It is often claimed that scientists and doctors are united in their belief in the value of, and necessity for, animal experiments to protect human health. This stream of quotes from scientists and doctors, stretching from as far back as the early 20th Century right up to today, shows that there has been a long tradition of scepticism about this issue. Many of the quotes are from scientists who support or conduct animal research; far from diminishing the impact of their words, this fact ought to give them extra weight.
Note: FDA stands for Food and Drug Administration, the US drug regulatory body.
Use of murine models to study the immunobiology of infectious diseases, such as malaria and herpes simplex virus, has severely skewed our understanding of immune control of these pathogens in humans, and it could be argued that over reliance on these model systems may have slowed progress in the development of effective vaccines against many human pathogens. Confidence in these model systems has eroded, as we now know that there are significant differences in human physiology and the immune regulatory pathways from these animal models. Indeed, clinical testing of the anti-CD28 monoclonal antibody TGN1412 illustrates this very well... In spite of these significant limitations, we continue to invest huge resources in conducting immunology studies using transgenic murine models, and many of our colleagues often feel highly defensive when questioned on the validity of their model systems... we hope our colleagues will join us in lobbying respective Governments and their funding agencies to invest in human immunology research, which will have important implications for human health... how long can we justify investing
millions of dollars of taxpayers’ funds on delineating the murine immune system, which in most cases has limited application for human diseases. (emphasis added)
Rajiv Khanna and Scott R Burrows, Australian Centre for Vaccine Development, Queensland Institute of Medical Research, Heston, Australia
Human immunology: a case for the ascent of non-furry immunology, Immunology and Cell Biology (2011) 89, 330–331; doi:10.1038/icb.2010.173
If you make a drug that's effective against HIV, sometimes it works against SIV and sometimes it doesn't. So that basically devalues SIV as an animal model for doing experiments involved with developing drugs…The slight problem (with using monkeys as an animal model for AIDS in humans) is the monkeys don't go on to develop AIDS, they don't get sick. Dr Paul Bieniasz of the Rockefeller University in New York. Quoted in Scientists make HIV that can infect monkeys, Reuters, 3rd March.
We've learnt a few important things [from the clinical trial]. We've learnt that one of the animal models, the SHIV [an artificial virus meant to mimic the human virus but capable of infecting monkeys] model, really doesn't predict very well at all. At least we now know that you can get a situation where it looks like you are protecting against SHIV and you're not protecting at all in the human model – that's important. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, quoted in the Independent, 24th April.
The following quotes are all taken from Catherine Guthrie, Putting Immunity in a Test Tube, Time, 27th March.
- In the end, you can only extrapolate so much from a monkey model. Wayne Koff, senior vice president of research and development at the International AIDS Vaccine Initiative.
- Best yet, researchers can test hundreds of different donors from a diverse genetic pool, a feat that's impossible to replicate with lab animals since they are bred to be genetically similar. "The information you get from this type of test is far and beyond what you'd get out of a mouse study, both because it's humans and because you can see the effect across a spectrum of genotypes." Michael Rivard, vice president of corporate development at VaxDesign.
- As things stand, it takes months for potential AIDS vaccines to graduate from small-animal trials to monkey studies. "That takes a lot of time, and, with HIV, we don't have a lot of time. We asked the question is there a way to do it faster and take it to humans more quickly?" Wayne Koff, senior vice president of research and development at the International AIDS Vaccine Initiative.
- Compared to what's available, MIMIC offers a dramatic increase in scale and speed, says Koff. "What's more, by collecting immune cells from different donors, promising vaccine candidates can be tested in diverse populations before they enter humans."
- From our point of view, [VaxDesign is] further advanced than anyone in the field in terms of tissue engineering and vaccine design. If they are successful it will revolutionize all of vaccinology. Wayne Koff, senior vice president of research and development at the International AIDS Vaccine Initiative.
- The possibilities for medical breakthroughs don't end at vaccines. VaxDesign hopes to use the MIMIC system to study autoimmune diseases... as well as inflammatory conditions. The aim is to better understand both how these diseases impact immune function as well as help design smarter drugs. Says Koff, "the opportunities are endless."
Many vaccines that are safe and highly immunogenic in mice have shown very little immunogenicity in humans and non-human primates. Weatherall, The use of non-human primates in research., Academy of Medical Science.
By enabling the assessment of immune reactions in a fully human system… we circumvent the limitations associated with the use of animal models… enabling our customers to run a more efficient drug development process – Dr Uwe Marx, co-founder of ProBioGen, ProBioGen news release 12 December 2007
Progress is further hampered by the lack of a reliable animal model to road test candidate vaccines. Monkeys with simian immunodeficiency virus (SIV) are the lab rats of HIV vaccine research, but important differences between monkeys with SIV and humans with HIV have misled researchers at least once. The gp120 vaccine worked well in chimpanzees. When it comes to testing HIV vaccines, only humans will do. Tonks, British Medical Journal, 334;1346-1348.
While we find the Adeno Associated Virus study... very interesting and we'll consider whether it can inform our future studies, their study was conducted in mice and there are fundamental differences between mice and humans in their respective immune responses, particularly with regard to the immune response against HIV. Dr Pat Fast of the International AIDS Vaccine Initiative. (Fox, Reuters, 11/15). http://aidswarning.blogspot.com/2007/11/several-vaccine-trials-affected-by-halt.html
Mice lie, monkeys sometimes lie, and humans never lie. Some monkeys have lied to us this time. Peggy Johnston, head of NIH’s AIDS vaccine program, quoted in: AIDS Research: Did Merck's Failed HIV Vaccine Cause Harm? Cohen, Science, 318: 1048-1049.
"Animal models are not suitable for predicting the immunogenicity of therapeutic mAbs in humans, and transposition of the immunogenic potential of therapeutic antibodies in animals to the human situation has no scientific rationale, even in primates" - Loisel, S., M. Ohresser, M. Pallardy, D. Dayde, C. Berthou, G. Cartron, and H. Watier. 2007. Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit Rev Oncol Hematol 62 (1):34-42
"The relevance of animal testing, whether artificially created disease models or healthy animals for toxicology, has to be very seriously questioned for testing of human-specific biologic drugs," notes immunotherapeutics expert David Glover. "That's one of the key lessons of TGN1412." Peter Mitchell, Nature Biotechnology 25, 485 - 486 (2007)
The more we learn about the immune system, the more we realise that the mouse is not a good model for humans. This mismatch may be a particular problem with CD28, where there is little or no cross reactivity between a human antibody and the mouse immune system. Dr Camilo Colaco, quoted in The Telegraph, 13th March 2006.
(Some scientists) question whether cynomolgus monkeys were an appropriate species for preclinical TGN1412 safety studies and refer to differences in the primary structure of human and rhesus monkey CD28. However, TeGenero chose cynomolgus monkeys, rather than rhesus monkeys, because the aminoacid sequences of the extracellular and intracellular domains of cynomolgus monkey CD28 are 100% identical to those of the human molecule. The Lancet 2006; 368:1387-1391.
Safety of drugs in animals can never guarantee the same for humans. Khan & Rodrigues, rapid response to Goodyear, Learning from the TGN1412 trial, British Medical Journal, 332: 677-678.
Whilst it is plausible that the development of a humanised monoclonal antibody might not be recognised in lower animals, no stone should be left unturned in the search for the cause of the alleged cytokine storm at Northwick Park. Apart from the species difference between humans and the animals used for testing TGN1412, there would also have been a huge difference in the background diets between the humans and the test animals, and hence immune behaviour which should not be overlooked in the search for answers. Indeed from what we know about the cell membrane and the lipid domains for the receptors, the binding of these antibodies to a specific part of the CD28 or indeed to other molecules would be expected to be influenced by the membrane lipid domain which will be very different in a human and a rat. Michael Crawford, rapid response to Goodyear, Learning from the TGN1412 trial, British Medical Journal, 332: 677-678.
...animal studies, even those conducted in non-human primates, have limited predictive power for immunogenicity in humans. Bugelski and Treacy, Current Opinions in Molecular Therapeutics, 6:10-16.
...it was generally accepted that predicting human immunogenicity, even in non-human primates was rare and thus, the predictive power of preclinical immunogenicity is low. Bugelski & collaborators from Centocor, US FDA, GlaxoSmithKline, Amgen & Pfizer. Predictive Power of Preclinical Data for Human Immunogenicity of Macromolecules: Proceedings of a Roundtable Discussion. (Discussion sponsored by the Immunotoxicology Technical Committee Health & Environmental Sciences Institute/ International Life Sciences Institute)
The discussants also felt that transgenics, SCID-human reconstituted and knock-out mice should be used with caution. Concern was expressed that use of a “manipulated system” can yield “manipulated data” of potentially little relevance to clinical immunogenicity. Bugelski & collaborators from Centocor, US FDA, GlaxoSmithKline, Amgen & Pfizer. Predictive Power of Preclinical Data for Human Immunogenicity of Macromolecules: Proceedings of a Roundtable Discussion. (Discussion sponsored by the Immunotoxicology Technical Committee Health & Environmental Sciences Institute/ International Life Sciences Institute)
If you want your vaccine to work in a human, you’d better get it into a human, quickly. Otherwise you’re going to spend a lot of time with animal studies and never be able to predict what it will do in people. Prof. Bob Edelman, June 2002. http://www.antigenics.com/whitepapers/qs21_adjuvant.html
A few labs have been plugging away for years to develop cheap, malleable animal models for AIDS, say, a rat or a mouse, to help speed up research, but HIV stubbornly refuses to infect animals other than humans and chimpanzees. Recent findings have brought the goal closer, but some AIDS researchers remain skeptical that it can be done. Some even argue that the whole effort is an exercise in futility, because by the time researchers engineer both the animal and the virus to produce a model, it will no longer bear enough resemblance to the actual disease. Jon Cohen, Science, Vol. 293. no. 5532, pp. 1034 – 1036.
More recently, researchers have used much more plentiful and cheaper rhesus macaque monkeys, originally from India. These monkeys develop an AIDS-like disease when infected with either SIV, a simian cousin of HIV, or a laboratory-made SIV/HIV hybrid called SHIV. The monkey model is a big improvement, but it has serious drawbacks of its own: SIV and SHIV are not HIV, one animal costs up to $5000, breeding takes years, and now Indian rhesus macaques are in short supply (Science, 11 February 2000, p. 959). Jon Cohen, Science, Vol. 293. no. 5532, pp. 1034 – 1036.
Some researchers even argue that the whole effort is an exercise in futility. “They’re wasting their time,” says Malcolm Martin of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), who once worked on the mouse model. By the time researchers engineer both the mouse and the virus to produce a model, he says, “you’re going to wind up with an animal that’s no longer a mouse or a virus that’s no longer HIV.” Jon Cohen, Science, Vol. 293. no. 5532, pp. 1034 – 1036.
One must be aware of the many limitations of using laboratory animals to model infectious processes… limited genetic diversity; one must recognize that observations made in a group of nearly isogeneic hosts with a single or a few strains of a specific pathogen may not represent the actual disease process seen in [human patients]. Few animal models are exact duplicates of human infection.” Handbook of Animal Models of Infection (publ. Academic Press), p9-10.
Up to this very day, all infectious diseases affecting humans are far from having appropriate animal models and, even in those cases where such infections are possible, the symptoms observed in animals and the course of the disease are often very different from those encountered in humans.” Handbook of Animal Models of Infection (publ. Academic Press), p7.
The pharmacokinetics of antibiotics in experimental animals can often differ markedly from those of humans. This is a consequence of differences in absorption, distribution, metabolism and excretion. Handbook of Animal Models of Infection (publ. Academic Press).
What good does it do you to test something [a vaccine] in a monkey? You find five or six years from now that it works in the monkey, and then you test it in humans and you realise that humans behave totally differently from monkeys, so you've wasted five years. Dr. Mark Feinberg, leading AIDS researcher and now director of pharmaceutical company Merck's HIV vaccine development, Atlanta Journal Constitution, 21st September.
The fact that most of the existing animal models in vaccine potency are artificial, poorly understood, and in fact do not always reflect vaccine-induced protective immunity in humans is all too often overlooked. Many of the traditional [animal] tests are highly variable, despite the use of a reference preparation, and the relevance of these tests may be questionable. Dr. Hendrickson, Lab Animal March, p24-30.
The critical events in the progression of AIDS occur in human lymphoid tissue... Primary cultures and cocultures of isolated cells cannot mimic the full cellular repertoire within lymph tissue, nor their functional relationship to lymphoid tissue structures. Animal models do not fully mimic the characteristic tissue pathology of human HIV infection. For this reason, we have developed a tissue culture method that retains the complex three-dimensional spatial, cellular organization found in normal human lymphoid tissue. Science, vol. 256, p 1630-1631.
Candidate antivirals have been screened using in vitro systems and those with acceptable safety profiles have gone directly into humans with little supporting efficacy data in any in vivo system. AIDS research and human retroviruses 8: 349-356.
I think we've already waited too long. The sooner we beging testing on humans, the sooner we'll hopefully be able to develop a vaccine. Dr. Allan Goldstein, George Washington University Medical Center, quoted in U.S. Said to Back AIDS Vaccine Test on Humans, the New York Times, 18th August 1987.
The immunological system too shows species differences which may have a role in the immunotoxic or immunostimulant effects of chemicals. Silvio Garattini, Toxic Effects of Chemicals: Difficulties in extrapolating data from animals to man, Critical Reviews in Toxicology, vol 16, issue 1, p1-29.
Work on prevention [the vaccine] was long delayed by the erroneous conception of the nature of the human disease, based on misleading experimental models of the disease in monkeys. Inventor of the polio vaccine, Albert Sabin MD. Statement before the subcommittee on Hospitals and Health Care, Committee on Veterans Affair’s, House of Representatives, April 26, serial no. 98-48.