Nonhuman Primates in Biomedical Research: Biology and Management

American College of Laboratory Animal Medicine Series

Steven H. Weisbroth, Ronald E. Flatt, and Alan L. Kraus, eds.:

The Biology of the Laboratory Rabbit, 1974

Joseph E. Wagner and Patrick J. Manning, eds.:

The Biology of the Guinea Pig, 1976

Edwin J. Andrews, Billy C. Ward, and Norman H. Altman, eds.:

Spontaneous Animal Models of Human Disease, Volume 1, 1979; Volume II, 1979

Henry J. Baker, J. Russell Lindsey, and Steven H. Weisbroth, eds.:

The Laboratory Rat, Volume I: Biology and Diseases, 1979; Volume II: Research Applications, 1980

Henry L. Foster, J. David Small, and James G. Fox, eds.:

The Mouse in Biomedical Research, Volume I: History, Genetics, and Wild Mice, 1981; Volume II: Diseases, 1982; Volume Ill: Normative Biology, Immunology, and Husbandry, 1983; Volume IV: Experimental Biology and Oncology, 1982

James G. Fox, Bennett J. Cohen, and Franklin M. Loew, eds.:

Laboratory Animal Medicine, 1984

G. L. Van Hoosier, Jr., and Charles W. McPherson, eds.:

Laboratory Hamsters, 1987

Patrick J. Manning, Daniel H. Ringler, and Christian E. Newcomer, eds.:

The Biology of the Laboratory Rabbit, 2nd Edition, 1994

B. Taylor Bennett, Christian R. Abee, and Roy Henrickson, eds.:

Nonhuman Primates in Biomedical Research, Volume I: Biology and Management, 1995; Volume II: Diseases, 1998

Dennis F. Kohn, Sally K. Wixson, William J. White, and G. John Benson, eds.:

Anesthesia and Analgesia in Laboratory Animals, 1997

James G. Fox, Lynn C. Anderson, Franklin M. Loew and Fred W. Quimby, eds.:

Laboratory Animal Medicine, 2nd Edition, 2002

Mark A. Suckow, Steven H. Weisbroth and Craig L. Franklin, eds.:

The Laboratory Rat, 2nd Edition, 2006

James G. Fox, Muriel T. Davisson, Fred W. Quimby, Stephen W. Barthold, Christian E. Newcomer and Abigail L. Smith, eds.:

The Mouse in Biomedical Research, 2nd Edition, Volume I: History, Wild Mice, and Genetics, 2007; Volume II: Diseases, 2007; Volume III: Normative Biology, Husbandry, and Models, 2007; Volume IV: Immunology, 2007

Richard E. Fish, Marilyn J. Brown, Peggy J. Danneman and Alicia Z. Karas, eds.:

Anesthesia and Analgesia in Laboratory Animals, 2nd Edition, 2008

Jack R. Hessler and Noel D.M. Lehner, eds.:

Planning and Designing Animal Research Facilities, 2009

Mark A. Suckow, Karla A. Stevens, and Ronald P. Wilson, eds.:

The Laboratory Rabbit, Guinea Pig, Hamster and other Rodents, 2011

Christian R. Abee, Keith Mansfield, Suzette Tardif and Timothy Morris, eds.:

Nonhuman Primates in Biomedical Research, 2nd Edition, Volume I: Biology and Management, 2012; Volume II: Diseases, 2012

Kathryn Bayne and Patricia V. Turner, eds.:

Laboratory Animal Welfare, 2012

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Preface

Biomedical research using nonhuman primates continues to provide important insights into the pathogenesis and treatment of diseases that impact human health. In recent years, translational research has become an increasingly emphasized area in biomedical research. This emphasis on translating discoveries made in basic research into treatments that are useful to patients requires animal models that allow scientists to predict human responses. Nonhuman primates have long been recognized as important models for translational research due to their phylogenetic proximity to human beings and their similarity in responses to treatment and pathogenesis of disease when compared to patients subsequently observed in clinical trials. For these reasons, the American College of Laboratory Animal Medicine (ACLAM) recognized the need for an authoritative textbook on the biology, management, and diseases of nonhuman primates used in biomedical research.

The first edition of Nonhuman Primates in Biomedical Research was edited by B. Taylor Bennett, Christian R. Abee, and Roy V. Henrickson as part of the textbook series sponsored by the American College of Laboratory Animal Medicine. It was published in two volumes, Biology and Management (1995) and Diseases (1998). The completion of the first edition required more than 10 years to plan, develop, edit, and publish. It has served as a seminal text in the field because it provided readers with the collective knowledge of experts in veterinary medicine, laboratory animal medicine, comparative medicine, and primatology as these disciplines are applied to the care and use of nonhuman primates in biomedical research. The first edition is no longer in print and used copies have become collector’s items selling for more than the original purchase price. This provided the Publications Committee of the American College of Laboratory Animal Medicine with strong justification to approve the development of this second edition of this important text.

Planning for the second edition of Nonhuman Primates in Biomedical Research began in 2006. Although much of the information in the first edition remains useful, there have been major advances in our understanding of the biology, veterinary medical care, pathology, and research uses of nonhuman primates. Planning for the second edition began with the return of Christian Abee as an editor followed by Keith Mansfield, Suzette Tardif, and Timothy Morris as co-editors.

The editors reviewed the first edition to determine those chapters that should be repeated with careful attention to chapters that required major revisions and those that required less extensive updating. The editors agreed that the text should have a more international perspective and chapters should be added that describe research areas in which nonhuman primates play a critical role. Therefore, this second edition has added chapters that provide a more international perspective on regulatory oversight of the care and use of nonhuman primates and chapters that describe important model systems and research areas. High-resolution color images have been included in this edition that illustrate gross and microscopic lesions characteristic of diseases of nonhuman primates. Color illustrations have also been included of imaging techniques that can be used in both clinical veterinary medical care and research applications.

The editors assembled an outstanding group of chapter contributors with many chapter authors from the first edition contributing once again. Chapter manuscripts were peer reviewed by experts in the respective subject areas. The reviewers of chapters provided a very important contribution by helping to make certain that chapters were accurate and fair in their review of the subject areas. Reviewers are listed in each respective volume, but are not identified with the specific chapter they reviewed.

Nonhuman Primates in Biomedical Research 2nd edition provides a comprehensive and current review of the collective knowledge of the biology, management, diseases, and research uses of nonhuman primates. The information in these volumes will be useful to clinical veterinarians, veterinary pathologists, primate caregivers and colony managers, scientists who work with nonhuman primates, and others who wish to know more about nonhuman primates.

Chris Abee, Keith Mansfield, Suzette Tardif and

Timothy Morris

Acknowledgments

There are many people deserving of recognition for their many hours of dedicated service in planning, developing, and editing Nonhuman Primates in Biomedical Research 2nd edition. The editors wish to thank Laura Zapalac and Jennifer Kurtz at the Michale E. Keeling Center for Comparative Medicine and Research of the University of Texas MD Anderson Cancer Center for the many hours they devoted to scheduling editors’ conference calls, maintaining spreadsheets that allowed the editors to follow the progress of each chapter through the arduous process of composition, chapter review, authors’ revisions, first copyedit, and finally, submission of each chapter to Elsevier. We are also grateful to Rachel Tardif for her outstanding efforts in the initial copyedit of most of the chapters. Her work allowed the editors to identify and correct mistakes in chapter manuscripts prior to final copyediting by Elsevier. The editors want to give special thanks to Mary Preap at Elsevier for her gentle pressure to keep us as close as possible to our deadlines and her timely responses to the book editors’ questions and requests. And finally, I would like to thank my co-editors, Keith Mansfield, Suzette Tardif, and Tim Morris for their tireless efforts to make certain that this second edition of Nonhuman Primates in Biomedical Research met the high standard expected of the American College of Laboratory Animal Medicine Blue Book series. The completion of this second edition was truly a team effort and a team accomplishment of the chapter contributors, the chapter reviewers, the book editors, administrative staff, and the staff at Elsevier.

Chris Abee

Reviewers

Karyn L. Armstrong Covance Research Products, Inc., Alice, TX

Lynne M. Ausmann Tufts University, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA

Michael B. Ballinger Amgen, Inc., Thousand Oaks, CA

Kathryn Bayne Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International, Frederick, MD

Mollie Bloomsmith Emory University, Yerkes National Primate Research Center, Atlanta, GA

Rudolf P. Bohm Jr. Tulane University, Tulane National Primate Research Center, Covington, LA

Kathleen M. Brasky Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX

William E. Britz Jr. Britz & Company, Wheatland, WY

Hannah Buchannan-Smith University of Stirling, Psychology, School of Natural Sciences, Scotland, UK

Thomas M. Butler Retired, Fair Oaks Ranch, TX

John Capitanio University of California, Davis, Department of Psychology, Davis CA

William Cole Retired, Lansdale, PA

Lita Drobatz GlaxoSmithKline (GSK) Pharmaceuticals, King of Prussia, PA

Bennett Dyke Retired, San Antonio, TX

Marisa Elkins St. Claire National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rockville, MD

James J. Elliott Texas A&M University, Comparative Medicine Program, College Station, TX

Lynn Fairbanks University of California at Los Angeles, Semel Institute, Los Angeles, CA

John Finch Charles River Laboratories, Edinburgh, UK

John Fleagle Stony Brook University, Department of Anatomical Sciences, Stony Brook, NY

Jeffrey D. Fortman University of Illinois at Chicago, Biologic Resources Laboratory, Chicago, IL

Margaret H. Gilbert Tulane University, Tulane National Primate Research Center, Covington, LA

Colin Groves Australian National University, Canberra, ACT, Australia

Patrick W. Hanley The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Robert F. Hoyt National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD

Denis Lambrights GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium

Judy MacArthur-Clark Animals in Science Regulation Unit, Home Office, London, UK

Christopher L. Medina Abbott Laboratories, Comparative Medicine, Abbott Park, IL

Yasmina A. Paramastri Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN

Sulli J. Popilskis New York Medical College, Department of Comparative Medicine, Valhalla, NY

Wendy Saltzman University of California at Riverside, Department of Biology, Riverside, CA

Michael Schillaci University of Toronto, Department of Anthropology, Toronto, Ontario, Canada

Mårten K.J. Schneider University Hospital of Zurich, Laboratory of Vascular Immunology, Division of Internal Medicine, Zurich, Switzerland

Mary Schneider University of Wisconsin-Madison, Departments of Kinesiology (Occupational Therapy Program) and Psychology, Madison, WI

M. Michael Swindle Medical University of South Carolina, Department of Comparative Medicine, Charleston, SC

Maureen Thompson Emory University, Yerkes National Primate Research Center, Atlanta, GA

Duane Ullrey Michigan State University, Departments of Animal Science and Fisheries & Wildlife, East Lansing, MI

Gary L. White The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

Gregory K. Wilkerson The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Lawrence E. Williams The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX

Roman F. Wolf The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

Simon Young AstraZeneca, Alderley Park, Cheshire, UK

Marcus Young Owl California State University, Long Beach, Department of Anthropology and Biological Sciences, Long Beach, CA

Contributors

Mark G. Baxter, Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA

Kathryn Bayne, AAALAC International, Frederick, MD

Irwin S. Bernstein, Department of Psychology, University of Georgia, Athens, GA

James L. Blanchard, Comparative Medicine Program, Tulane University, Covington, LA

Mollie A. Bloomsmith, Yerkes National Primate Research Center, Atlanta, GA

Rudolf P. Bohm Jr., Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA

Saverio Capuano, Wisconsin National Primate Research Center, Madison, WI

Angela Carville, New England Primate Research Center, Southborough, MA

Donna J. Clemons, Abbott Laboratories, Comparative Medicine, Abbott Park, IL

Kristine Coleman, Oregon National Primate Research Center, Beaverton, OR

David K.C. Cooper, Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA

Carolyn M. Crockett, National Primate Research Center, University of Washington, Seattle, WA

David Elmore, Charles Rivers Laboratories, San Diego, CA

Paul A. Flecknell, Comparative Biology Centre, The Medical School, The University of Newcastle, Newcastle-upon-Tyne, UK

Elizabeth W. Ford, The Scripps Research Institute, LaJolla, CA

Margaret H. Gilbert, Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA

James C. Ha, National Primate Research Center, Department of Psychology, University of Washington, Seattle, WA

Dennis O. Johnsen, Port Townsend, WA

David K. Johnson, Cascade Biosciences Consultants, Inc., Sisters, OR

Stephen T. Kelley, Department of Comparative Medicine, University of Washington, Seattle, WA

Brian J. Kelly, Behavioral Sciences Department, Fitchburg State University, Fitchburg, MA

Liz Koutsos, Mazuri Exotic Animal Nutrition, PMI Nutrition International LLC, St Louis, MO

Joshua A. Kramer, New England Primate Research Center, Harvard Medical School, Southborough, MA

Vince Meador, Anatomic and Clinical Pathology, Integrated Science and Innovation, Covance Laboratories Inc., WI

Jerrold S. Meyer, Department of Psychology, University of Massachusetts, Amherst, MA

Nancy Minugh-Purvis, Department of Pathology and Laboratory Medicine and Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, PA

Kathy L. Murphy, Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA

Timothy H. Morris, The School of Veterinary Medicine and Science, The University of Nottingham, Leicestershire, UK

Marek A. Niekrasz, Animal Resources Center, University of Chicago, Chicago, IL

Melinda A. Novak, Department of Psychology, University of Massachusetts, Amherst, MA

Michael L. Power, Nutrition Laboratory, Smithsonian Conservation Biology Institute, National Zoological Park, Washington, DC

Karen Rice, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX

Kasi E. Russell-Lodrigue, Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA

Steven J. Schapiro, The University of Texas MD Anderson Cancer Center, Bastrop, TX

David Glenn Smith, Department of Anthropology and California National Primate Research Center, University of California, Davis, CA

Suzette Tardif, Barshop Institute of Longevity & Aging Studies, University of Texas Health Science Center, San Antonio, TX

Barbara Toddes, Philadelphia Zoo, Philadelphia, PA

Jean E. Turnquist, Department of Anatomy and Neurobiology, University of Puerto Rico Medical School, San Juan, Puerto Rico

Robert Wagner, Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA

Alex Wakefield, Covance Laboratories Inc., Greenfield, IN

Craig L. Wardrip, Animal Resources Center, University of Chicago, Chicago, IL

James L. Weed, Division of Veterinary Resources, National Institutes of Health, Bethesda, MD

Gerhard F. Weinbauer, Developmental and Reproductive Toxicology, Covance Laboratories, Kesselfeld, Muenster, Germany

Gary L. White, The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

Robert A. Whitney Jr., RADM (0–8 Retired), US Public Health Service, Steilacoom, WA

Lawrence E. Williams, Michale E. Keeling Center for Comparative Medicine and Research, Department of Veterinary Sciences, The University of Texas MD Anderson Cancer Center, Bastrop, TX

Roman F. Wolf, The University of Oklahoma Health Sciences Center, Comparative Medicine, Oklahoma City, OK

TABLE OF CONTENTS

Cover Image

Title

American College of Laboratory Animal Medicine Series

Copyright

Preface

Acknowledgments

Reviewers

Contributors

Chapter 1. History of the Use of Nonhuman Primates in Biomedical Research

Human and Nonhuman Primates to 1960

Establishment of the National Institutes of Health’s National Primate Research Centers Program in the USA: Crossing the Threshold

1960–1980: Period of Growth in a World of Increasing Constraints

1980S and 1990S: Progress Paying off in the Face of Serious Challenges

Primate Research Beyond the Year 2000

Looking Toward the Future

Chapter 2. Laws, Regulations and Policies Relating to the Care and Use of Nonhuman Primates in Biomedical Research

Introduction

National Laws on Use of Nonhuman Primates in Biomedical Research

Nonlegislative Initiatives that Affect the Care and Use of Nonhuman Primates

Good Laboratory and Manufacturing Practice

Human and Animal Disease Control

Species Conservation

Transport

Health and Safety

Appendix 1

Chapter 3. Taxonomy of Nonhuman Primates Used in Biomedical Research

Introduction

Biomedically Relevant Primate Species

The Old World Primates

The New World Primates

From Phylogenetics to Phylogenomics

Acknowledgment

Chapter 4. Functional Morphology

Introduction

Morphological Definition of Primate Order

Sexual Dimorphism

Growth and Development

Body Size and Integument

Head and Neck Morphology

Back and Spine Morphology

Limb Morphology

Thoracic Morphology

Abdominal and Pelvic Morphology

Perineal Morphology

Conclusions

Acknowledgments

Selected Readings

Chapter 5. Study of Nonhuman Primate Social Behavior

Introduction

Levels of Behavioral Analysis

Definition of Nonhuman Primate Societies

General Statement on Nonhuman Primate Social Structures

Methodologies used to Study Behavior

Behavior Research to Colony Management

Conclusions

Chapter 6. Behavioral Management, Enrichment, and Psychological Well-being of Laboratory Nonhuman Primates

Introduction

Definitions of Terms

Why Perform Behavioral Management?

Managing Behavior

Environmental Enrichment Plans

Positive Reinforcement Training

Balancing Psychological Well-Being and Research Needs

Managing Behavioral Management Programs

Conclusions

Acknowledgments

Chapter 7. Behavioral Disorders of Nonhuman Primates

Introduction

Etiology of Psychological Disorders

Therapeutic Strategies for Reversing Psychopathology

A Practical Guide to Managing Abnormal Behavior in the Laboratory

Summary

Acknowledgments

Chapter 8. Reproduction and Breeding of Nonhuman Primates

Basic Reproductive Biology

Housing, Husbandry, and Population Management for Breeding

Pregnancy Management

Nonhuman Primates from Foreign Breeding Programs

Chapter 9. Laboratory Housing of Nonhuman Primates

Introduction

Primary Housing Design for Individuals, Pairs, or Small Groups

Group Enclosures

Security

Conclusion

Acknowledgments

Chapter 10. Nutrient Requirements and Dietary Husbandry Principles for Captive Nonhuman Primates

Introduction

Primate Nutrient Requirements

Considerations for Feeding Protocols

Chapter 11. Animal Identification and Record Keeping for Nonhuman Primates

Introduction

Animal Identification

Record Keeping

Data and Database Format

Reports and Analyses

Summary

Acknowledgments

Chapter 12. Preventative Medicine in Nonhuman Primates

Introduction

Occupational Health and Safety

Quarantine

Husbandry Measures Contributing to Preventive Health

Disease Surveillance

Animal Vaccination Program

Chapter 13. Clinical Techniques used for Nonhuman Primates

Introduction

Handling

Digestive System

Urinary System

Respiratory System

Reproductive System

Circulatory System

Central Nervous System

Musculoskeletal System

Integumentary System

Body Cavities

Chapter 14. Surgery in Nonhuman Primates

Introduction

Nonclinical Concerns

General Principles of Experimental Surgery

Chapter 15. Emergency Medicine and Critical Care for Nonhuman Primates

Introduction

General

Emergencies and Diseases Common to Nonhuman Primates Requiring Critical Care

Chapter 16. Xenotransplantation

Introduction

History

Pathobiology of Pig-To-Primate Organ Transplantation

The Pig-to-Nonhuman Primate Model

Results and Complications

Genetic Modification of Pigs

Summary

Acknowledgments

Chapter 17. Anesthesia and Analgesia in Nonhuman Primates

Introduction

Preanesthetic Considerations

Selecting an Anesthetic Regime

Anesthetic Management and Monitoring

Dealing with Emergencies

Special Considerations

Postanesthetic Care

Analgesia

Chapter 18. Biosafety in Laboratories using Nonhuman Primates

General Biosafety Considerations

Disease Prevention

Facilities Management

Equipment

Personnel Management

Veterinary Care, Animal Health, and Husbandry Practices

Zoonoses, Biohazards, and Other Health Risks

Viral Diseases

Bacterial Diseases

Spirochetal Diseases

Mycoplasmal Diseases

Rickettsial Diseases

Chlamydial Diseases

Mycotic Diseases

Parasitic Diseases

Model Occupational Health Program for Persons Working with Nonhuman Primates

Participants

Components

Records

Health Services/Personnel

Acknowledgments

Chapter 19. Safety and Efficacy Evaluation Using Nonhuman Primates

History and Regulation of Primate Testing

Nonhuman Primate Models of Safety Assessment

Efficacy Studies in the Nonhuman Primate

Index

Chapter 1

History of the Use of Nonhuman Primates in Biomedical Research

Dennis O. Johnsen∗, David K. Johnson† and Robert A. Whitney, Jr‡

∗Port Townsend, WA,†Cascade Biosciences Consultants, Inc., Sisters, OR, ‡RADM (0–8 Retired), US Public Health Service, Steilacoom, WA

Chapter Outline

Human and Nonhuman Primates to 1960

Roots of Modern Primatology

First Primate Centers

Soviet Institute of Experimental Pathology and Therapy

Robert Yerkes and the Primate Laboratory of the Yale Institute of Psychobiology

Cayo Santiago and the Caribbean Primate Research Center

Virological Research in Nonhuman Primates

General

Polio

Kuru

Virus (Herpes B Virus or Macacine Herpesvirus 1)

Other Contributions

The Work of Harry Harlow

Breeding and Reproductive Physiology

Establishment of the National Institutes of Health’s National Primate Research Centers Program in the USA: Crossing the Threshold

Initial Activity

Developing the Concept

Launching the New Program

National Primate Research Centers Program Today

1960–1980: Period of Growth in a World of Increasing Constraints

Emulation of the Center Concept

General

Southwest Foundation for Research and Education

Wake Forest University Primate Center

Duke Primate Center

Laboratory for Experimental Medicine and Surgery in Primates

Michale E. Keeling Center for Comparative Medicine and Research

Caribbean Primate Research Center

Department of Defense, Department of Health and Human Services’ Public Health Service, and other US Government Laboratories

Activities Abroad

Constraints

Regulation

1978 Indian Ban on Monkey Exports

Similar Actions in Other Countries

Responding to the Constraints

Rise of Domestic Breeding

Interagency Primate Steering Committee

Other Conservation Activities

Non-Governmental Organizations

Transition to the 1980s

Patterns of Usage

Retroviral Disease

1980S and 1990S: Progress Paying off in the Face of Serious Challenges

A Nobel Prize

Retroviral Disease and Simian Immunodeficiency Virus (SIV)

Emergence and Impact of the Animal Rights Movement

People for the Ethical Treatment of Animals

1985 Amendment of the Animal Welfare Act

Other Effects of AIDS Research

Chimpanzee Breeding and Research Program

Virus, Zoonotic Diseases, and AIDS Provide the Stimulus for Specific Pathogen Free Breeding

Ebola Virus and Interruption of Imports

Captive Breeding Goes Global

Primate Research Beyond the Year 2000

Significant Scientific Advances

Mapping the Chimpanzee and Rhesus Monkey Genome

Genomic Research

Infectious Disease

Growth in the Use of Nonhuman Primates

General

The NPRC Program

CDC Import Data, CRO, and Pharmaceutical Activity

International

Regulation and Review

Transportation

Animal Extremism and its Effects

Chimpanzees

Demand for Specific Pathogen Free and Genetically Defined Nonhuman Primates

Specific Pathogen Free (SPF) NHPs

Advances in Genetics and Genomics

Living in the 3R (Replacement, Refinement, and Reduction) World

Looking Toward the Future

General Trends

Pharmaceutical and Biotechnological Research

Conclusion

References

Human and Nonhuman Primates to 1960

Roots of Modern Primatology

Nonhuman primates probably first became valuable to humans as pets, but they are also the oldest recorded animal subjects for scientific research (Hill, 1977). Nonhuman primate pet trading is known to have occurred in Egypt as long as 5000 years ago (Morris and Morris, 1966); their use for medical purposes came somewhat later, although still in respectably ancient times. Galen (130–200 AD) did anatomical studies on animals including monkeys (Cohen and Loew, 1984) and Vesalius (1514–1564) used barbary apes (Macaca sylvanus) in his studies of circulatory anatomy (Morris and Morris, 1966; Kavanaugh and Bennett 1984; Loeb et al., 1989). Ruch (1941) has also documented that monkeys and apes were studied from ancient times through the middle ages by Hanno, Aristotle, Pliny the Elder, Pliny the Younger, Petrus, Candidus, and others.

Darwin’s research on evolution and particularly his notes on the behavior of the gorilla established his credentials as one of the first observational primatologists (Darwin, 1871). Also late in the 19th century, the British physician David Ferrier conducted comparative neuroanatomy studies of apes and monkeys (Morris and Morris, 1966). During the same time period, Pasteur discovered that the passage of the rabies virus through monkeys caused it to lose its virulence for dogs (Pasteur et al., 1884a, b). Some 20 years later, poliovirus was isolated by inoculating spinal cord material collected from fatal human cases intraperitoneally into monkeys (Landsteiner and Popper, 1908, 1909). The primatological knowledge that was generated came largely from relatively few behavioral and biomedical investigators working independently. With the institutionalization of nonhuman primate research, a profound change became possible.

First Primate Centers

Soviet Institute of Experimental Pathology and Therapy

According to Held and Gay (1983) and Lapin (1983), the first Commissar of Health in the USSR was persuaded by Mechnikov, a pioneer of modern Soviet experimental primatology, to establish a primate breeding station in 1923. Located in Sukhumi on the subtropical shores of the Black Sea in the then Soviet State of Georgia, the station was intended to be a quarantine, breeding, and holding center for nonhuman primates and to support a network of 50 medical and biomedical research institutions. It began operations in 1927 when it received the first shipment of hamadryas baboons (Papio hamadryas) and chimpanzees (Pan troglodytes) from Africa. At first, captive breeding was unsuccessful. However, there was improvement as experience in maintaining and breeding nonhuman primates was gained. Charting a course that has been followed elsewhere, activities of the Sukhumi station’s service gradually expanded to encompass initiatives in independent research. In 1957, now under the auspices of the Academy of Medical Sciences of the USSR, the station became the Institute of Experimental Pathology and Therapy (IEPT) in recognition of its status as a full-fledged research institution. By 1990, the IEPT had production colonies of over 7000 animals consisting primarily of baboon and macaque species, a staff of about 1000 people, and research programs focusing on oncology, physiology, biochemistry, infectious diseases, and the biology of nonhuman primates (B. A. Lapin, personal communication, 1990). The institute also served as a principal source of nonhuman primates for the Virology Institute in Moscow and the Russian space program. It was also an international resource with productive research links to medical scientists in the USA and elsewhere (Figure 1.1).

FIGURE 1.1 Drs Boris Lapin and Orville Smith at the IEPT in Sukhumi in 1987. Lapin, who became director of IEPT in 1958 and continued in that capacity after the move to Adler in 2010 had directed a major primate research center longer than anyone else. Smith was a longtime director of the Washington NPRC and studied the behavioral components of hypertension in baboons and collaborated extensively with investigators at IEPT and IMP.

The secession of Georgia from the former Soviet Union and the disturbances associated with the declaration of independence of Abkhazia seriously disrupted continued operations in Sukhumi. These problems forced completion in 1992 of a move of less than 100 miles to a satellite site in Russia near the city of Adler (D. M. Bowden, personal communication, 1993). Despite this adversity, the institute, now the Institute of Medical Primatology of the Russian Academy of Medical Sciences, remains not only one of the largest nonhuman primate research centers in the world but one of the most enduring as well.

Robert Yerkes and the Primate Laboratory of the Yale Institute of Psychobiology

Robert Yerkes, an accomplished comparative psychologist, had a vision for what the future held for nonhuman primate research and how to realize those dreams (Yerkes, 1916). Yerkes established the Primate Laboratory of the Yale Institute of Psychobiology at Orange Park, Florida, in 1930 (Bourne, 1971; Maple, 1979). His plan was to establish and develop an institute of comparative psychobiology in which the resources of the various natural sciences should be used effectively for the solution of varied problems of life (Yerkes, 1932). As early as 1919, he proposed the idea of establishing a nonhuman primate research institute for the systematic study of the fundamental instincts and social relations of nonhuman primates. Yerkes was a contemporary of other notable early investigators of the time such as Kohler and Kohts who were interested in nonhuman primate research (Maple, 1979). Interest in Kohts’ perceptual and sensory work with chimpanzees in the Soviet Union may have contributed to the initiative for the establishment of the Sukhumi station (Yerkes, 1943).

Yerkes established his Orange Park station in 1930 with funds from Yale University and the Rockefeller and Carnegie Foundations. He received an initial gift of 13 chimpanzees from a breeding facility belonging to Rosalia Abreu in Cuba (Maple, 1979). The colony was expanded during the next several years with 16 additional chimpanzees from Africa, a gift from the Pasteur Institute. Laboratory studies were multi-categorical, encompassing neurophysiology, anatomy, pathology, nutrition, growth, and development (Bourne, 1971). Orange Park was the first organization of its kind in the western hemisphere.

In 1965, the laboratories in Orange Park were moved to Atlanta, Georgia, and the animals were re-established in the new Yerkes Regional Primate Research Center of Emory University.

Cayo Santiago and the Caribbean Primate Research Center

Clarence Ray Carpenter, a student of Yerkes and an accomplished field primatologist (Maple, 1979), has as one of his most enduring accomplishments the establishment of the Cayo Santiago Colony of rhesus monkeys. Rawlins and Kessler (1986) and Kessler (1989; M. J. Kessler, personal communication, 2007) have provided extensive accounts of the history of the Cayo Santiago Colony. Much of the following historical information is derived from those accounts.

Carpenter formulated plans in the early 1930s for establishing a population of both gibbons and rhesus macaques on an island in the American tropics. The possibility of conducting both behavioral and biomedical research on an island colony was basic to those plans. He interested a number of people, including the staff of Harvard’s Museum of Comparative Zoology, the faculty of Columbia University’s College of Physicians and Surgeons, and the Columbia University/University of Puerto Rico’s (UPR) School of Tropical Medicine in San Juan (later to become the UPR School of Medicine), in a planning effort. He selected Cayo Santiago, a 15.2-hectare (approximately 38-acre) island one kilometer off Puerto Rico’s eastern coastal town of Humacao that was donated to the university by a wealthy Puerto Rican sugar cane and banking family.

With the help of a $60 000 grant from a private foundation, Carpenter set off for Indochina and India in 1938. He fared well in collecting the desired number of macaques. Survival of the 47-day sea voyage from Calcutta with the caged animals shipped as deck cargo was a testimonial to the enduring qualities of rhesus monkeys as well as to the care that they received. In late 1938, he released 409 rhesus monkeys, 14 gibbons, and three pig-tailed macaques on Cayo Santiago. Eventually only the rhesus monkeys remained.

Maintenance of the island and breeding were not without problems. Local fruits and vegetables did not provide an adequate diet and malnutrition was overcome only by feeding fox chow, the early precursor to monkey chow. Wells were dug, but the water was brackish. Cisterns and a system for collecting rainwater had to be constructed. A number of monkeys were lost through fighting or being denied access to feed by other animals. Under this pressure, some monkeys even escaped by swimming to the mainland. Various diseases also took their toll, but persistent efforts were successful in eventually eliminating tuberculosis.

Another problem was the lack of dependable financial support. In 1947, the UPR, which had assumed full responsibility for the project, actually offered it free to any institution that would support it. In 1948, a Puerto Rican neuroanatomist from the University of Michigan came to the rescue and succeeded in getting a $5000 grant to support his research and the colony as well. This was the first of many federal awards and marked the beginning of sustained federal support. In 1956, Cayo Santiago was incorporated into the NIH Institute of Neurological, Communicative Disorders, and Stroke’s (NINCDS) Laboratory of Perinatal Physiology. The work of the laboratory focused on finding the cause and cure for neonatal asphyxia using rhesus monkeys as research models.

At the closure of the laboratory in 1970, the Cayo Santiago colony became a part of the UPR Medical Science campus’s Caribbean Primate Research Center. The colony on Cayo Santiago has remained a favored site for naturalistic behavioral and noninvasive biomedical research for almost 70 years (Figure 1.2). It has also provided an extensive database on rhesus monkey genetics, thousands of rhesus monkey skeletons in the CRPC’s osteological collection, and genetically well-defined animals that have provided founder stock for starting new breeding colonies at the center and elsewhere.

FIGURE 1.2 A male rhesus monkey patrolling his territory on Puerto Rico’s Cayo Santiago Island, Caribbean Primate Research Center. Cayo Santiago is the longest standing primate breeding and research resource in the western hemisphere. The monkey is likely a direct descendant of Indian origin breeding stock that was introduced to the island by Ray Carpenter in 1938.

(Photo courtesy of R.G. Rawlins@rgrstockphoto.com)

Virological Research in Nonhuman Primates

General

Technically, the modern use of nonhuman primates in biomedical research had its origins in Pasteur’s work with rabies and the studies of others with smallpox and vaccinia in the late 1800s. Kalter and Heberling (1971) and Gerone (1974) have provided comprehensive reviews of virological research in nonhuman primates, including work on yellow fever and a variety of encephalitis viruses through the 1930s.

Polio

The Nobel prizewinning achievement of Landsteiner and Popper (1908, 1909) in isolating poliovirus in Vienna provided the real beginning of serious and widespread use of nonhuman primates in biomedical research. The unique susceptibility of nonhuman primates to this relatively new and frightening disease threat clearly established their special importance in research.

The intense efforts to develop a vaccine against polio that followed were unprecedented. They spanned the next 45 years, were international in scope, and involved a host of major investigators. However, it was a complex process that experienced serious setbacks. There were some promising early findings based on nonhuman primate studies using inactivated or partially inactivated vaccines, but cases of paralytic polio unfortunately occurred following vaccination in human clinical trials (Horstmann, 1985).

Nevertheless, nonhuman primates played an important role in helping to put polio research back on track. In 1931, throat washings from patients were inoculated into monkeys and resulted in infection (Paul and Trask, 1932). Later work showed that poliomyelitis was an enteric infection. The discovery by Enders et al. (1949) that poliovirus could be grown in human tissue culture was a major scientific advance for which the Nobel prize was awarded in 1954. Any possibility that this might reduce the need for nonhuman primates in the development and testing of a vaccine for polio was never realized. Vastly expanded research and testing programs immediately followed that were heavily dependent on using nonhuman primates for many years to come.

Jonas Salk’s report of formalin-inactivated polio vaccine grown in monkey kidney cell culture paved the way for extensive and successful field trials (Salk et al., 1953). This dramatic achievement was overshadowed shortly after use of the vaccine began when an improperly inactivated lot of commercial vaccine resulted in a number of cases of polio in 1955 (Horstmann, 1985). This incident led the US Food and Drug Administration (FDA) to adopt the much more vigorous vaccine testing program that constituted a major use of macaques for many years afterwards.

At about the same time, Sabin was working on the development of a polio vaccine from another direction. Depending greatly on the use of monkeys and chimpanzees, he searched for attenuated strains of naturally occurring poliovirus. His painstaking work reportedly used 9000 monkeys and 150 chimpanzees (Sabin, 1985). The result was the development of an oral polio vaccine that remained in wide use for many years. Interestingly, Sabin’s vaccine was widely tested in the Soviet Union. Because the IEPT in Sukhumi was initially the only nonhuman primate based research institution there, it tested candidate vaccines for both safety and efficacy and, during the period from 1946 to 1955, carried out basic research on the etiology, pathogenesis, clinical features, and pathomorphology of poliomyelitis (B. A. Lapin, personal communication, 2010).

While relatively modest in the early years, the use of monkeys increased dramatically following Salk’s discovery of an effective vaccine. The high point of this usage was in 1957 and 1958 when about 200 000 monkeys were imported annually into the USA (Lecornu and Rowan, 1979). According to Lecornu and Rowan, the greatest single use of the more than 1.2 million rhesus monkeys that were imported into the USA during the 20 years that followed Salk’s discovery was for producing and testing polio vaccine.

The legacy of the 1955 polio vaccine incident continued for many years. The more rigorous testing program that was adopted after the incident accounted for 20–25% of all nonhuman primates used in research and testing (Marten, 1981). However, the number of monkeys required for producing and testing polio vaccine declined through the years as the result of refined testing procedures and the adoption of preferable models. Two events have been of particular importance in this respect. The first was the decision by FDA in 1998 to replace the use of oral polio vaccine with inactivated vaccine, which dramatically reduced the need for monkeys. The second was a recommendation by the World Health Organization (WHO) at about the same time, which has been widely adopted internationally, to replace neurovirulence testing in monkeys with a newly developed transgenic mouse test. There was no longer a need to use monkeys for the routine production and testing of polio vaccine.

Kuru

Carlton Gajdusek won the Nobel Prize in Medicine in 1976 for showing that the neurodegenerative disease Kuru, which was associated with the cannibalistic rituals of a tribe of New Guinea natives, was caused by a transmissible agent that produced a noninflammatory encephalopathy atypical of that seen in viral infections. Although he attempted to demonstrate the transmissibility of the disease in a number of species, it was not until he inoculated the brain tissue of Kuru victims into chimpanzees that he began to see the delayed progression of neurological and behavioral clinical signs typical of the disease (Gajdusek et al., 1967). Gajdusek was an eclectic and accomplished researcher with well-established credentials in social anthropology as well as in infectious disease and cancer research, where he used a variety of nonhuman primates in his studies. As noted later (see the section Retroviral disease and simian immunodeficiency virus (SIV) below), Gajdusek’s continued work with nonhuman primates touched tangentially on the discovery of SIV. His research helped set the stage for the later work of Stanley Prusiner, who was awarded the Nobel Prize for Medicine in 1997 for his discovery of prions. That discovery not only defined the nonviral etiology of Kuru but also a host of similar diseases like scrapie in sheep, Creutzfeldt–Jacob disease, and bovine spongiform encepalopathy.

Virus (Herpes B Virus or Macacine Herpesvirus 1)

Until 1934, the only biohazards people thought about when working with nonhuman primates were bites and physical injuries. Tuberculosis was recognized fairly early as a relatively common disease, but it was more devastating to nonhuman primates than it was to humans. However, in that year, a fatal human case of encephalitis occurred in a laboratory worker after he was bitten by a monkey (Sabin and Wright, 1934). This report was the beginning of a concern that henceforth was to become inextricably associated with the interaction of macaques and man.

Other Contributions

The Work of Harry Harlow

Harry Harlow started his studies on the learning abilities of monkeys in 1930 at the University of Wisconsin. After conducting comparative studies of learning capabilities of cebus and rhesus monkeys at the local Vilas Park Zoo, he developed a modest laboratory on the university campus. During a career spanning nearly 50 years, Harlow expanded these resources into a large interdisciplinary research complex that included the Wisconsin National Primate Research Center (Davenport, 1979). The research enterprise eventually had a staff of over 200 people and a nonhuman primate colony numbering in excess of 1000 monkeys.

Harlow shed light on the nature and limits of rhesus monkey intelligence. Studies in the infant monkey nursery focused on the results of enriched versus impoverished social rearing conditions, development of measures of learning ability, and surrogate-mother testing to demonstrate the importance of infant–maternal tactile sensations relative to biological drives such as hunger. His work opened new areas of study including nonhuman primate parent–child relationships, peer interaction, play, heterosexual behavior, emotions such as love, and psychological impairments that result from social deprivation and separation (Suomi and Leroy, 1982).

Breeding and Reproductive Physiology

Surprisingly little information exists on the subject of nonhuman primate reproductive physiology and breeding prior to the 1960s. The first chimpanzee, or any ape for that matter, was not born in captivity until 1915 (Montane, 1915). As late as 1938, Carl Hartman, a prominent reproductive physiologist, predicted that rhesus monkeys would not breed in the American tropics (Rawlins and Kessler, 1986).

Gertrude van Wagenen, a faculty member in the Department of Obstetrics and Gynecology at Yale University School of Medicine, may have been the first to establish a captive rhesus monkey laboratory breeding colony (van Wagenen, 1972; D. M. Horstmann, personal communication, 1989). Over a career spanning 45 years, she collected detailed information from birth to death on all of the 1261 monkeys that lived in the colony. The colony produced 600 live births through 15 generations. Her many publications provided an abundance of basic information on rhesus reproduction and rearing. This work represents one of the first major efforts to focus on characterizing this facet of rhesus monkey biology. Studies of monkey biology, as an end in itself, did not come until later.

Establishment of the National Institutes of Health’s National Primate Research Centers Program in the USA: Crossing the Threshold

Initial Activity

The extended process that led to the establishment of the National Institutes of Health (NIH) National Primate Research Centers Program (NPRCP) has been well documented (Anonymous, 1968). It dates back to 1947 and 1949, when the NIH unsuccessfully tried to establish a procurement program to make an adequate supply of chimpanzees available to researchers in the USA.

In the period from 1955 to 1957, a number of groups and individuals advising the NIH and the National Academy of Sciences-National Research Council noted the need for developing additional nonhuman primate research facilities. Not much happened until James Watt, the director of the NIH National Heart Institute (NHI, eventually to become the National Heart, Lung, and Blood Institute or NHLBI), and eventually the director of the NIH, James Shannon, became interested in the problem.

Developing the Concept

In 1956, Karl F. Meyer, a veterinarian who later became known to the world of science for his research in microbiology and directorship of the University of California at San Francisco’s Hooper Institute, visited the Sukhumi station in the USSR (Figure 1.3). On his return, he urged Shannon to develop a nonhuman primate research colony in the USA. In the same year, Watt, along with Paul Dudley White, President Eisenhower’s physician, also visited Sukhumi. They were particularly interested in the baboon studies there on the role of social stress as a causal factor in essential hypertension (Smith, 1975).

FIGURE 1.3 Dr Karl Meyer, initially trained as a veterinarian, headed the Hooper Institute at the University of California, San Francisco, for many years. He was a respected researcher in infectious diseases and played a key role in the initial development of the national primate research centers program, particularly with the center in California NPRC. He may have been the first to publish a paper in the emerging field of laboratory animal medicine.

(Photo courtesy of www.wikipedia.org)

Watt’s report led the advisory council of the NHI in 1957 to recommend the development of a nonhuman primate colony to serve as a site for a long-term multidisciplinary approach to research on cardiovascular problems. Shannon, probably one of the NIH’s most visionary leaders, had differing views about the wisdom of establishing a single station with a focus limited only to long-term cardiovascular research.

In late 1958, the NIH concluded that a nonhuman primate station was both feasible and desirable. With increased interest in this idea within Congress, the NIH began to plan for a station. Conspicuous in this planning effort were George Burch, a noted cardiovascular researcher from Tulane University, and Willard Hal Eyestone, a veterinary pathologist on the NHI staff.

Congress received the planning report on the NIH’s plans for a nonhuman primate program in mid-1959. This plan reflected a transition in thinking about a single station, as conceived by NHI, to a number of smaller nonhuman primate research centers. These centers were still to focus on cardiovascular research, but their roles were expected to expand to include other disease categories and other disciplines, until ultimately the functions of the stations or centers is the full and complete investigation of the primate (Anonymous, 1968).

The NIH planners felt that the focus of the centers should be on research and not just on serving as a source of monkeys and that support should be provided by the NIH for a long period of time. Between 50 and 100 years was originally suggested. Other ideas also became cornerstones of the new program. Research was to be conducted on nonhuman primates in conjunction with other basic and clinical studies. Investigations were to be carried out on the usefulness of various species of nonhuman primates in research. A national reservoir of information on nonhuman primates and for nonhuman primate research was to be provided. There were to be facilities for visiting scientists and research training. Extensive local participation with appropriate universities or research institutions and the need for seeking outside funding to augment the core budget were also identified as basic concepts.

Launching the New Program

Congress appropriated the first funding for the program, $2 million, in 1959. There were to be several centers. These centers were to be geographically distributed, be part of a university environment, and support biomedical and health research broadly instead of being limited to a particular area such as cardiovascular research. Hal Eyestone played a key NIH staff role along with Dr Burch, NHI staff, and others in getting the program up and running. He shortly became the new program’s first director. Richard Dukelow has provided a detailed account of early center development and the personalities involved in his book, The Alpha Males (Dukelow, 1995).

Following announcement of the new program in January 1960, the NIH received 11 applications. Seven applications were approved by the study section which reviewed the applications. NHI awarded the first grant to establish the Oregon National Primate Research Center (Oregon NPRC; originally each center was designated as a regional primate research center, but they were later re-designated as national primate research centers) in Beaverton, Oregon.

With a congressional appropriation of $7 million in 1961 for the following years, NHI awarded grants to establish the Washington NPRC at the University of Washington in Seattle; the Wisconsin NPRC at the University of Wisconsin in Madison; the Yerkes NPRC in Atlanta in association with Emory University; the Delta NPRC in association with Tulane University at Covington, Louisiana (later renamed the Tulane NPRC); and the New England NPRC in association with Harvard University at Southboro, Massachusetts ( Figure 1.4).

FIGURE 1.4 The Alpha Males as described in Dukelow’s book of the same name. The first directors of the seven national primate research centers and NIH staff, taken in Bethesda, 1965. Front, left to right: William Montagna, Oregon NPRC; Geoffrey Bourne, Yerkes NPRC; Lloyd Neurauter, NIH staff; Leon Schmidt, California NPRC; Harry Harlow, Wisconsin NPRC; Bernard Trum, New England NPRC. Back: Theodore Ruch, Washington NPRC; Arthur Riopelle, Tulane (Delta) NPRC, and Willard (Hal) Eyestone, the first director of the NIH’s NPRC program.

(Photo courtesy of Dr R.W. Dukelow and the Jacobsen Library, Wisconsin NPRC.)

Still preoccupied with the perceived need for a national station, the advisory council of the NHI continued to urge the establishment of a conditioning center for nonhuman primates. Its function was to be the development of techniques for procuring, conditioning, and maintaining various nonhuman primates for study. In 1962, NHI awarded a grant to establish such a center at the University of California, Davis. The center, initially designated as the National Center for Primate Biology, later became the California NPRC. This change was made after it became apparent that it was much more important and realistic to have the California center function as a NPRC rather than serving the more specialized role originally envisaged.

By the time the initial establishment of the seven centers was complete in 1968, the eight years of cumulative federal funding provided by the NIH totaled about $52 million, including funds for the purchase of land sites, construction of the centers’ facilities, other start-up costs, and a rapidly expanding research program. Administration of the program was formally transferred from the NHI in 1962 to the NIH’s Division of Research Facilities and Resources. This division later became the NIH Division of Research Resources (DRR) and, in 1990, the National Center for Research Resources (NCRR).

National Primate Research Centers Program Today

In 1999, an eighth center was added to the NPRC program. Following the submission of a grant application by the Southwest Foundation for Biomedical Research (SFBR) to the NIH, an award was made by NCRR that formally established the Southwest NPRC, already a fully functional nonhuman primate research and resource center at the SFBR in San Antonio. By the end of 2007, the eight NPRCs had 320 core doctoral scientists, 2000 collaborators and affiliates, and a total of about 26 000 nonhuman primates representing 20 different species or species groups including 17 250 rhesus monkeys (J. D. Harding, personal communication, 2010). The program was very successful. The eight centers played a pioneering role in which multidisciplinary interactions among veterinarians, reproductive physiologists, and behaviorists were crucial in developing techniques for large-scale captive breeding of macaques. As a measure of the center’s impact on science more broadly, Fridman (1972) noted that the number of scientific publications based on research using nonhuman primates trebled in the 4- to 5-year period following 1964. He pointed out that the temporal relationship of this phenomenon to the establishment of the centers was not accidental.

1960–1980: Period of Growth in a World of Increasing Constraints

Emulation of the Center Concept

General

By 1972, there were 40 research centers in the world devoted to experimentation with nonhuman primates and another 1800 institutions using nonhuman primates in research (Fridman, 1972). Fridman described growth in the field as explosive. Between 1965 and 1971, the number of research projects using nonhuman primates increased from 666 to 1183 in the USA, an 80% increase (Goodwin, 1975a). Referring to data provided by the Primate Information Center of the Washington NPRC, Goodwin reported that the 5000 nonhuman primate references on record in 1960 had increased sevenfold to 35 000 by 1971. The status, usage, and availability of nonhuman primates in the USA during this period have been extensively reviewed by the Institute of Laboratory Animal Resources (Southwick, 1975).

Southwest Foundation for Research and Education

The Southwest Foundation for Research and Education (SFRE) was established in San Antonio, Texas, in 1941 and it first obtained baboons in 1957 (Vagtborg, 1973). In 1958, the NIH made a grant award to SFRE to support the development and operation of a baboon colony, and this support continued until 1972. In addition to the research and production colony at SFRE, funding was also provided to support conditioning and trapping facilities in Kenya and numerous baseline studies on the baboon. The success of the husbandry and baseline studies established the baboon as a nonhuman primate model for many areas of biomedical research and the SFRE as a leading baboon research center.

A reference center for nonhuman primate viruses was established at SFRE in 1965 and was designated as the NIH–WHO Simian Viruses Reference Center in 1968 (Kalter and Heberling, 1971, 1974; Kalter, 1974). In 1982, a major research and diagnostic B virus program was also established there (Hilliard et al., 1986). This program was later relocated to Georgia State University, where, under the direction of Dr Julia Hilliard, it continued to serve as a US and international B virus reference center. In 1977, the NIH awarded a grant to SFRE for developing and operating a semi-free ranging national baboon breeding program. While direct NIH support for this program was later discontinued, baboons continued to be bred there for meeting the needs of biomedical researchers both at the SFRE and elsewhere (W. J. Goodwin, personal communication, 1993).

In 1999, as noted earlier, the SFRE, which by then had become the Southwest Foundation for Biomedical Research and in 2011 became the Texas Biomedical Research Institute, became the eighth center in the NIH’s NPRC program.

Wake Forest University Primate Center

Beginning in the late 1950s, coincident with the creation of the NIH’s National Primate Research Centers Program, Dr Thomas Clarkson began developing in his Department of Comparative Medicine at Bowman Gray School of Medicine, a part of Wake Forest University, a nonhuman primate resource to support his research. This activity prospered and grew through the years to the point in 2007 that the university formally recognized it as the Wake Forest University Primate Center (WFUPC). During this period, Dr Clarkson led the development of a research program based on using monkeys as clinical surrogates to study diseases of human relevance. The success of the program has been amply demonstrated and supported through an uninterrupted succession of competitively awarded grants and contracts from the NIH, particularly the National Heart, Lung, and Blood Institute, for many years. In 2008, the center’s nonhuman primate population numbered about 1200 rhesus and long-tailed (cynomolgus) macaques and vervet monkeys, which included breeding colonies established and managed to meet in-house research as well as national resource needs. Its faculty included 14 DVMs and four PhDs.

While Dr Clarkson’s success in establishing this center represented a remarkable achievement in itself, his record of using the program to train the next generation of professionals in nonhuman primate based research and laboratory animal medicine is of comparable import. Through his years of leadership more than 50 veterinarians received such training, most of whom became board certified by the American College of Laboratory Animal Medicine (ACLAM) (Figure 1.5). About 20 of these trainees made significant contributions to nonhuman primate medicine and seven became presidents of ACLAM (T. B. Clarkson, personal communication, 2007). In every sense of the term, WFUPC was a major primate research center.

FIGURE 1.5 Dr Thomas Clarkson in his office with photos of his former postdoctoral trainees. Through his long tenure at Wake Forest University’s School of Medicine, Clarkson probably trained more veterinarians in laboratory animal medicine than any other person in the specialty, some 20 of whom pursued careers in nonhuman primate medicine.

(Photo courtesy of Dr Thomas Clarkson.)

Duke Primate Center

The Duke Lemur Center of Duke University began as a small research colony of lemurs obtained from Madagascar in 1960. Izard (1989) related that the colony was initially located at Yale University but was moved to its present location in 1966 with NIH and National Science Foundation (NSF) support. The colony has grown through breeding and acquisitions and presently has the world’s largest collection of prosimians with a population of 250 animals including 20 different species (C. V. Williams, personal communication, 2008). Financial support is provided for the center by Duke University, the NSF, and private donors. Research is the center’s primary focus; however, both education and conservation are integral components of the center’s mission.

Laboratory for Experimental Medicine and Surgery in Primates

The Laboratory for Experimental Medicine and Surgery in Primates (LEMSIP), associated with New York University (NYU), began to serve the metropolitan New York City needs for a nonhuman primate center in 1965 (Anonymous, 1988). Jan Moor-Jankowski, a physician and immunologist, came to New York from Poland earlier to work with Alexander Wiener. Wiener, a New York hematologist and a co-worker of Landsteiner’s, had earlier described the Rh factor in experiments using rhesus monkeys (Landsteiner and Wiener, 1940). Wiener and Moor-Jankowski cooperated with other New York area investigators by making research work with nonhuman primates possible. By 1966, LEMSIP was under the direction of Moor-Jankowski and 23 local investigators were using its resources. At one point in its history, some 300 chimpanzees and 300 monkeys were housed in LEMSIP’s nearby suburban facility located in Sterling Forest, New York. They were used in studies of hepatitis, AIDS, reproduction, and blood transfusion. LEMSIP was closed by NYU in 1997 and its chimpanzees, many of whom were government owned, were moved elsewhere or placed in sanctuaries.

Michale E. Keeling Center for Comparative Medicine and Research

In 1975, the University of Texas MD Anderson Cancer Center established the Veterinary Science Division at the Science Park in Bastrop, Texas. Michale E. Keeling, a veterinarian who began his career in nonhuman primate medicine at the Yerkes NPRC as a primate clinician, was named the division’s director (Figure 1.6). The center evolved over the next 25 years under his leadership into a major nonhuman primate research resource which probably became most widely known for its contributions to advance knowledge about the housing, maintaining, and breeding of chimpanzees. The division and Dr Keeling were probably among the most influential and significant participants in the NIH’s National Chimpanzee and Breeding and Research Program and later went on to play a similarly successful role in the production of B virus, SIV, simian retrovirus (SRV), and simian T cell lymphotropic virus (STLV) specific pathogen free rhesus monkeys in the NIH-supported rhesus monkey breeding and research program. In recognition of its importance not just as a research animal resource but as a growing full spectrum research and training activity, the division was renamed a center in Dr Keeling’s honor in 2004 upon his death. The center has continued to grow under the present director, Dr Chris Abee, who brought with him from his previous position at the University of South Alabama breeding and research colonies of owl and squirrel monkeys that were among the world’s largest. The center’s amount of sponsored research, which totaled more than $40 million in 2008, showed that it also had attained the status of a major primate research center.

FIGURE 1.6 Dr Michale Keeling, who was one of the first veterinarians in the 1960s to gain recognition as a nonhuman primate clinician at the Yerkes NPRC. Later Dr Keeling became the first director of the University of Texas MD Anderson Cancer Center’s Veterinary Sciences Division at Bastrop, Texas, which was later named in his honor. He was most widely known for advancing knowledge about housing, maintaining, and breeding nonhuman primates, particularly chimpanzees.

(Photo courtesy of the Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, TX.)

Caribbean Primate Research Center

The establishment of the Caribbean Primate Research Center (CPRC) in Puerto Rico in 1970 represents a continuation of the Cayo Santiago story. Goodwin (1989) and Frontera (1989) have provided extensive background on this subject. In 1970, the NINCDS decided to discontinue the Laboratory for Perinatal Physiology and its facilities, including animals, reverted to the University