I was at a talk a while ago given by some volunteers from Animal Aid. They gave some great arguments against animal testing and showed some horrific, illegally filmed videos displaying the animal testing that happens in the labs run by so many of the companies whose brands we see everyday.
The speakers addressed the obvious conundrum of animal testing in medical research as well as cosmetic testing, saying there are alternatives to animal testing for medical purposes.
As I am hoping to study biomedical sciences and there is a high chance I will end up in an occupation which may use animals in experiments, I thought I should definitively answer whether or not I am against animal testing. Luckily, there are research jobs that no longer use animals in testing so if I do decide that I am against animal testing then I am not completely heading down an unrealistic career path. Currently, I am impassively against animal testing and do not exactly campaign either way because I do not feel I know enough about the topic yet.
I will start with arguments against animal testing.
The main argument against animal testing (other than ‘it is cruel’) is that the animals used in testing do not give a reliable representation of how a human body would react to the same testing. Humans do not have fur and tails so how could a mouse realistically represent human physiology? Humans and mice share 97.5% of coding DNA which seems like a lot but if that 2.5% can make the change between tails and no tails, fur and no fur, no complex language and complex language, whiskers and no whiskers, etc. why do we assume that our bodies will respond to drugs in the same way? It is also important to consider here that 98.5% of the human genome is non-coding, so sharing 97.5% of 1.5% of our DNA that codes for proteins with mice is not that significant (it comes to 0.014625% of our DNA). Another example is monkeys. Macaque monkeys, the most frequently used primates in medical research, are resistant to doses of paracetamol that would be deadly in humans as their livers function differently. This is incredibly dangerous. If human trials begun based on macaque research that suggested a certain drug was safe but it was not realised that this was only due to the fact that the monkeys’ livers were particularly efficient at dealing with the drug, then the humans would likely be killed. A prime example of this is the 2006 ‘drug trial gone wrong’. Theralizumab, an immunomodulatory drug in development for the treatment of arthritis and cancer, induced life-threatening inflammatory responses in all 6 of the first humans treated.
Because I am a bit of a biology nerd I looked into how the drug works and how it caused such adverse reactions. Theralizumab, also called TGN1412, is a monoclonal antibody that is a superagonist for the CD28 receptor of T cells. Unlike other monoclonal antibodies, TGN1412 causes activation and proliferation of regulatory T cells regardless of signal received by T-cell receptor. Usually activation of regulatory T cells by antigens is controlled by co-stimulatory signal from antigen presenting cells, mainly dendritic cells. This along with co-stimulation of CD28 receptor by a ligand (a molecule which produces a signal by binding to a site on a target protein) is required for T-cell activation. In vitro it was possible to stimulate regulatory T cells by the use of combination of antibodies against T-cell receptor and CD28 receptor. However, monoclonal anti-CD28 antibody TGN1412 was capable of activating T cells by just binding to CD28 receptor alone even when T-cell receptors were not activated. This was seen as a good thing and and TGN1412 was termed as a CD28 superagonist.
More geeky info – the reason TGN1412 is a super antagonist compared to other monoclonal antibodies is due to where TGN1412 binds. TGN1412 binds to a loop called the C”D loop of CD28 receptors in contrast to other CD28 antibodies which bind to a site far away from this loop.
Regulatory T cells are thought to be key in preventing and treating autoimmune diseases as oftentimes the cause of autoimmune diseases is the loss of this regulatory T-cell mechanism.
Because of this and TGN1412’s superagonist activity, TGN1412 began to be investigated for their therapeutic potential in animal models, namely macaque monkeys.
Back to animal testing. TGN1412 underwent rigorous preclinical investigation prior to its approval for clinical trials. In preclinical (animal) studies, increased activity of regulatory T cells was observed without any measurable proinflammatory reaction (when T-cells secrete inflammatory cytokines that promote inflammation). Thus, TGN1412 was thought to be useful for treating diseases related to low numbers of activated regulatory T cells such as B-cell lymphoma or rheumatoid arthritis (an autoimmune disease).
In March 2006 TGN1412 had its first human clinical trials. Swiftly the drug caused catastrophic organ failure in all 6 healthy subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg of body weight. This dosage was over 500 times lower than the dose found safe in macaque monkeys. The drug company said there was “unforeseen biological action in humans”, rather than breach of trial protocols. In early 2007, those investigating the incident proposed that the reason the human subjects reacted so poorly due to the presence memory T cells (T cells that have memory of their specific antigen from prior infection, encounter with cancer, or previous vaccination, so are faster acting). It is suggested that animals raised in a sterile lab would have no ‘memory’ of previous illnesses, thus would not have memory T cells. However, the research said that lab animals studied did have memory T cells although much fewer than humans. It has since been discovered that stimulation of the CD28 receptors of memory T cells does cause them to infiltrate organs and activates them.
Whether the reason for the differing responses of humans and animals was due to memory T cells or another difference between the test macaques and humans, it is clear that the animal research ended up redundant as that form of TGN1412 was never used again. Also, the 6 human test subjects’ lives were changed forever due to their organ failure. Additionally, this brings up the point that animal research can lead to excess expense as drugs will be brought to human trials at great cost even if there is no chance of the drug working in humans because of the differing physiology. In fact, 94% of drugs that pass animal tests fail in human clinical trials.It would perhaps be more effective to find more accurate alternatives to animal testing (although the alternatives will probably not be cheaper).
Furthermore, beagles, the most commonly used animals for heart disease drug testing, can be severely poisoned by chocolate, grapes, raisins, avocados and macadamia nuts but I have eaten ⅘ of those foods today. How many drugs have been discounted as toxic to dogs but could in actual fact be safely metabolised by humans? In this way, animal tests may mislead researchers into ignoring potential cures and treatments. This quote from the Cruelty Free International website sums this argument of animals being too dissimilar from humans to reliably replicate human response to drugs up: “The history of cancer research has been the history of curing cancer in the mouse. We have cured mice of cancer for decades and it simply didn’t work in human beings.” ~ Dr. Richard Klausner, former director of the US National Cancer Institute.
Similarly the conditions animals are exposed to in laboratory conditions can influence an experiment. For instance, the stress induced in the animals from
Another argument against animal testing is that there are now alternative testing methods that can replace the need for animals. The main and most promising example of this is in vitro testing using cell cultures derived from stem cells, such as studying cell cultures in a petri dish. This can produce more relevant results than animal testing as human cells are used. This removes the issue of the different physiologies of humans and animals leading to inaccurate preclinical trials. Another alternative to animal testing is microdosing, which is the administering of doses too small to cause adverse reactions. The blood of the volunteers is then analysed to determine what affects the drugs had*. There is also, artificial human skin sheets, alike the stem cells, are grown and can be used to test skin products in a more relevant way than using animals’ skin. Likewise, microfluidic chips, which are lined with human cells and recreate the functions of human organs, and computer models are in advanced stages of development. Computer models are used as virtual reconstructions of human molecular structures which can predict toxicity of substances.
To the contrary of not using animals in testing as they do not give a reliable representation of how a human body works, if you do ‘cut out the middleman’ and jump straight to human trials without testing on animals, the chances of human fatality are more likely because in reality many things that will kill a mouse or a monkey or a beagle will also kill a human. Finding human volunteers to trial a drug that has never been tested on another independently living whole being will be incredibly difficult.
Also, the alternate methods to animal testing are certainly not without faults of their own. In opposition to in vitro testing using cell cultures derived from stem cells are all of the ethical implications of using stem cells. This is a debate in itself. Although adult humans still have stem cells, they are already partially specialized, for instance, blood stem cells only make blood cells. Adult stem cells are said to be multipotent which means they can develop into more than one cell type but are limited in the type of cells they can form. The next level up is pluripotent cells (acquired from late stage embryos) which are more useful as they can give rise to all cell types that make up a body with the exception of placenta or embryo cells. Lastly, totipotent cells, which are taken from only blastocysts (early stage of an embryo – just 5 or 6 days after conception), can form all the cell types in a body including embryo and placenta cells. Therefore, the best stem cells for research are totipotent and pluripotent cells as they have the most potential to develop into many types of cells. The principal arguments against stem cells are, one, the moral issue of destroying blastocysts formed from laboratory-fertilized human eggs and, two, the difficulty the process of developing cells cultures involve. For people who believe life begins at conception, the blastocyst is a human life and to destroy it is immoral and unacceptable. Growing stem cells is costly, and requires a large area. The environment for successful stem cell growth is very specific and to produce the large number of cells needed for reliable studies entire floors of buildings are needed. Recently to combat the space issue 3D scaffolding has been developed to grow the stem cells in a cubed root size space of the previous area that was needed (more information here http://medicalphysicsweb.org/cws/article/research/71103). Also, it has been discovered that stem cells seem to grow faster and to a better quality in space more information here https://www.nasa.gov/mission_pages/station/research/news/stem_cells).
Another issue with stem cell use in drug development is that the stem cells used in research will be from one human and the drug will likely then be used on a different human and as each human is only 99.5% similar to any other human the 0.5% difference may make the drug react differently. This is a similar argument to why animal research is unreliable as mice and humans are not genetically identical. Of course, two humans are more similar than a beagle and a human.
However, the issue of adult stem cells being useless as they are only pluripotent and so embryonic stem cells are required instead may be resolved in the near future. Dedifferentiation is the process of specialised cells regressing from having a specific function to an unspecialised state very similar to stem cells. Inducing dedifferentiation is only in preliminary stages of research but the idea is that dedifferentiation of someone’s own cells could be used to test a drug so any risk of genetic incompatibility or immune rejection can be mitigated and there are fewer ethical debates than the use of stem cells derived from embryonic tissue. My main query is how the cell cultures will be able to represent the entire body. If stem cells are used to make liver cells to test a drug that affects the liver, the effect of the drug on other tissues will remain unknown: the drug could kill brain cells. Cell cultures would need to be made for every type of cell in the body, all 200 of them (+ the effect on the 40 trillion species in the essential microbiome needs to be known). Also, the tests will need to be repeated multiple times to be reliable. This is beginning to sound expensive and very time consuming, so perhaps cell cultures is not a great alternative.
The idea of microdosing sounds promising until you refer back to the TGN1412 case. The doses given to the 6 trial patients were a supposed sub-clinical dose of 0.1 mg per kg of body weight and 500 times lower than the dose found safe in macaque monkeys – this sounds like microdosing to me. Not so promising, after all perhaps.
The microfluidic chips actually do seem promising. The iCHIP (in-vitro Chip-based Human Investigational Platform) imitates four major biological systems vital to life: the central nervous system, peripheral nervous system, the blood-brain barrier and the heart. More info in this video: https://youtu.be/J3YvlC8Q8BE
Of course, the chip alone cannot replicate the entire body but it can give a more rounded idea than cell cultures. Likewise, the microfluidic chip will probably not be able to predict anomalies that occur naturally in real bodies. The same arguments apply to using computer models as alternatives to animal testing. Also, it can be argued that computer models can only be reliable if accurate information is acquired from animal research in the first place and even the most powerful supercomputers will not be able to perfectly simulate the human brain – unfortunately this is not Iron Man III and Advanced Idea Mechanics does not exist.
In summary, there is no sufficient alternative to testing on a living, whole-body system. Living beings are extremely complex and studying cells in a petri dish, while sometimes useful, does not highlight the interrelatedness of the body’s different systems (the circulatory, respiratory, digestive, excretory, nervous, endocrine, immune, integumentary*, skeletal, muscle and reproductive systems).
*consisting of the skin, hair, nails, and exocrine glands
As well as the argument of all the flaws of the alternatives to animal testing, there are more arguments which support of animal testing.
Despite the above arguments, animals are appropriate research subjects as they are similar to humans in many ways. All animals have a common ancestor and all mammals have a similar set of organs that function in essentially the same codependent way. This biological similarity between all mammals means many are susceptible to the same illnesses, so each can sub in for any other in a relatively accurate way. This also means that all animals benefit from the results of animal testing. For example, koalas are used in chlamydia research and, as chlamydia has pushed koalas towards extinction, when a successful vaccine is created the koala population can be aided and make a comeback.
Another argument for animal testing is that animals often make better research subjects than human beings because of their shorter life cycles. Flies and mice have short lifespans so the effects of treatments or genetic manipulation can be observed across several generations, which would be infeasible using human subjects.
Furthermore, comparatively few animals are used in research. In the UK 2.8 million cows, 9.8 million pigs, 15 million sheep, 18 million turkeys, 945 million chickens and 4.5 billion fish are consumed each year. So, 8.1 billion animals are eaten each year. There were 1.2 million experiments on mice, 200 thousand on rats, 100 thousand on birds, 15 thousand on rabbits, 26 thousand on guinea-pigs, 3 thousand on monkeys, 4 thousand on dogs, 190 on cats, 9 thousand on horses, 48 thousand on sheep, 5 thousand on pigs and 300 thousand on fish in 2016. That is 1.9 billion animals used in testing and 8.1 billion being eaten. For every 1 pig used in research, 1980 pigs are eaten. From this perspective it seems that animal testing is a small sacrifice for the advancement of medical research.
In conclusion, the arguments for and against animal testing are both convincing and this is probably why this argument is so prevalent. I have condensed arguments against animal testing down to two main arguments: there are alternative methods to animal testing and animals are too different from human beings to be reliable test subjects as this difference can mean they react differently to drugs. This is ignoring moral and religious arguments. The main two arguments in support of animal testing are that only a whole-body organism can reliably imitate drug action and the animals used in research are a minimal sacrifice to lead to benefits across all species.
For me, the fact that animal tests can be misleading is the argument that is most outstanding. Therefore, overall, I think animal testing should be more strictly regulated and the number of animals used reduced to only the absolute necessary amount. Ideally, all methods of testing should be used in combination to make up pre-clinical trials. For instance, firstly microfluidic chips and computer models can be used as preliminary tests. Then, the cell cultures can be used to ensure the computer models are in fact accurate. Then the minimum number of animal trials can be carried out before human volunteers can be paid to test a drug.
Learning in Parallel 