Guest Post: Animal models in research are necessary and ethical

The following post was originally published in The Daily of the University of Washington on April 26, 2015. It has been reproduced with permission from the newspaper and the original author. Benjamin Cordy is a neurobiology student at UW, he is also the Editor-in-Chief of Grey Matters Journal – an undergraduate neuroscience journal whose mission is to educate the public and develop effective science communicators.

Guest editorial: Animal models in research are necessary and ethical

On Saturday hundreds gathered in Red Square to voice their opposition to scientific research. At its core, this is the true message of the animal rights movement, which believes that research should never rely on animal models. The march on UW was about stopping science altogether. Is this really the best move for society?

Debates about animal models in research are emotional, contentious, and unfortunately, often fraught with demonstrably false “facts.” This is a serious problem. It is impossible to have a thoughtful conversation about the role of science and medical research in society if a position is based on misinformation and inaccurate beliefs.

Two of the most frequently repeated claims of the animal rights movement are that animal models are not actually useful in science and that there are more effective, humane ways to engage in research. While appealing, both statements are wrong.

The history of science provides countless examples of the utility of animal research. For example, until as recently as 1940 and the development of the “antibiotic age”, a knee scrape, if it became infected, could be a death sentence.

In 1928 Alexander Fleming discovered that when grown in proximity to one another, the mold Penicillim notatum killed the colonies of the often-fatal bacteria Staphylococcus aureus. Unfortunately, Fleming’s test-tube studies failed to show the antimicrobial properties he expected from Penicillin. These results, and the difficulty of isolating Penicillin, ultimately led Fleming to believe that it might only be useful as a topical antiseptic.

Although Fleming’s work showed some promise, Penicillin was not a high priority for antimicrobial researchers. In addition to being very difficult to isolate, its therapeutic properties seemed to be inactivated in blood — making it a poor candidate for treating systemic infections. But by 1940 enough Penicillin was isolated for testing. In a landmark study Ernst Chain and Howard Florey infected eight mice with a deadly dose of Streptococcus pyogenes. One hour later, four of the mice were injected with Penicillin. These mice survived the infection and changed modern medicine forever.

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(Left to Right) Alexander Fleming, Howard Florey and Ernst Chain – Shared the Nobel Prize for Physiology or Medicine in 1945

The amount of Penicillin required to treat a human infection is 3,000 times greater than for a mouse. If animal models were unavailable to Chain and Florey, they would have had to undergo the perfectly unreasonable task of isolating huge quantities of a substance that, as far as they could understand, had no therapeutic value. Simply put, without animal models Penicillin would not have been developed.

Fortunately, the story of Penicillin is not unique. There are literally thousands of medical interventions, drugs, and procedures whose discovery and development required the use of research animals. Modern therapies that require animal models include: vaccines, organ transplants, cancer treatments, HIV/AIDS drug development, and thousands more. The claim that animal models are “bad science” and fail to provide important insights into biological understanding and therapeutic development is dishonest and wrong.

The second position of the animal rights movement is that there are alternatives that are simultaneously more effective and humane. The three most often suggested alternatives are human cell cultures, computer models, and experimentation on human subjects.

Tissue and cell culture experiments are extremely powerful research techniques. Their use provides important insights into the function of individual cells and helps identify potential targets for future therapeutics. However, these studies, by their very nature, can only reveal a fraction of the whole picture. For example, a few cells could never describe the complexity of an entire organ — much less the entire organism. Though important for reducing the number of animals used, these techniques could never replace them.

Computational techniques are another tremendously valuable tool. With mathematical models and data analysis, computers allow researchers to better understand the systems they study. But again, computation is a supplement to animal research, not a replacement. Every computer model has to be validated against data collected from animal research. There is no other way to ensure that a modeling program is accurate.

Furthermore, animal rights activists overestimate the power of computer models. In 2007 researchers were able to simulate a virtual brain of 8,000,000 neurons, roughly the complexity of half a mouse brain. While impressive, this is less than 1/10,000th the number of neurons in a human brain and likely much less complex. The simulation ran on the fastest supercomputer and could only do so for 10 seconds at 1/10th the speed of a real brain. In all, this program required the world’s most powerful supercomputer to model one second of one half a mouse brain. How could a desktop PC possibly predict the behavior of the human brain?

The most troubling alternative proposed by animal rights activists is the use of human volunteers for basic science. In practice, such policies would effectively halt biomedical research. For one, the cost of recruiting and paying human subjects would bankrupt already sparse science funding within months. This of course, assumes that enough people volunteer to participate. Considering that clinical researchers already have difficulty in recruiting people for fairly benign studies, it is highly improbable that eight people would volunteer to receive a deadly dose of Streptococcus pyogenes, for example.

Beyond the practical limitations of using only human subjects, there are serious questions about the morality of doing so. Which population is likely to accept payment for becoming test subjects: the socioeconomically disadvantaged or the wealthy? The argument that humans ought to replace research animals raises real concerns about the exploitation of disadvantaged communities.

It was not long ago that I was sympathetic to some of the positions of the animal rights activists. But, as I learned the science behind biomedical therapeutics, it became clear that because animal models save millions and millions of lives, they are necessary. A powerful research program, which includes the use of animal models, is the responsibility of an ethical society.

Benjamin Cordy, UW neurobiology student

18 responses to “Guest Post: Animal models in research are necessary and ethical

  1. They are mainly used during the research and investigation of human disease, in order to help researchers understand the physical mechanism in a better way and then discover more effective clinical applications for current diseases.

  2. it’s one of the most persuasive articles that why animal model is important and not such inhumane as some people claimed. What’s worth to mention is that a new kind of drug screening tech can replace animal models in some researches.

  3. So, tell me Tom…

    Jack Botting’s book is a peer reviewed source?

    Jonathan Morris (Ph.D.) is ”clearly a massive antivivisectionist”? Really?Even Bernice Shacter (Ph.D.) and Kary B. Mullis (Nobel Prize winner)? https://koleksibuku191177.files.wordpress.com/2015/03/jonathan_morris_the_ethics_of_biotechnologybookos-org.pdf

    I think that a scientific evidence is a ”super partes” truth.

    So, we have different sources about penicillin and congenital abnormalities in rats:

    1. Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109. (peer reviewed source)

    2. Liangli Yu et al. Food Safety Chemistry: Toxicant Occurrence, Analysis and Mitigation. CRC Press, 28 ott 2014

    3. Jonathan Morris (Ph.D.). The Ethics of Biotechnology. Infobase Publishing, 2006

    4. New Scientist 17 gen 1963:

    ”Even antibiotics, such as penicillin, tetracycline and streptomycin are know to cause congenital abnormalities in rats: this has been demonstrated by Professor B. Filippi of Turin.”

    5. Persaud, T, V, N. (MD, PhD, DSc, MRCPath, F ACOG. Professor of Anatomy and Director, Teratology Research Laboratory, University of Manitoba; Consultant in Teratology and Pathology, Health Sciences Centre, Winnipeg, Canada). Problems of Birth Defects. From Hippocrates to Thalidomide and After (1977). MTP Press Limited, St Leonard’s House. Lancaster, England:

    ”Table 1 – some drugs and other chemicals shown to be teratogenic in one or more species of laboratory mammals:

    antibiotics: Chloramphenicol, streptonigrin, penicillin.”

    And don’t forget what Fleming and Florey have says:

    ”How fortunate we didn’t have these animal tests in the 1940’s, for penicillin would probably never been granted a license, and possibly the whole field of antibiotics might never have been realized.”

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    van Meer, P. J. K. et al. The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals. Eur J Pharmacol. 2015 Jul 15;759:3-13. doi: 10.1016/j.ejphar.2015.02.055. Epub 2015 Mar 27.

    ”Mice were used in the initial toxicity tests because of their small size, but what a lucky chance it was, for in this respect man is like the mouse and not the guinea-pig. If we had used guinea-pigs exclusively we should have said that penicillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for trial in man.”

    Florey, H. (1953) The advance of chemotherapy by animal experiment.
    Conquest 41: 12.

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    ”We present penicillin as an example. The introduction and success of penicillin as an antibiotic have been attributed by its inventors to the lack of a toxicological response in mice, which then translated successfully to most other mammals and humans. In contrast, had guinea pigs or hamsters been used for toxicity evaluation, the severe toxicity of penicillin in those species would have probably halted any further development. Nowadays we know that the toxicity in these species is related to species-specific adaptations of highly penicillin-susceptible gut flora.”

    (van Meer et al. 2015)

    ”Animal models – represent nothing more than an extraordinary, and in most cases irrational, leap of faith.”

    Horrobin, D, F. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat Rev Drug Discov. 2003 Feb;2(2):151-4.

    I couldn’t have said it better.

    • You’re missing the point. None of the links you provided actually went to a paper where experiments were done to show teratogenic effects in rats from penicillin. The links just asserted it was true (and the root source of Demain and Sanchez didn’t even mention the issue).

      I have no idea about Karen Mullins (who wrote the forward – what’s your point?!) or Shacter (who was editor, not resident fact checker).

      Let’s go through your supporting evidence:
      1. Greek – No evidence to support claim
      2. Liangli Yu – No evidence to support claim (the provided link doesn’t discuss teratogenics to rats at all)
      3. Morris – No evidence to support claim
      4. New Scientist – No evidence to support claim
      5. Problems of Birth Defects – No science to support claim – supporting source is “Wilson’s Environment and Birth Defects” – there is also no indication of what species it is teratogenic to.

      Your repeated, and already addressed, quotes are getting cumbersome and boring. These points have been addressed.

  4. And here you can read about penicillin and teratogenic effects in rats:

    Liangli (Lucy) Yu, Shuo Wang, Bao-Guo Sun. Food Safety Chemistry: Toxicant Occurrence, Analysis and Mitigation. CRC Press, 28 ott 2014

    Jonathan Morris. The Ethics of Biotechnology. Infobase Publishing, 2006

    (Demain & Sanchez, 2009)

    • You REALLY need to start reading your sources.

      Liangli et al’s book states there are teratogenic effects, using Demain and Sanchez as evidence, but Demain and Sanchez (2009) doesn’t have ANYTHING about rats, or teratogenicity in it (read it here: http://www.researchgate.net/publication/23766836_Demain_A._L.__Sanchez_S._Microbial_drug_discovery_80_years_of_progress._J_Antibiot_%28Tokyo%29_62_5-16)
      It would appear that Liangli (et al) simply uses the reference to evidence that antibiotics are used in agricultural products. Ultimately – they provide no evidence for their claims on teratogenicity.

      Jonathan Morris (who is clearly a massive antivivisectionist) also makes the assertion without any supporting evidence (not even an incorrect reference this time).

      Neither book produces any evidence. Neither book is peer reviewed. Nowhere in your links can I “read about penicillin and teratogenic effects in rats” – I can simply read a single sentence which states it. I would hazard a guess that the authors have been stung by some erroneous original reference somewhere which has spread.

  5. I’m sorry, Fleming have says this:

    ”How fortunate we didn’t have these animal tests in the 1940’s, for penicillin would probably never been granted a license, and possibly the whole field of antibiotics might never have been realized.”

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    van Meer, P. J. K. et al. The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals. Eur J Pharmacol. 2015 Jul 15;759:3-13. doi: 10.1016/j.ejphar.2015.02.055. Epub 2015 Mar 27.

    This is what Florey have says:

    ”Mice were used in the initial toxicity tests because of their small size, but what a lucky chance it was, for in this respect man is like the mouse and not the guinea-pig. If we had used guinea-pigs exclusively we should have said that penicillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for trial in man.”

    Florey, H. (1953) The advance of chemotherapy by animal experiment.
    Conquest 41: 12.

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    ^_^

  6. Yes, i read the sources that i cited. Did you Tom?

    ”The possibility remained that guinea pigs are more susceptible than other animals.”

    Hamre, D M, Rake, G, McKee, C M and MacPhillamy, H B (1943) The toxicity of penicillin as prepared for clinical use. Am. J. Med. Sci. 206 642-52.

    Maybe because there are fundamental biological differences between animal models and humans?

    Mak, I.W.Y. et al. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014; 6(2): 114–118. Published online Jan 15, 2014.

    Sriram, S. & Steiner, I. (2005) Experimental allergic encephalomyelitis: A misleading model of multiple sclerosis. Ann Neurol. Dec; 58(6): 939-45.

    Lai, M. et al. You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes. Nature Nutr Diabetes. 2014 Sep 8;4:e135. doi: 10.1038/nutd.2014.30 .

    Langley, G, R. Considering a new paradigm for Alzheimer’s disease research. Drug Discov Today. 2014 Mar 21. pii: S1359-6446(14)00090-7. doi: 10.1016/j.drudis.2014.03.013.

    This is why animal models are poor predictive systems for human outcomes:

    https://commonfund.nih.gov/regulatoryscience/meeting100112/index

    Greek & Hansen are a peer reviewed source, it’s right?

    I know (and remember) what Fleming have says about the value of animal models:

    ”Mice were used in the initial toxicity tests because of their small size, but what a lucky chance it was, for in this respect man is like the mouse and not the guinea-pig. If we had used guinea-pigs exclusively we should have said that penicillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for trial in man.”

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    van Meer, P. J. K. et al. The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals. Eur J Pharmacol. 2015 Jul 15;759:3-13. doi: 10.1016/j.ejphar.2015.02.055. Epub 2015 Mar 27.

    ”We present penicillin as an example. The introduction and success of penicillin as an antibiotic have been attributed by its inventors to the lack of a toxicological response in mice, which then translated successfully to most other mammals and humans. In contrast, had guinea pigs or hamsters been used for toxicity evaluation, the severe toxicity of penicillin in those species would have probably halted any further development. Nowadays we know that the toxicity in these species is related to species-specific adaptations of highly penicillin-susceptible gut flora.”

    (van Meer et al. 2015)

    • Surely given your statement it would be better to say fundamental differences between guinea pigs and other animals (given most animals react like humans to penicillin)? The reality is that no one is pretending all animals are the same (indeed guinea pigs ARE more susceptible) – there are huge differences, but also huge similarities. Given the huge amount that we know about humans and animals we can effectively learn a lot about treating the former by using the latter.

      You seem to have answered your own quotes at the end. The success of penicillin was partially down to mouse experiments (they played a crucial part). Had they used guinea pigs it would have still worked had the dosage been correct. Nonetheless, if they were testing penicillin now, they clearly wouldn’t use guinea pigs because we know a lot more about the physiology of the animals now than we did then – that’s what years of scientific progress does.

  7. What’s amusing is that you reel of off your sources without reading them. I used the same Hamre source to point out that Penicillin does not kill guinea pigs unless you overdose them. That said, you have named two species of animal with gut positive flora. Here is a quick guide to toxicology:
    (1) Humans have gram-negative gut flora
    (2) A few species of animals, which we are well aware of, have gram-positive flora
    (3) Antibiotics affect gut flora – particularly gram-negative gut flora.
    Therefore:
    (4) Scientists have enough common sense not to run toxicology tests for antibiotics in animals with gram-positive gut flora.

    Can you provide a scientific paper detailing experiments on rats that show them to have teratogenic effects from penicillin, because all I can find is unsourced assertions from Greek.

    Had Fleming had no animal studies – do you think he would have taken it forward? A basic mouse safety test was the only thing which saved penicillin from historical insignificance. The problem for Fleming wasn’t that he did the animal tests, its that he didn’t do proper ones (and that he hadn’t properly purified penicillin) – all of this because clear through Florey and Chain’s animal experiments.

  8. Maybe Fleming says that assertion because animal models are unreliable for human outcomes? I think yes.

    There are actually numerous specie-specific responses to penicillin. Under
    certain circumstances, penicillin kills guinea pigs and Syrian hamsters:

    Harare DM, Rake C, McKee CM, MacPhillamy HB (1943) The toxicity of
    penicillin as prepared for clinical use. Am J M Sc 206: 642-652.

    SCHNEIERSON SS, PERLMAN E (1956) Toxicity of penicillin for the Syrian
    hamster. Proc Soc Exp Biol Med 91: 229-230.

    In addition, penicillin is teratogenic in rats, causing limb malformations in offspring. This is one of the problems with using animal models to predict human response: interspecies variation is to be expected when studying evolved complex systems.

    Weisse sates that Fleming was discouraged about penicillin’s possible use for many reasons including:

    ”…after injection into an ear vein of a rabbit and with blood samples taken periodically thereafter for testing, it was found that penicillin was rapidly removed from the bloodstream. Samples taken at 30 minutes were found almost completely devoid of activity. Of what use might be an antibacterial agent that took several hours to act but was removed from the body within 30 minutes and inhibited by the blood with which it would obviously be mixing”?

    Weisse AB (1991) The long pause. The discovery and rediscovery of penicillin. Hosp Pract (Off Ed) 26: 93-96, 101-4, 107 passim.

    Steffee reinforces this discouragement, stating:

    ”Fleming considered penicillin a potential chemotherapeutic agent, but his early in-vivo investigations were discouraging. In rabbits, serum levels of penicillin dropped rapidly after parenteral administration, too fast to allow the several hours of contact with bacteria required for an effect
    in vitro”:

    Steffee CH (1992) Alexander Fleming and penicillin. The chance of a lifetime? N C Med J 53: 308-310.

    So, again, animal models are serious misleading in biomedical and toxicological research.

  9. ”How fortunate we didn’t have these animal tests in
    the 1940’s [sic], for penicillin would probably never been granted a
    license, and possibly the whole field of antibiotics might never have
    been realized.”

    Alexander Fleming

    ”Mice were used in the initial toxicity tests because of their small size, but what a lucky chance it was, for in this respect man is like the mouse and not the guinea-pig. If we had used guinea-pigs exclusively we should have said that penicillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for trial in man.”

    Howard Walter Florey

    Greek, R. & Hansen, L, A. (2013) The Strengths and Limits of Animal Models as Illustrated by the Discovery and Development of Antibacterials. Biological Systems: Open Access 2:109. doi: 10.4172/BSO.1000109.

    Have a nice day ^_^

    • It’s a pity the first quote is never given any context. It was reported by a former student of Fleming when discussing the wide range of animal toxicology tests, but it’s unclear from the original source (ATLA) why Fleming says this. Indeed, had the mouse safety test not been used, then Penicillin’s benefits would never have been discovered (It took 10 years after its discovery for it to be used at all).

      Scientists are unlikely to use an animal with gram-positive flora to test antibiotics (it won’t work on them very well). That said, Hamre showed that if you gave guinea pigs doses of penicillin equal to humans (per kg), it is not toxic – and thus would not have caused penicilin not to be discovered.
      “When treated with the same dose of penicillin per kg. as that given to man, guinea pigs did not die and, in fact, failed to show any signs of toxicity”

      The reality is that without the role of mice, we wouldn’t have penicillin – a fact you appear to have purposely overlooked in your answer.

      Hamre, D M, Rake, G, McKee, C M and MacPhillamy, H B (1943) The toxicity of penicillin as prepared for clinical use. Am. J. Med. Sci. 206 642-52.

      I recommend Jack Botting’s book which takes a look at these arguments over Penicillin more detail:
      http://www.openbookpublishers.com/htmlreader/978-1-78374-117-5/Ch-17.xhtml#_idTextAnchor072

  10. James Keele

    You are merely cherry picking arguments against animal rights advocates. Firstly, you have given no evidence that animal research was actually necessary for discovery now, merely that in the way such discoveries were made historically animal research were used. Are you for instance saying that modern technology could not synthesize enough penicillin to test on humans?

    Secondly, Animal rights are not just something that can be thrown aside just because it benefits humans, anymore than just throwing away human rights whenever it suits a majority of humans. Think about the millions of lives that could be saved by forcibly experimenting on humans? We dont do so because humans have rights, even humans who lack the ability to use language etc. because to do so is wrong. Stop being so hypocritical and stand up stand up for the rights of animals that consistency demands we respect

    • On your first point the mice were essential for discovering the ability of penicillin to fight infection inside the body. The compound had been shelved by Fleming for 10 years until these animal experiments allow Chain and Florey to discover their true potential. This was done just in time to save millions of lives in World War II.

      Might its true potential have been randomly discovered in the future without animal experiments? We can’t prove either way; but it was unlikely to be in time to save those millions in WWII.

      Secondly, the author doesn’t mention animal rights. Your comment already presupposes animals have rights – something which is far from clear.

  11. Laurella Desborough

    I am going to put the link to this article on my facebook page for all to see and ask that it be shared widely. It is critical that the general public learn more about the importance of animal research.

  12. Reblogged this on unlikelyactivist and commented:

    What an articulate, clear and truthful defense of the importance of humane, responsible and regulated animal research. I urge students involved in biomedical research across the world to do what Mr. Cordy has done and communicate the importance of our work to the broader public.

  13. I am proud to see such an articulate, clear and truthful description of the importance of humane, responsible and regulated animal research. I urge students involved in biomedical research across the world to do what Mr. Cordy has done and communicate the importance of our work to the broader public.