Abbie Lathrop, Baruj Benacerraf, Biomedical research animal use, Charles Hume, David Henry Smyth, Frank Ruddle, George Davis Snell, Gregor Mendel, Guide for the care and use of lab animals, Jean Dausset, John Gordon, Mario R. Capecchi, Martin J. Evans, Oliver Smithies, Rex Burch, William Russell
Tirumalai Kamala’s answer:
Based on my knowledge of current biomedical research enterprise, the picture is not one of cooperation and collaboration so much as of co-option. Today Medicine and Veterinary science are deeply intertwined, and have been since at least the 1950s. In fact, Medical + Veterinary fields = Modern biomedical research. OTOH, pragmatism has led to Botany + Medicine = Transgenic plants for new generation of edible biopharmaceuticals and vaccines for humans.
Over the last 60 years biomedical research animal use has expanded greatly, use that’s codified and regulated by a vast bureaucracy within which veterinarians are essential, albeit co-opted, gatekeepers. Why co-opted gatekeepers ? It’s not they but scientists who control the biomedical research agenda. Though gatekeepers mandated by federal regulations, over the decades veterinarians have become consigned to the role of rubber-stampers. Today, biomedical scientists and veterinarians have to work together. Consider for example toxicology, the science of adverse effects of chemicals on living things. All these new chemicals we’ve been using since the last century. How could we surmise if they are safe for us, other animals and the environment? Before unleashing them on ourselves, we tested them on lab animals for developmental and reproductive toxicity, how else? Rodents as well as non-rodents.
What’s the process for using animals in research? First, let’s outline why we use animals in research. Second, a brief summary of the numbers. Third, processes behind the numbers. Fourth, history, and fifth and finally, limitations and conflicts of interest of this vast bureaucracy that illustrate how veterinary science has been co-opted to service modern biomedical research.
I. Why do we use animals in research?
- By gradual societal consensus over the course of the 20th century, we can no longer directly experiment on ourselves. We need to first test on ‘lower’ animals.
- To understand basic biology. e.g. mouse, rat, zebra fish, nematode (Caenorhabditis), fruit fly (Drosophila).
- To develop animal models of human disease. e.g. mouse, rat, zebra fish.
- To develop drugs and vaccines for human and animal use. e.g. mouse, ferret, rat.
- To develop novel surgical procedures. e.g. pig, sheep.
- To develop and test new medical devices. e.g. pig, sheep.
- To culture pathogenic microorganisms that can’t be cultured in vitro. e.g. nine-banded armadillo for Mycobacterium leprae.
- To assess toxicity of drugs, vaccines, chemicals and other consumer products. e.g. mouse, rat.
- In education and training. e.g. in schools, colleges, medical and veterinary schools.
II. Research animal use by the numbers.
- Of 103 Nobel prizes in Physiology or Medicine, 83 involved non-human vertebrate animal research (1).
- No accurate numbers, only extremely rough estimates. Likely huge under-estimate.
- Data incomplete. Excludes animals used for breeding, surplus animals that are culled, multi-year use of same animal used in long-term experiments such as carcinogenicity or two-generation reproductive toxicity.
- US is far and away largest user of research animals. Next Japan and Great Britain.
- Official US numbers are extremely unreliable since they exclude mouse, rat, fish, reptile, amphibians. In short, most animals used in research and toxicity testing!
- In the US, >90% of research animals are mice and rats.
- In the EU, ~80% are rodents, ~10% are fish, amphibians and reptiles, and ~6% are birds (2).
- EU’s ultimate goal is full replacement of animal experiments (3).
- The Humane Society of the US (HSUS) hopes for full replacement by 2050 (4).
- With all the above caveats, Taylor et al (5, see below) conservatively estimate (very loosely) more than 115 million research animals among 179 countries for the year 2005.
III. Research animal use process
I’m most familiar with the US process so I’ll elaborate on that.
- The mission of USDA (US Department of Agriculture), in particular USDA-Aphis (Animal and Plant Health Inspection Service) is ‘To ensure that animals intended for use in research facilities or for exhibition purposes or for use as pets are provided humane care and treatment’.
- However, USDA monitors less than 10% of federally-funded research animal use, namely pigs, rabbits, guinea pigs, hamsters, goats, sheep, cattle, horses, dogs and cats.
Public Health Service Policy
- Oversees all research animal use, especially rodents (mice and rats), which comprise >90%.
- Entities that receive federal funding for animal research commit to follow the Guide for the Care and Use of Laboratory Animals (The Guide).
- Such entities need to submit an Assurance statement to the Office of Laboratory Animal Welfare (OLAW).
What’s the Guide?
- A 220-page booklet (6).
- Defines an animal as ‘any vertebrate animal used in research, teaching or testing’.
- Outlines research animal housing requirements, facility operations and veterinary care.
- Outlines the Institutional Animal Care and Use Committee (IACUC) setup and procedure.
The IACUC (Institutional Animal Care and Use Committee) process
- Authorized by federal law under auspices of USDA and OLAW to oversee research animal use, procedures and facilities.
- Reviews all research animal use protocols.
- Research with animals can only proceed with IACUC approval.
- Inspects research animal facilities at least annually if not more frequently.
- Should at minimum comprise a veterinarian, scientist and community member (non-scientist).
- At least one member should be outsider, i.e. not employed/affiliated with the entity.
- Animal use protocols reviewed annually.
- Protocol updates and revisions also require IACUC approval.
AAALAC(Association for Assessment and Accreditation of Laboratory Animal Care, International).
- Full accreditation by AAALAC is the goal of every US research animal facility.
- Why? AAALAC Accreditation is the perceived gold standard for research animal use.
- So what is AAALAC? A non-profit organization that peer reviews research animal care and use programs.
- At each accredited site, AAALAC teams perform site inspection and program evaluation every 3 years.
IV. Research animal use history
Discoveries and techniques that enabled increasing research animal use
- Domesticated rat, Rattus norvegicus, has been used since at least 1828. Half of lab rats used today descend from the Wistar rat, the first standard rat strain developed in 1909 (7, 8).
- Domesticated mouse, Mus musculus, was famously used by Gregor Mendel in his heredity studies of coat color, only switching to peas when admonished by his local bishop that mouse rearing was inappropriate for a priest (9).
- pioneered the use of mouse in study of Mendelian genetics.
- In early 20th century, mouse fanciers like Abbie Lathrop (10) made inbred mouse strains easily available to scientists.
- Inbred mouse strains proved valuable genetic tools especially in the discovery of histocompatibility genes ( ) for which , and were awarded the 1980 .
- In 1980 John Gordon and Franck Ruddle developed the first transgenic mouse (11).
- In 2002, the mouse became the second mammal, after humans, to have its whole genome sequenced.
- Mario R. Capecchi (born 1937), Martin J. Evans (born 1941), and Oliver Smithies (born 1925) developed the first gene knockout mouse model in 1988, and received the 2007 Nobel Prize for Physiology or Medicine ( ).
- 5, 6, 7, 8 plus new technologies exponentially accelerated mouse model gene function studies. Today mouse is the most commonly used animal model (12, 13).
How did our current structure of research animal use come to be?
- In the UK, the Universities Federation for Animal Welfare first published its Handbook on the Care and Management of Laboratory Animals in 1954.
- The organization’s founder Charles Hume commissioned zoologist and polymath William Russell (1925–2006) and microbiologist Rex Burch (1926–1996) to develop a guide for humane techniques in animal experimentation (14, 15, 16).
- Russell and Burch developed the tenet of the “Three Rs”—Replacement, Reduction, Refinement (17). They proposed that ‘humane science’ is the ‘best science’.”
- Replacement: ‘any scientific method employing non-sentient material [to] replace methods which use conscious living vertebrates’.
- Reduction: ‘the number of animals used to obtain information of a given amount and precision.
- Refinement: ‘decrease in the incidence or severity of […] procedures applied to those animals which have to be used’.
- Russell and Birch also proposed that well-being of laboratory animals is a basic requirement for the quality of science (14).
- Russell and Burch’s proposal was largely ignored until 1978 when physiologist David Henry Smyth (1908–1979) aligned the 3R concept with the notion of alternatives (18) defined as ‘all procedures which can completely replace the need for animal experiments, reduce the numbers of animals required, or diminish the amount of pain or distress suffered by animals in meeting the essential needs of man and other animals’ (19).
- Since Smyth’s revision, research animal users have to justify their research animal use with compelling evidence (20).
- Today, the 3Rs provide the framework for research animal use.
- Philosophically, research animal use hews to ‘s patriarchal Welfarist/Utilitarian rather than ‘s Abolitionist stance. Thus, while we grant research animals tenuous protection from suffering, we use them as means to our end because we consider our well-being more important than theirs.
- Unfortunately for animals, the current bureaucratic structure of modern scientific enterprise took shape prior to our improved understanding of cognitive and emotional capabilities of animals (21) while human society itself has undergone a profound shift towards animals from utilitarian expedient to almost or indeed sentient (22).
V. Research animal use limitations and conflicts of interest
- Are research animals effective and predictive for human disease outcomes? A slow and steady drip-drip-drip of evidence now makes us seriously question this (23, 24, 25, 26, 27, 28, 29, 30, 31, 32). The >90% failure rate of new drugs during the development process from pre-clinical (mouse) to human shows the current chain of human drug development from mouse to non-human primates to humans is seriously flawed.
- Inertia and apathy attendant to bureaucracy means we continue to use outmoded tests that cause research animals unrelieved pain and distress which we can only explain away disingenuously. Case in point? Rabies vaccine. Each and every batch of every vaccine has to be tested for its effectiveness and safety before it can be released for use. This is the potency test. For rabies vaccine, we continue to use a 60-year old animal potency test called the NIH test. Flawed at many levels: highly variable (up to 400%!); infected animals suffer severe pain and distress; safety risk to lab staff; lengthier than newer alternatives. There are at least two newer alternatives that greatly minimize animal pain and distress and are much more reliable. Yet the NIH test for rabies vaccine potency remains the required regulatory gold standard (33). Why?a) The current generation of regulators was trained 20 to 30 years back when the motto was ‘in vivo veritas’ (truth in living things). This mindset engenders discomfort with alternatives to animal models.b) a 3R model is not merely a technology change but also change in regulations, infrastructure and end-user practices.
c) The ‘validation challenge’, i.e. the regulatory mindset that the newer 3R model be compared to conventional animal model. In most cases, the two are incomparable.
d) Not science-driven. Rather fear of litigation drives risk avoidance behavior among regulators. Result? When in doubt fall back on custom and practice.
Botany + Medicine = Transgenic plants for new generation of edible biopharmaceuticals and vaccines. What’s the process?
See figure 1 in reference 34.
On May 1, 2012, the US FDA approved carrot-cell produced glucocerebrosidase (GCD), commercially called ELEYSOTMfor treating Gaucher’s disease (35).
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- Stephens, M.L. Pursuing Medawar’s challenge for full replacement. ALTEX Proc. 2012, 1, 23–26.
- Taylor, Katy, et al. “Estimates for worldwide laboratory animal use in 2005.” (2008).
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- Daniell, Henry, et al. “Plant-made vaccine antigens and biopharmaceuticals.” Trends in plant science 14.12 (2009): 669-679.
- FDA. FDA approves new orphan drug to treat a form of Gaucher disease.
- Chen, Qiang, and Huafang Lai. “Plant-derived virus-like particles as vaccines.” Human vaccines & immunotherapeutics 9.1 (2013): 26-49.