History of the National Academies of Sciences, Engineering, and Medicine’s Institute for Laboratory Animal Research

Abstract

The Institute for Laboratory Animal Research (ILAR) was created within the National Academies of Sciences, Engineering, and Medicine (National Academies) in 1953 when biomedical research using animals was in its infancy in terms of quantity, quality, complexity, sophistication, and care. Over the intervening 69 years, ILAR has witnessed unprecedented growth, followed by unprecedented decline, and then regrowth in usage of specific species and models and an overall shift in experimental burden away from larger to smaller species (ie, mice, fish, and rats). ILAR has contributed much to the evolution of necessary research using animals and animal models for the benefit of humans, animals, and the environment and to the development and implementation of humane principles and standards for care and use of research animals. ILAR has served as a “neutral broker” seeking consensus, solutions, common ground, and pathways forward for all professional constituencies engaged in conduct of animal research. In 2022, ILAR will become the Board on Animal Health Sciences, Conservation, and Research (BAHSCR) within the Division on Earth and Life Studies of the National Academies and the ILAR Journal will pause publication with volume 62. This manuscript recounts the history and accomplishments of ILAR 1953–2022, emphasizing the past 2 decades. The manuscript draws upon ILAR’s communications and previously published histories to document ILAR’s leaders, reports, publications, conferences, workshops, and roundtables using text, tables, references, and extensive supplemental tables. The authors’ intention is to provide the scientific community with a single source document for ILAR, and they apologize for any omissions and errors.

INTRODUCTION: ORIGINS OF ANIMAL RESEARCH AND INCEPTION OF ILAR

The founding of the Institute for Laboratory Animal Research (ILAR) in 1953 is best viewed in the historical context of the evolution, collaboration, and funding for use of animals to expand scientific knowledge, advance basic science and practices of clinical and veterinary medicine, train new scientists and physicians, and, most recently, to support discovery and development of new medicines and medical therapies for humans and animals in the United States and internationally. Histories of animal experimentation and evolution of clinical and veterinary medical disciplines are extensively covered elsewhere, but these lack critical elements necessary to understand the formation of ILAR, which is recapitulated below.^1–8

Galen (c. 130–200 AD) is widely considered to be the first to use animal experimentation to derive information about the systems of the body and is considered the founder of research using animals. Jean Fernel (1497–1558) first introduced the term “physiology” in approximately 1550 from ancient Greek meaning “study of nature, origins.” Publication in 1628 of William Harvey’s (1578–1657) “An Anatomical Dissertation Upon the Movement of the Heart and Blood in Animals” further established physiology as a scientific discipline. Other early physiologists who used animals included Leonardo da Vinci (1452–1519), musculature and movement; Marcello Malpighi (1628–1694), capillary blood flow; Robert Hooke (1635–1703), lung respiration; and Stephen Hales (1677–1761), aortic blood pressure.^9–11

In the latter half of the 18th century, Europe experienced a pause in generation of new physiologists and physiological/medical knowledge lasting approximately 100 years. Medical education consisted of reading ancient texts based on Hippocrates’ concept of the 4 humors (blood, phlegm, yellow bile, and black bile) and was considered more of an art than a science. The precise reasons underpinning the relative paucity of new physiologists/physiological findings during this period are unclear and may include wars and political upheavals, the waning of the first Industrial Revolution (1760–1840), and the influence of I. Kant’s and F.J.W. von Schelling’s concepts of “Natur Philosophie”: “because the intelligent human is able to understand the natural phenomena the experiment-based approach is unnecessary.”^11,12

The mid-19th century brought new momentum for science-based medicine and medical training with contributions from Matthias Schleiden (1804–1881) and Theodor Schwann (1810–1882) in cell theory; William Beaumont (1785–1853), gastric physiology; Rudolf Virchow (1821–1902), pathophysiology; Carl F.W. Ludwig (1816–1895), cardiovascular physiology; Claude Bernard (1813–1878), fluid-electrolyte physiology; and Eduard F.W. Pflüger (1829–1910), neuromuscular physiology. Rekindled interest in animal experimentation was part of a general revival of the sciences and advancements in medical practice associated with the second Industrial Revolution (1860–1914), including publication of Charles Darwin’s (1809–1882) “The Origin of Species” (1859), Dmitri Mendeleev’s (1834–1907) periodic table (1869), and August Waller’s (1856–1922) and Willem Einthoven’s (1860–1927) electrocardiogram (1895). New branches of medical science appeared: anesthesia (ether, chloroform, and nitrous oxide), analgesia (Adolf von Baeyer, 1837–1917, synthesis of barbituric acid), antisepsis (Joseph Lister, 1827–1912, and Ignaz Semmelweis, 1818–1865, carbolic acid); and bacteriology (Louis Pasteur, 1822–1895, and Robert Koch, 1843–1910). Notably, all these scientists, apart from William Beaumont, were based outside the United States.

There are very few references regarding funding sources for animal experimentation prior to the mid-20th century. It is reasonable to presume that most if not all early physiologists were educated individuals of independent means and able to self-fund their experiments, travel, and communications or with the aid of wealthy patrons or institutions. William Beaumont, a physician in the US army, was able to employ his patient Alexis St Martin as a servant in his household so that he could continue his studies of St Martin’s gastric function. Walter Cannon mentions receiving funding from private sources, including his university’s endowment, for his research activities. Notably, Cannon also expressed skepticism on accepting government funding for academic research.^13–15

There are also very few references for the sources and numbers of animals used in experimentation prior to the mid-20th century. Domestic species were readily available, and those of convenient size and tractability (eg, dogs) appear frequently in documentation.¹⁶ August Waller bred bulldogs and described the use of his pet male “Jimmy” in his demonstrations of the “electrocardiogram.”¹⁷ Nathan Brewer mentions physiologists keeping research animals and/or performing experiments at their homes in the early 20th century.¹⁸ E.B. Verney (1894–1967) reported use of his pet dogs in his experiments on the antidiuretic hormone and osmoregulation.¹⁹ Application of statistical methods in research and experimental design dates from the 1920s, suggesting that much of prior animal research was “demonstrational” and likely underpowered for statistical purposes.²⁰ Animal shelters and pounds were important sources of animals for academic research and teaching in the United States into the latter part of the 20th century.²¹ In a previous ILAR Journal review, Kinter and DeGeorge (2016)⁴ concluded that from antiquity to the early 20th century the primary species used in physiological and pharmacological experimentation was the human being, that very few animals were used to demonstrate pharmacological efficacy, and that there was no evidence of animal use to demonstrate pharmacological safety. It seems safe to conclude that prior to the mid-20th century, scientists conducting research using animals (1) self-funded their research using personal resources and/or with the support of personal benefactors; (2) collected, acquired, or raised the animals used in their laboratories or homes, housed and cared for experimental animals in their laboratories or homes without the support of a modern animal research facility or veterinarian; and (3) designed, directed, and executed research activities in their laboratories at their discretion alone and without external direction or approval^18,22 All this would change dramatically during the latter half of the 20th century, with ILAR serving as a catalyst.

The mid-20th century witnessed milestones that impacted animal use in research and product testing and initiated efforts and organizations to improve the quality of science and animal care and welfare.

• The Federal Food, Drug, and Cosmetic Act of 1938 required safety testing of pharmaceuticals and cosmetics, and Good Laboratory Practice regulations (1987) established the first standards for animal use in medical product testing.⁴

• National Institutes of Health (NIH) funding of extramural research began around 1938 with National Cancer Institute (NCI) grants to nonfederal scientists for research on cancer and fellowships at NCI for young researchers. After WWII, NIH extra mural funding expanded to other NIH institutes with the 1944 Public Health Service Act. From just over $4 million in 1947, the program grew to more than $100 million in 1957 and to $1 billion in 1974.^23–27

• Peer review gained traction for publications in medical and scientific journals beginning in the 1940s.²⁸

• The Laboratory Animal Welfare Act P.L. 89-544, 1966 (AWA)

In the 1950s, engagement of veterinary expertise in the care, breeding, and use of animals in research was progressively organized in the United States, based in part on the seminal work “The Principles of Humane Experimental Technique”²⁹ and included:

• The Animal Care Panel (ACP) in 1950, which later became the American Association for Laboratory Animal Sciences¹

• The Institute for Animal Resources (IAR), the predecessor of ILAR, in 1953^1,3

• The American College Board of Laboratory Animal Medicine in 1957, which became the American College of Laboratory Animal Medicine, in 1965³⁰

• The International Committee on Laboratory Animals in 1956, which became the International Council for Laboratory Animal Science (ICLAS)^31,32

• American Society of Laboratory Animal Practitioners in 1966³³

• Association for Assessment and Accreditation of Laboratory Animal Care (now AAALAC International) was founded in 1965³⁴

THE INSTITUTE OF ANIMAL RESOURCES (IAR)

The IAR (1953) is unique among US and European organizations supporting animal research in that it was established by a longstanding professional non-governmental organization, the National Academies of Sciences, Engineering, and Medicine (National Academies).^1,3,35 The IAR was renamed the Institute of Laboratory Animal Resources in 1956 and Institute for Laboratory Animal Research (ILAR) in 1997, reflecting its evolving roles from identifying and sharing animal resources and developing standards to modern research practices and animal welfare in scientific investigations. In 2022 ILAR will become the Board on Animal Health Sciences, Conservation, and Research (BAHSCR) in the Division on Earth and Life Sciences of the National Academies (Figure 1).

Rapid growth of academic, government, and industrial biomedical research following World War II (1939–1945) resulted in unprecedented demand for research animals and exposed systemic weaknesses in supply, standardization, procurement, and quality of these animals. Standards for animal production, genetics, breeding, husbandry, quality, and transportation did not exist, and there were few if any mechanisms for information exchange, nationally or internationally. Education and training in laboratory animal sciences was in its infancy and without guidelines. These concerns surfaced in the National Academy of Sciences in 1952 with the recognition that research animals were a potential national security concern and that current supply mechanisms were likely inadequate.

Dr Paul Weiss, a member of the National Academy and Chairman of the Division of Biology and Agriculture of the Academy’s National Research Council (NRC), organized the Conference on Animal Procurements (July 10, 1952). Chaired by Dr Clarence Cook Little (Jackson Memorial Laboratories, Bar Harbor, ME), the conference recommended that the NRC establish a Committee on Animal Resources (CAR) “for the purpose of recommending a long-term procurement and supply mechanism of animals for biologic, medical, and agricultural research.” Four months later the CAR proposed formation of the Institute of Animal Resources (IAR); the proposal was accepted by the NRC, and the new institute was launched in July 1953.¹

The first IAR publication was in 1954, the “Handbook of Laboratory Animals.”³⁶ The Handbook was a compilation of the first reports of IAR committees covering genetics, nutrition, diseases, sources, uses, international exchange, users, and supporting agencies. Follow-up editions included the “Handbook of Animals for Research – A Catalogue of Commercial Sources” (1958), distributed in ILAR’s mailed communication format “Information on Laboratory Animals for Research” (ILAR), and “Laboratory Animals. II. Animals for Research” (1961), published by National Academies Press (NAP).^37,38 These 3 early ILAR publications illustrate the chaotic state of basic information on animals used in research at that time. When much of scientific journal access was limited to academic libraries that could bear subscription costs, ILAR and the National Academies strived to make curated information widely accessible at modest cost.

ILAR Organization

From its inception ILAR executed the recommendations of the CAR to leverage organizations and individuals across academia, government, and industry engaged in animal research to develop policies, standards, and guidelines to benefit animals, animal experimentation, and human and animal health. ILAR has consisted of a voluntary advisory committee (currently the ILAR Council), ILAR staff consisting of a director and the support staff necessary to carry out the current mission, and an editor. From earliest days the advisory council has consisted of representatives (largely veterinarians and scientists) of academic organizations, animal breeding organizations, government institutes and laboratories, commercial suppliers, research organizations (industry/pharma), and independent foundations and has frequently included National Academies members. Chairs of the ILAR Advisory Council and ILAR Directors and Editors 1953–2022 are listed in Table 1, and members of the ILAR Council and ILAR members of the National Academies are listed in Supplemental Tables 1 and 2.

ILAR Mission/Objectives/Processes

The original tasks and objectives of IAR/ILAR were published in Science in 1953 (Table 2).³⁹ ILAR Council and staff identify specific topics and find sponsors willing to fund agreed-on projects, resulting in formation of ILAR committees; organization of workshops, meetings, and conferences; and subsequent publication of reports. As with other National Academies organizations, ILAR receives requests for studies from government agencies and others, and with the Academy’s approval appoints committees to research and produce reports on specific topics. Listings of ILAR committees and membership can be found in Information on Laboratory Animals for Research (ILAR vols 1–9, 1957–1966) and in frontmatter in ILAR News (vols 10–36, 1966–1994) and ILAR Journal (vols 37–62, 1995–2022).

Early ILAR accomplishments included:

• 1) The orderly development and dissemination of animal research information across a wide range of topics. From 1953 through 1957, ILAR received and processed approximately 2000 requests for advice and assistance per year—of which some required dispatch of existing reports and others required literature searches and site visitations.¹ A more formal approach to information distribution was established in 1957 with quarterly publication of Information on Animals for Research (ILAR Vols 1–9). These communications evolved from a quarterly newsletter to a peer reviewed journal. See Supplemental Tables 3 and 4 for tables of contents of ILAR, ILAR News, and ILAR Journal issues. Several seminal articles previously published in ILAR communications are republished in this issue of ILAR Journal.

• 2) ILAR organized studies, conferences, and workshops sponsored by government and non-government organization stakeholders, and, most recently, roundtables sponsored by roundtable members. Early topics focused on animal production, long-term holding, specific pathogen-free animals, procurement and production of rhesus macaques, animal diseases and zoonotic diseases transmissible to humans, and workshops on graduate education in laboratory animal medicine and animal technician training. The proceedings of these activities were generally summarized in ILAR periodicals or published by the NAP, with some still available from NAP. In 1956 the ILAR initiated its publication of standards for animals involved in research, testing, and teaching—and that effort is currently ongoing. Early publications included minimum standards for the commercial production of random-bred and inbred mice, minimum standards for the commercial production of random-bred and inbred rats, principles for laboratory animal care, and guiding principles in the use of animals by secondary school students and science club members.^40–43

• 3) ILAR has addressed specific issues involving research animal availability and quality. In 1955 ILAR formed a “Subcommittee on Health Standards,” which produced ILAR’s first report, “Parasitic and Infectious Diseases of Laboratory Animals.”^1,3 That report called for “a system of accreditation and certification of laboratory breeders…” and for “the elimination of certain diseases in animal colonies” (gnotobiotics) for accreditation and certification to succeed.^44–47 That same year the Cancer Chemotherapy National Service Center (CCNSC) of the NCI began an extensive program of study of cancer chemotherapy. With release of the Diseases report, ILAR was positioned to partner with CCNSC when it became clear that insufficient attention was being given to quality in the breeding of animals for the CCNSC program. This was the impetus for ILAR’s original rodent production and transportation standards. A third example occurred after India’s 1955 decision to cease exportation of rhesus macaques for research. ILAR was asked by the US Department of Defense to survey rhesus macaque availability in the United States. The work resulted in the establishment in 1962 of a network of national primate research centers.^1,3

ILAR Reports

ILAR participated in surveys of commercial animal production thru the 1950s, providing the institute and biomedical community with data on producers, users, genetic stocks, and characteristics. The ILAR Committee on Transportation was active in studying the difficulties and proposing solutions for shipping millions of mice annually to research facilities across the United States. Reports published prior to 2000 are referred to in previous manuscripts by Hill and Wolfle and in Supplemental Tables 5, 6.^1,3,35 Reports produced by ILAR between 2000 and 2022 are listed in Table 3.

The Guide

Perhaps the most well-known of ILAR’s efforts has been the compilation of guidance and standards for laboratory animal care, currently known as the Guide for the Care and Use of Laboratory Animals 8th Edition (the Guide).⁴⁸ In a recent Scopus search of citations of 58 different regulatory and guidance documents in the animal research literature, the Guide was cited 1985 times—more often than all other documents in this category combined.⁴⁹ This section will review the development of the Guide and highlight the new direction being taken by ILAR regarding upcoming revisions.

Establishment of guidance and standards in laboratory animal care has been part of the mission of ILAR since its inception (Table 2). The first such guidelines were Minimum Standards for the Commercial Production of Random-bred and Inbred Mice.⁴⁰ Additional standards and guidelines proposed for other species and activities followed over the next several years, including Principles of Laboratory Animal Care as well as Guide for Laboratory Animal Facilities and Care, which was published under the aegis of the Public Health Service (PHS).^50,51 Authorship was credited to the Animal Facilities Standards Committee of the ACP. The composition of this authorship committee is shown in Table 4. This manuscript was the first edition of the Guide, and while it was not officially generated by ILAR, it was adopted by ILAR prior to publication on January 28, 1963.^52,53 According to the preface of the current (8th) edition, the ACP received a grant from the NIH to author these initial guidelines.⁴⁸ Many of the authors were heavily involved with ILAR, and ILAR endorsed it as a publication of the NRC. In addition, it was cited in the ILAR Newsletter as an “important new guide now available.”⁵³ Much of the content of these efforts was incorporated in law in the AWA.

This inaugural version of the Guide was divided into 3 major sections: (I) Personnel, (II) Physical Plant, and (III) Laboratory Animal Housing and Care.⁵⁴ Many elements endured through subsequent editions, including use of professional judgment, personnel qualifications, cage sizes (for 8 species in the first edition), cleaning frequencies, and guidelines for surgical and post-surgical care (located in the Laboratory Animal Housing and Care section in the first edition). Even the well-known numerical guidelines of 10–15 air changes per hour for housing room ventilation and 180°F for cage washing temperature appear in this initial version. Interestingly, there is also a discussion on the issue of exercise for dogs, which culminates in a recommendation that “exercise” should be a matter of professional judgment and that “there are reasons for providing both cages and pens or runs in the routine maintenance of dogs in the laboratory.”⁵² Ironically, this foreshadowed future developments over the next 20 years in both the Guide and the US Department of Agriculture (USDA) regulations.

One of the benefits of electronic publication is that lengthy supplemental material can be included with articles, and so the editorial team for this issue of the ILAR Journal has chosen to republish the very first edition of the Guide later in this issue of ILARJ.⁵⁴ We hope that you enjoy seeing both the differences and similarities between the first and current editions.

The development of the Guide and other standards regarding research using animals was paralleled by the creation of an accreditation process to assess animal care and use programs. This process also evolved from an ACP committee, known as the Animal Facilities Accreditation Board, and culminated in the creation of the American Association for Accreditation of Laboratory Animal Care (AAALAC) in 1965. From the beginning, AAALAC stated its intention to use the Guide as its primary resource: “The US Public Health Service’s Guide for Laboratory Animal Facilities and Care, serves as the basic guide used in evaluating institutional animal care facilities.”^34,55,56

After the inaugural edition of the Guide, each of the subsequent editions was produced by ILAR providing Guide revisions in 1965 and then again in 1968, 1972, 1978, 1985, and 1996. The sixth edition of the Guide (1985) was significant in that it paralleled a revision in the regulations promulgated by the USDA in compliance with amendments to the AWA. It was also published contemporaneously with the US PHS “Policy on the Humane Care and Use of Laboratory Animals by Awardee Institutions,” which was intended to implement and supplement the “U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training” developed by the Interagency Research Animal Committee as well as the provisions of the Health Research Extension Act of 1985.

It was at this time that Institutional Animal Care and Use Committees (IACUCs) were mandated throughout various documents, with categories of required members delineated in both the Guide and the new AWA regulations, although the member categories differed slightly. Additional changes included separation of surgical procedure functions by rooms, addressing social enrichment for nonhuman primates (which over time would logically extend to more species), and exercise for dogs.

The other major development in association with the 1985 Guide revision was the adoption of AAALAC accreditation as an institutional category by the agencies of the PHS (eg, the NIH). Institutional programs accredited by AAALAC were noted as “Category 1” and as such had a reduced set of requirements for grant submissions compared with unaccredited institutions in “Category 2.”⁵⁶ As a result, although AAALAC accreditation was still voluntary, it now had new significance in government research granting mechanisms, and because the primary reference for AAALAC was the Guide, it now had a sharper role within the animal research regulatory library.

The seventh edition of the Guide was published in 1996 and the current eighth edition in 2011. The eighth edition was mostly noted for its separate section on “Aquatic Animals” and inclusion of “Key Concepts,” which featured formal definitions of “must,” “may,” and should” and “engineering, performance, and practice standards.”⁴⁸ Other notable changes included

• Addition of a new section on post-approval monitoring, and considerations such as humane endpoints and multiple survival surgical procedures

• Endorsement of the American College of Laboratory Animal Medicine’s “Guidelines for Adequate Veterinary Care”

• Recommendations for minimum space for female rodents with litters and an increase of cage height for rabbits to 16″; rodent breeding recommendations were accompanied by substantial guidance.

• Endorsement of social housing as the default and provision of some species-specific guidance

• Increase from 7 to 8 weight-based groups for monkey cage sizes and conversion of the “Apes (Pongidae)” section to “Chimpanzees (Pan)” were made to the table on “Recommended Minimum Space for Nonhuman Primates ...”.

• Introduction of animal biosecurity that upholds its central role in ensuring the health of laboratory animals

• Recommendations on animal procurement, transportation, and preventive medicine, and expansion of the sections on clinical care and management, surgery (with a new section on intraoperative monitoring), pain and distress, and euthanasia

• Addition of new material on vibration control; physical security and access control; hazardous agent containment; and special facilities for imaging and whole-body irradiation, barrier housing, behavioral studies, and aquatic species housing

• Discussion of centralized vs decentralized animal facilities and introduction of the concept of variable-volume HVAC systems with a nod toward energy conservation and efficiency

A challenge for the Guide has been the continually increasing scope since its inception as well as the increasing time periods between revisions (Figure 2) in the face of accelerating scientific advancement. In 2020, ILAR staff and the ILAR Council developed an entirely new approach for revisions to the Guide to address these and other issues. Instead of a complete Guide revision by a consensus committee every decade or so, a new 5-year, 5-phase process was developed and approved by the National Academies whereby a new standing committee, the Standing Committee for the Care and Use of Animals in Research, would be established. With funding from external sponsors, the standing committee is not an advisory committee that will write a consensus report with recommendations for changes to the Guide; rather, it will provide a venue for the exchange of ideas and knowledge-sharing among those involved in scientific research and animal care and use in the academic, government, private, and non-profit sectors. The Standing Committee consists of 13 individuals (Table 5),^57,58 and its Statement of Task is as follows:

• Engage with the animal research stakeholder communities on a regular basis and monitor issues relevant to animal research and humane animal use by scientists in a variety of topical areas and settings, including but not limited to diverse research environments (eg, physical building laboratories, field laboratories, and other terrestrial or marine settings); various animal types (eg, wildlife, domestic, companion animals, pets, and other privately owned animals); and other special categories;

• Provide a forum to discuss issues related to the enhancement of animal well-being, the quality of research, and the advancement of scientific knowledge that is relevant to both humans and animals (eg, data availability, rigor, transparency and translatability to improve research involving animal models, institutional protocol reviews);

• Identify topics that may be considered for any future updates to the Guide and other related products;

• Provide a forum for a discussion of methods of implementing a phased, iterative review-revision cycle of scientific evidence that would have the potential of leading to timely updates of the Guide and other related products;

• Provide forums for discussions about distribution platforms for content of the Guide and related products that could strengthen the confidence in, timeliness of, and usability and accessibility of information by stakeholders around the world.

Among the first activities for the Standing Committee is convening various stakeholders to determine which areas covered by the Guide are in the greatest need of revision and identify any new areas that need inclusion. This is the phase of the process in which we find ourselves at the time of this writing. The next phase overlaps with the first and includes global webcast of free public workshops on 3–4 target areas, specifically for knowledge sharing and identifying knowledge gaps. The first workshop, entitled “Animal Welfare Challenges in Research and Education on Wildlife, Non-Model Animal Species, and Biodiversity,” was held in February of 2022. The workshop was organized and convened as a collaboration between the Standing Committee and the ILAR Roundtable on Science and Welfare of Laboratory Animal Use and served as the inaugural event for ILAR’s expansion into an exciting portfolio of activities involving wildlife, non-model animal species, and biodiversity.

As these workshops conclude, the Standing Committee will identify the most pressing issues for Guide revisions or new content based on phase 1 and 2 activities. The committee and staff will develop a statement of task for the first targeted consensus study, which will be separately approved by the leadership of the National Academies and separately funded. A separate consensus committee with relevant expertise and experience will be appointed to address the statement of task and author the report specifying recommendations for updates, revisions, and/or new content or products for the next edition of the “Guide on the Care and Use of Animals in Research.”

It is expected that this new approach will have multiple advantages over past revision efforts: (1) while the Standing Committee shepherds redevelopment of the Guide, the ILAR Council will be able to focus on other projects and topical areas; (2) more convening activities will enable stakeholders to be more continuously engaged with the Guide and note the sections of the Guide with which they have general or specific concerns; (3) revisions will be focused on those areas of greater concern; (4) sections of the Guide can thus be modified more rapidly than could be accomplished by a complete new edition; and (5) upon completion of revisions, the Standing Committee can immediately embark on other areas to revise, if necessary.

Through the efforts of the Standing Committee and the eventual authorship committees that will germinate from the proposed process, the Guide will be revised in a new and more focused manner and thus continue to be the respected resource that it has been for animal research professionals for the past 6 decades.

ILAR Conferences, Meetings, Workshops, and the ILAR Roundtable

ILAR-sponsored conferences, meetings, and workshops are often an initial activity of a new ILAR committee. These gatherings are designed for collection of information and perspectives leading to committee reports, guidance, and standards. One early area of ILAR focus was control of microbial contamination in laboratory rodent stocks. A series of meetings co-sponsored by ILAR beginning in 1959 were designed to show scientists how to adapt then-current techniques in germ-free technology to their investigations (eg, gnotobiotic workshops). These efforts led to the first attempts by commercial breeders to produce germ-free animals. Beginning in the 1990s the ILAR News and later the ILAR Journal identified participants in ILAR programs to recruit authors for manuscripts to be published together in individual issues (eg, themed issues). A list of early ILAR conferences, meetings, and workshops, including proceedings if available, can be found in Information on Laboratory Animals for Research (ILAR vols 1–9, 1957–1966) and in front- and backmatter in ILAR News (vols 10–36, 1966–1994) and ILAR Journal (vols 37–62, 1995–2022) (Supplemental Materials Tables 3 and 4), in previous publications by Hill (1980) and Wolfle (1999, 2003), and in Table 6 summarizing 2000–2022.^1,3,35

To more formally bring together individuals for the development of activities directly related to issues encountered in the field, ILAR developed the Roundtable on Science and Welfare in Laboratory Animal Use (ILAR Roundtable). The ILAR Roundtable concept was discussed at ILAR Council meetings in 2012 and brought for approval to the Executive Committee of the Governing Board of the National Academy of Science in January 2013.⁵⁹ The ILAR Roundtable is unique among ILAR programs in that individual institutions annually subscribe for membership, and member representatives discuss and prioritize topics for upcoming activities. Individual institutional members have always represented a combination of academic institutions, government agencies, non-governmental organizations, and corporate (frequently pharmaceutical) entities. Initially the ILAR Roundtable was led by its 2 founding co-chairs: Dr Steve Niemi, then with Harvard University, and Dr Lynn Anderson, then with Covance. In 2017 the roundtable leadership transitioned to a chair and co-chair, with other roundtable members comprising an executive committee. The chair and co-chair are elected by the roundtable membership and then appointed by the National Academies (RCD, personal communication).

The ILAR Roundtable organized twelve 1- or 2-day workshops (2014–2022) that collected experts from across the nation and around the world to give presentations on specific topics in an area of interest. The ILAR Roundtable aimed to host at least 1 workshop per year, and this has been accomplished except in 2020 due to the COVID-19 pandemic. Most workshops have featured in-person and webcasting components, except for those in 2021 and 2022, which were held entirely virtually. The list of ILAR Roundtable workshops and their related publications can be found in Table 7. Overall, the workshops have been positively received by their intended audiences and are now viewed as integral components of the success of ILAR by the ILAR Council, Roundtable, and staff.

ILAR Periodicals

Beginning in 1957 ILAR published quarterly “Information on Laboratory Animals for Research” (ILAR), which by the mid-1960s had several thousand subscribers worldwide.¹ Although not among the most widely cited publications today, ILAR (vols 1–9, 1957–1966), ILAR News (vols 10–36, 1966–1994), and ILAR Journal (vols 37–62, 1995–2022) provide first-hand and compelling descriptions and details of the expansion, evolution, and maturation of research using live animals in the United States and worldwide in the 20th and early 21st centuries (Supplemental Tables 3, 4; Table 8). No other set of Academy or any other professional publications provides such detailed primary source material for students, faculty, investigators, veterinarians, historians, ethicists, and IACUC members. The ILAR periodicals are literally a “time capsule” for present and future generations for evolution of animal research in the United States and internationally.

Information on Laboratory Animals for Research: Volumes 1–9 (1957–1966)

Information on Laboratory Animals for Research (ILAR) was produced quarterly as a typescript with whimsical hand-drawn illustrations (Figure 3a) and was generally under 15 pages in length. The first editor (Berton F. Hill) and artist (Letty V. Hill, Berton’s wife) were only disclosed in 1963. In the early years the ILAR was a clearing house of information on sources for specific species and strains, husbandry, diseases and veterinary care, training, workshops and symposia, professional organizations and activities, standards, recommendations, guidance, and advice. Standard features in ILAR included Legislative Activities (culminating in passage of the AWA and subsequent implementing legislation), ILAR Activities (eg, ILAR Advisory Committee, committees and sub-committees, leaders, and members), Recommendations and Guidance from ILAR committees and others, Notes from Abroad, and Publications. Publications were originally limited to those available from ILAR and expanded over time to include book reviews, review and recommendation of published research articles, annotated bibliographies, and much more. The ILAR contained very few “articles,” and those that were published tended to be short. Early examples are included in Supplemental Table 5.

The year 1966 marked the first time that the newsletter requested its readers to contribute information “in any area that you feel there has been an omission,” suggesting that the editor felt it necessary to actively solicit content for future issues.⁶⁰ Thereafter and until 1973 ILAR and ILAR News frontmatter specifically invited contributions for publication in the next issue, contributing to the diversity of ILAR and ILAR News contents. The January 1966 issue was the first to contain a black and white photographic image and a color illustration. The next issue [ILAR 9(3) 1966], and first edited by R.H. Yager and F.L. Judge, introduced a new blue mimeograph format (Figure 3a), a table of contents, and an increase to 21 pages. This and the following issue also introduced the first surveys of laboratory animal production and usage in 1965.^61,62

Publication of ILAR coincided with a period of unprecedented year-to-year increases and complexities of research animal usage reflecting rapid expansion of the United States and global biomedical research enterprise in the post-WWII period (Figure 4).

ILAR News: Volumes 10–36 (1966–1994)

Commencing with volume 10, ILAR was rebranded ILAR News, and the first issue announced the passage of the AWA (Figure 3B)⁶³  ILAR News adopted more of the organization of a professional scientific journal and increased issue page count to 40 or more pages per issue, with regular incorporation of featured articles and ILAR committee reports. The editors began to experiment with 2 or more articles on the same or similar theme and sometimes multiple themes covered in a single issue or extended over multiple issues. Articles published in ILAR News (1966–1996) are listed in Supplemental Table 6. ILAR News also published the full text of reports and guidelines from ILAR Committees and Editors from 1966 to 1996 (Supplemental Table 7).

In 1960 ILAR Council Chair George E. Jay Jr announced ILAR’s intention to initiate a survey of US laboratory animal production and usage.⁶⁴ ILAR and ILAR News subsequently published annual surveys of research animal usage conducted in 1965, 1966, 1967, 1968 (including animals used in gerontological research), 1969, 1970, and 1971.^65–71 Thereafter, the annual voluntary ILAR surveys were superseded by AWA-mandated US Department of Agriculture - Animal and Plant Inspection Service (USDA-APHIS) annual reporting of research animal usage. The USDA-APHIS scope was limited to reportable species, notably excluding laboratory mice, fish, and rats and other species that had appeared in the ILAR surveys.

After volume 29 (4) in summer of 1986, ILAR News did not publish volume 30 (1) until winter 1988 and thereafter published 3–4 issues per year through 1994. Themed issues of invited review articles began in the 1990s (Supplemental Table 8). Publication of the ILAR News coincided with a period of all-time peak year-to-year research animal usage, followed by precipitous decline in the latter decades of the 20th century. The decline reflected a transition to cellular and molecular models and technologies as the “backbone” of non-clinical biomedical experimentation and shifting of hypothesis testing to cellular and sub-cellular levels. However, new and unanticipated technologies, including manipulation of mammalian genomes for purposes of gene therapy and creation of transgenic animal strains (ie, MetaMouse, AngioMouse, Big Blue mouse and rat, Ras-1 mouse), were beginning to impact research animal usage (Figure 4).^4,5

ILAR Journal: Volumes 37–62 (1995–2022)

In 1995 beginning with volume 37, ILAR News was rebranded the ILAR Journal (ILAR J), published by the Academy and since 2013 by Oxford University Press. ILAR J completed the transition of ILAR communications from a newsletter to a professional scientific journal format, publishing 3–4 themed issues per year containing up to 10 or more solicited review manuscripts. The editorial board and ILAR Council members identified themes and issue editors. Issue editors and the editorial board then collaborated to identify topics and potential authors, and review manuscript outlines with the authors, prior to manuscript submission for peer review. Supplemental Table 4 includes contents of ILAR J volumes/issues 1995–2022. Supplemental Table 9 lists themed issues published from 1995 to 2022.

Publication of the ILAR J coincided with reversal of the decline in annual research animal usage statistics, driven by the advent of genetic engineering. This impact is apparent in comparison of annual USDA-APHIS and United Kingdom Home Office research animal usage statistics. The USDA-APHIS statistics exclude laboratory mice, rats, and fish and reflect 50% or greater decreases from peak levels and continued decline for all but 1 reported species (ie, nonhuman primates). The USDA-APHIS data could support a view that research using living animals is phasing out and no longer necessary in the 21st century. However, the UK Home Office statistics and ILAR J themed issues provide a very different perspective of evolving research capabilities and needs driven by genetic technologies predominantly involving mice, fish, and rats. The impact of genetic technologies almost totally reversed previous decades of decreases in total annual research animal statistics while primarily impacting only 3 vertebrate species (Figure 4).^4,5

The ongoing COVID-19 coronavirus pandemic and use of animals to elucidate COVID-19 virology and to identify and develop anti-viral agents and vaccines underscores the ongoing value of robust animal science expertise. Animal use data have reflected the impacts of novel technologies and disease challenges on demand for animals, expertise, and resources, which ILAR has been, and now BAHSCR will be essential to address.^72–75

ILAR’s themed issues benefitted from the expertise in ILAR committees, workshops, conferences, and council and editorial board. Thus, they became important resources for the scientific community, including investigators, veterinarians, and IACUCs. However, recruiting authors and managing production of 3–4 themed issues per year became increasingly challenging with contemporary publishing logistics; added pressures on authors, reviewers, and editors; and then the impacts of the global COVID pandemic. Further, the changing landscape of scientific publication, data management and integrity, and data mining and presentation all demand new strategies to maximize the utility of scientific resources for the scientific community. Thus, the ILAR J will be on hiatus while BAHSCR plans new options and opportunities for effective publication and communication with the scientific community.

ILAR Collaboration on Laboratory Animals

In 1956 ILAR joined with the United Nations Educational, Scientific, and Cultural Organization, the International Union of Biological Sciences, the Committee on International Organization of Medical Sciences, and other organizations to discuss international transportation, supply, and quality of laboratory animals. As a result of these discussions an International Committee on Laboratory Animals was formed to promote high standards of laboratory animal quality, care, and health. The committee was renamed the International Council of Laboratory Animal Science (ICLAS) in 1979.^31,32 ILAR’s relationship with ICLAS has been important for global dissemination of ILAR reports and ILAR’s continuing assistance to investigators in developing countries.

More recently, the National Academies and ILAR activities have emphasized the interdependence of human, veterinary, and environmental health. Since 2003 the Academies have supported collaborations including the One Health Action Collaborative, the Forum on Microbial Threats, and interactive workshops on One Health approaches to preparing for infectious disease outbreaks, mitigating the threat of food-borne pathogens, and countering the emergence of antimicrobial resistance genes.^76–79 Finally, over the past 13 years, the ILAR Journal has regularly featured scholarship focused on zoonotic pathogen transmission through livestock, insects, and humans, to the importance of animals as sentinels for the effects of global climate change.^80–86

SUMMARY AND CONCLUSIONS

ILAR was founded in 1953 on the premise that from human, animal, and public health perspectives a robust and state-of-the-art animal science and research capability was a national strategic imperative. The past 69 years have affirmed that these perspectives will remain relevant for the foreseeable future. Rebranding ILAR as BAHSCR reflects the evolution of animal science, conservation, and education, with the emergence of new scientific knowledge, new technologies and disciplines, and new challenges.⁸⁷

ILAR history from 1953 through 1980 is elegantly summarized by former Director and Editor B.F. Hill and recounts the rapid evolution of United States–based animal research from the province of individual investigators to an integrated national enterprise involving academic, government, and industrial constituencies.¹ This period witnessed unprecedented growth in research animal usage (Figure 4). The AWA of 1966 marked the beginning of US federal regulation of animal research.^48,88–90 Topics actively advocated by ILAR during this period are summarized by Hill (1980)¹ and detailed in author-attributed manuscripts published in ILAR and ILAR News, ILAR tasks and objectives (Table 2), and reports and statements of ILAR committees. Major accomplishments during this period include (1) support of the first standards for research animal care and use, leading to promulgation of the first edition of the ILAR Guide for the Care and Use of Laboratory Animals, currently in its eighth edition^48,54; (2) efforts to document research animal production and use prior to USDA-APHIS implementation of annual reporting in 1973; and (3) efforts to respond to shortages of rhesus macaques beginning in the 1950s contributing to formation of the US regional primate facilities. Indeed, current challenges in sourcing of cynomolgus macaques has resulted in formation of an ad hoc committee, “Solutions to Address the Critical Role of Nonhuman Primates Essential for Advancing Medical Research in the USA,” by the National Academies and led by ILAR (BAHCR).⁹¹

ILAR history from 1980 to 2000 is summarized by former Director T.L. Wolfle and recounts the maturation of ILAR as animal use declined in the latter decades of the 20th century, due in part to the rise of cellular and molecular research technologies and refocusing of the biomedical sciences away from the phenomenological (eg, bioassay) to more reductionist (eg, molecular mechanism) research approaches (Figure 4).^3,35 USDA-APHIS annual statistics document this dramatic decline for USDA sensitive species (not including mice, fish, and rats), whereas UK Home Office statistics document similar declines for all species.⁵ This period witnessed implementation of AWA amendments and the Health Research Extension Act of 1985 required new infrastructure, Institutional review of Animal Care and Use, USDA-APHIS oversight, mandatory annual reporting of selected vertebrate species, and further reporting to Office for Protection from Research Risks—then Office of Laboratory Animal Welfare—regarding PHS-funded animal research.^49,88–90 The sixth and seventh editions of the Guide had key roles in the understanding and implementation of the evolving guidance, legislation, and oversight.

During this period ILAR’s informational newsletter format transitioned to peer reviewed themed issues, first in the ILAR News and then in the ILAR Journal. Topics actively covered by ILAR during this period are summarized by Wolfle^3,35 and detailed in ILAR’s peer reviewed ILAR News and ILAR Journal and in reports and statements of ILAR committees.

In the 21st century ILAR has faced questions of the continued necessity, reliability, and value of animal research, fundamental issues of clinical translatability, research reproducibility, and application/implementation of non-animal alternative models. Authors posit that research reproducibility is not a new issue but an evolution of previous concerns from the previous century that led to (1) widespread use of scientific peer review; (2) recognition that research quality and animal welfare are inextricably linked and bidirectional;²⁹ (3) new organizations devoted to laboratory animal science, including ILAR; and (4) relevant guidance and legislation. COVID-19, the greatest and most destructive global pandemic in a century, demonstrated the value of “state of the art” observational and interventional capabilities using animals to drive acquisition of new scientific knowledge and the discovery and development of new therapeutic interventions while minimizing risk to human patients.^72–74

In saying good-bye to ILAR after 69 years, we welcome the new board and wish them continued success in these aims.

Acknowledgments

Authors acknowledge and thank the following for research and technical assistance in support of this manuscript: Audrey Thevenon, Fran Sharples, and Teresa Sylvina.

References

Author notes