continued to espouse her father’s views and her own strong opinion that too many scientists were insufficiently concerned about humane treatment of animals in research. These views have included critical commentary about NSMR and AALAS (Stevens, 1963, 1976, 1977). The Gesell–APS–NSMR controversy highlighted issues that, to this day, underlie the difficult relations between the scientific community and the animal rights movement. Perhaps a positive result has been that the controversy also contributed to the climate of opinion that led additional numbers of medical research institutions to employ veterinarians to care for research animals. Ultimately, the controversy raised questions that influenced and should continue to influence all those LABORATORY ANIMAL MEDICINE 14 1. Laboratory Animal Medicine: Historical Perspectives having a constructive concern for both science and animal welfare. What, if any, are the appropriate limits on scientific freedom in animal research? Who is best qualified to make judgments about the propriety of animal studies? Can humaneness be legislated? Is there not a moral imperative to conduct animal studies in the interest of human and animal welfare? How best can refinement of animal studies, reduction in the numbers of animals used, and replacement of animals, where appropriate, best be incorporated into the design of experiments (Russell and Burch, 1959)? In the 1980s, the National Society for Medical Research merged with the Association for Biomedical Research, which had been organized in 1979, to become the National Association for Biomedical Research (NABR), with Dr. Edward C. Melby as its first president. The NABR advocates for sound public policy in support of ethical and essential animal research. The Scientists’ Center for Animal Welfare was formed in 1978 to contri­ bute scientific perspectives to laboratory animal welfare. C. The American Association for Laboratory Animal Science By 1949, veterinarians were managing the laboratory animal facilities at five Chicago-area institutions: the University of Chicago (Nathan R. Brewer), the University of Illinois (Elihu Bond), Northwestern University (Bennett J. Cohen), the Argonne National Laboratory (Robert J. Flynn), and the Hektoen Institute for Medical Research of Cook County Hospital (Robert J. Schroeder). The veterinarians sought one another out to exchange information and experience on the day-today problems they were encountering. The group met at least monthly, starting during the summer of 1949. Among the subjects reviewed at these meetings were husbandry and diseases of laboratory animals, the need to develop basic standards of animal care, and the need to counter the strident antivivisection attacks on medical science in the Chicago area. The Chicago veterinarians knew that few other veterinarians elsewhere in the country were engaged in the activity they had begun to identify as laboratory animal care. For example, in reviewing the proceedings of a symposium on animal colony maintenance, held under the sponsorship of the New York Academy of Sciences in 1944 (Farris et al., 1945), they noted that not a single veterinarian had presented a paper. Their perception was that the problems of laboratory animal care merited organized attention, and they wondered whether others felt the same way. Special meetings were arranged when colleagues from other institutions visited Chicago. Among these colleagues were C.F. Schlotthauer, D.V.M., Mayo Clinic; Charles A. Slanetz, Ph.D., director of the Central Animal Facility at the College of Physicians and Surgeons, Columbia University; Harry Herrlein, Rockland Farms, New City, New York (then a major commercial rodent and rabbit breeding facility); C.N.W. Cumming, Carworth Farms, New City, New York (also a major rodent breeding facility at the time); and W.T.S. Thorp, D.V.M., then chief of the Laboratory Aids Branch, NIH. These meetings were exciting, interesting, and rewarding to the participants. They demonstrated that interest in laboratory animal problems extended well beyond the Chicago area and included individuals who had a broad range of scientific, professional, and technical backgrounds. In a letter signed by the five Chicago veterinarians and sent in May 1950 to individuals in the United States and Canada thought to have an interest in the care of laboratory animals, the development of a national organization was proposed “to be open to all individuals interested in animal care work on an institutional scale” (Flynn, 1980). The response was overwhelmingly favorable, and the first meeting was convened in Chicago on November 28, 1950, with an attendance of 75. The founding members named the organization the Animal Care Panel (ACP), reflecting their broad concern with the care of laboratory animals (Fig. 1.15). Panel was used in the name to emphasize the organization’s purpose as a forum for the exchange of information on all aspects of animal care. Dr. Brewer was elected the first president, a post he held until 1955. During the early meetings of the ACP, its programs were dominated by papers on animal colony management, design of facilities and equipment, FIGURE 1.15 Cover of early descriptive brochure about the Animal Care Panel, now the American Association for Laboratory Animal Science. LABORATORY ANIMAL MEDICINE IV. The Organizations of Laboratory Animal science and descriptions of common diseases. This reflected the relatively under­developed state of the art with respect to the technology of animal care. ACP meetings became more sophisticated with each passing year. By the sixth meeting, in 1955, original research was being presented (Flynn, 1980). In 1963, the annual Proceedings of the Animal Care Panel was transformed into the scientific journal Laboratory Animal Care and in 1971, renamed Laboratory Animal Science. The ACP grew rapidly in its institutional and individual membership, and was characterized by the unique diversity of scientific, professional, and technical backgrounds of its members. By 1960, the ACP was able to employ a full-time executive secretary, Joseph J. Garvey. He had served earlier as assistant executive secretary of the NSMR and, in this position, had assisted with ACP administration, reflecting the support and encouragement the ACP received from the NSMR in its formative years. From its inception, the ACP also worked to enhance the stature and training of laboratory animal technicians. This activity is exemplified in the career and contributions of George Collins (1917–1974), who served successively as supervisor of the animal facilities at the Argonne National Laboratory, Rockefeller University, the AMA Education and Research Foundation, and the University of Illinois at Chicago (Brewer, 1980). He was a founding member of the AALAS and, in 1963, received the AALAS Animal Technician Award. In 1967, he edited the first edition of the AALAS Manual for Animal Laboratory Technicians, a landmark in its time (Collins, 1967). Development of standards was another early activity of the ACP. Indeed, the first edition of the Guide for Laboratory Animal Facilities and Care (Cohen, 1963), now known as the Guide for the Care and Use of Laboratory Animals (Moreland, 1978) was prepared under ACP auspices. The guide has become the benchmark standard regarding the care and use of animals in American research institutions. In 1967, the name of the Animal Care Panel was changed to the AALAS. Today, the AALAS has more than 12,200 individual and institutional members and more than 47 active local branches. Its annual meeting and scientific journals – Comparative Medicine and the Journal of the American Association forLaboratory Animal Science – are the principal means of scientific exchange in the field. In 1999, the AALAS published its 50-year history (McPherson and Mattingly, 1999). D. The Institute for Laboratory Animal Research Many problems of supply, standardization, and procurement of animal resources accompanied the rapid growth of medical and biological research after World War II. Concerns surfaced about these problems within 15 the National Academy of Sciences (NAS). These concerns developed independent of those that led to the formation of the AALAS. The NAS is a private organization with a federal charter. Since 1863, it has been a principal advisor to the federal government on matters related to science and science policy (Seitz, 1967). Election to membership in the NAS or its Institute of Medicine is among the highest honors a scientist can receive. It is a prestigious organization, and therefore, NAS advisory groups, all of which serve without compensation, have a standing and authority they might not otherwise have. In the early 1950s, organized efforts to improve and standardize animal supply and quality had barely been initiated. Scientific standards for laboratory animal production, genetics, breeding, husbandry, and transportation did not exist. There were no good mechanisms to facilitate information exchange about laboratory animals internationally. Education and training in laboratory animal science were in an undeveloped state, and no guidelines for such training existed. Problems such as these led Dr. Paul Weiss, then chairman of the Division of Biology and Agriculture of the National Research Council (the NAS advisory arm), to appoint a Committee on Animal Resources in 1952. Dr. Weiss appointed Dr. Clarence Cook Little, the eminent geneticist and founder of the Jackson Laboratory (Bar Harbor, Maine), to be chairman. The Committee on Animal Resources recommended establishment of an Institute of Animal Resources (IAR). The IAR commenced fulltime operation in July 1953 (Hill, 1980). In 1956, it was renamed Institute of Laboratory Animal Resources. In 1997, it was renamed the Institute for Laboratory Animal Research (ILAR). Historically, the ILAR office has been headed by an executive secretary (now named the director), with oversight from an advisory council and executive committee that is appointed in accordance with NAS-National Research Council (NRC) procedures. Dr. Orson Eaton, a geneticist from the Bureau of Animal Industry, was the first executive secretary. He was succeeded by the vigorous and energetic Berton F. Hill, who also had a background in genetics. During Hill’s tenure (1955–1965), the ILAR became established as the major standards development organization within laboratory animal science. In 1965, Hill was succeeded by Dr. Robert H. Yager, former director of the animal facilities at the Walter Reed Army Institute of Research. Dr. Yager was one of the founding fathers of the ILAR, having served on the Committee on Animal Resources in 1952. Among many important ILAR accomplishments during Dr. Yager’s tenure were the development of the first guidelines for education and training in laboratory animal medicine (Clarkson, 1967); the publication of an important national survey of animal facilities in the United States (Trum, 1970), following up on the first such survey, LABORATORY ANIMAL MEDICINE 16 1. Laboratory Animal Medicine: Historical Perspectives during Hill’s tenure (Thorp, 1964); and enlargement of the U.S. participation in international laboratory animal activities through support of the ICLAS, known then as the Intentional Committee on Laboratory Animals. During the formative years of ILAR and AALAS, there were obvious areas of overlap. Both organizations had been involved in standards development, both were holding scientific meetings, and in many other areas their interests coincided. In 1962, the executive committees agreed on a division of responsibility that solidified the ILAR’s role in standards development (Garvey and Hill, 1963). This proved to be an important agreement because it enabled ILAR and AALAS to concentrate on the things each could do best. It also was important because of the position that ILAR standards subsequently achieved under the umbrella of the NAS. The ILAR began publishing a journal, the ILAR Journal, in 1990. The ILAR Journal is published quarterly and is a peer-reviewed, theme-oriented publication of the ILAR. The journal provides timely information for all those who use, care for, and oversee the use of animals in research. Through the ILAR, expert committee reports, workshops, presentations, and other fora ILAR identifies and disseminates practices for improved animal welfare, and evaluates and encourages the development and validation of non-animal alternatives in research and testing. E. The American College of Laboratory Animal Medicine Formal recognition of veterinary medical specialty fields by the American Veterinary Medical Association (AVMA) began in 1951 with the establishment of the American Board of Veterinary Public Health and the American College of Veterinary Pathologists (Grafton, 1974). In 1957, laboratory animal medicine was accorded the same recognition, when the American Board of Laboratory Animal Medicine was incorporated under the laws of the state of Illinois, with 18 Charter Fellows. In August 1961, the name was changed to the American College of Laboratory Animal Medicine (ACLAM), and the designation Fellow was discontinued in favor of Diplomat, a term used by other specialties. The ACLAM was established to encourage education, training, and research in laboratory animal medicine; to establish standards of training and experience for qualification of specialists; and to certify specialists by examination. These objectives, which today are well understood and accepted, were but a vague concept in the early 1950s. On June 23, 1952, 34 veterinarians assembled in a meeting room at the Ambassador Hotel in Atlantic City, during the AVMA meeting, to consider the role of veterinarians in laboratory animal care. There was a lively discussion about this rapidly developing field, with special emphasis on defining activities that veterinarians were uniquely qualified to pursue (News reports, 1952). Those in attendance noted that medical schools were employing an increasing number of vete­ rinarians and that further growth seemed likely. They felt that more specific definition of this newly developing field was needed. The group organized as the Committee on the Medical Care of Laboratory Animals, with Dr. Nathan R. Brewer as chairman, Dr. Mark Morris as vice chairman, and Dr. W.T.S. Thorp as secretary. The decision was made to organize programs of special interest to laboratory animal veterinarians at future AVMA meetings. During the ensuing 4 years, the term laboratory animal medicine came into use to differentiate the activities of veterinarians from other professional or technical people working in the broad area of laboratory animal science. Additionally, within this period, a number of laboratory animal veterinarians were able to establish academic units in their institutions (Clarkson, 1961a), some of which were identified as sections, divisions, or departments of laboratory animal medicine or comparative medicine. With this development, laboratory animal medicine began to establish its separate identity. The committee then proceeded to seek recognition of specialization in the field by the AVMA. Late in 1956, the committee disbanded in favor of the American Board of Laboratory Animal Medicine and the new specialty was born. F. The American Society of Laboratory Animal Practitioners The American Society of Laboratory Animal Practitioners (ASLAP) promotes the acquisition and dissemination of knowledge, ideas, and information among veterinarians and veterinary students having an interest in the practice of laboratory animal medicine. The Society does so for the benefit of laboratory animals, other animals, and society in general. Founded in 1966 as an organization open to all vete­ rinarians with an interested in the practice of laboratory animal medicine, the ASLAP was incorporated in the State of Illinois on July 11, 1967, and was recognized as an ancillary organization of the AVMA. In 1971, the ASLAP attained a sufficient number of members to be recognized as a Constituent Allied Veterinary Organization and to have a seat in the AVMA House of Delegates. In this role, the ASLAP represents laboratory animal practitioners within organized veterinary medicine. One of the key ASLAP Committees is the Veterinary Student Liaison Committee (VSLC) with a faculty representative at every North American Veterinary School. Veterinary students interested in a career in laboratory animal medicine can obtain career information and learn LABORATORY ANIMAL MEDICINE V. Education and Training in Laboratory Animal Medicine about ASLAP student memberships from their school’s liaison. The VSLC manages the Veterinary Student Award Program, which is intended to increase awareness of the practice of laboratory animal medicine by recognizing students who have demonstrated significant interest and potential in the field. G. The Association of Primate Veterinarians The Association of Primate Veterinarian (APV) held its first meeting in 1973 as the Association of Primate Veterinary Clinicians and membership was limited to veterinarians who spent 50% of their time providing direct care for nonhuman primates. Today the association has over 400 members and provides a forum for the dissemination of information relating health and welfare of nonhuman primates and a mechanism for veterinarians to speak collectively on matters affecting nonhuman primates. The APV has published a formulary and guidance documents on subjects such as food restriction, humane endpoints, anesthesia, and analgesia. H. The International Association of Colleges of Laboratory Animal Medicine The IACLAM was founded in 2006. The IACLAM is an association of associations and currently includes the ACLAM, the European C