South Aussies for Animals Inc. SAFA

Support is needed for human-relevant medical research

Opposition to experimentation on sentient animals has a long history on moral grounds. However, these days calls to move to human-based research are also based on the need for more reliable and efficient methods to develop understanding of disease processes and drug treatments. Such calls are found in prestigious medical journals, such as the British Medical Journal (1), the Journal of the Royal Society of Medicine (2), and the Journal of the American College of Cardiology (3-4).

The Wyss Institute, part of the respected Harvard University in the US, has outlined the problem as follows (5)

“Drug development is notoriously slow and expensive – it can take up to 10 years and cost more than $3 billion to bring a new compound from the lab bench to market. A major cause of this inefficiency is the traditional reliance on testing drugs in animals before they are tested in humans. Animal models often do not accurately reflect human physiology, meaning that drugs that appear to be safe and effective in animals frequently turn out to be harmful or ineffective in humans. This mismatch in biology causes many useless or toxic drugs to advance through clinical trials at great expense, while potentially effective compounds never make it to market. A better way to model human biology and diseases in vitro is needed to accelerate the development of new drugs and personalised medicine.”

Problems with animal research

One review examined the results of over 100 experiments involving more than 3000 animals, focusing on agreement between treatment effects in animal experiments and clinical trials (1). The health conditions studied included head injury, haemorrhage, stroke, neonatal respiratory distress and osteoporosis. The results were variable, but overall animal models were not a reliable predictor of effective treatments in humans, no better than tossing a coin.

Treatments for stroke have a particularly poor record in animal research. One neurologist has commented that the ‘animal model’ used to test treatments is itself inadequate (6, p.409): “… most animals don’t naturally develop significant atherosclerosis, a leading contributor to ischemic stroke. In order to reproduce the effects of atherosclerosis in animals, researchers clamp their blood vessels or artificially insert clots. These interventions, however, do not replicate the elaborate pathology of atherosclerosis and its underlying causes.” Not surprisingly, then, more than 114 potential therapies tested in animals failed in human trials.

In some cases, drugs found to be safe and effective in animal studies have disasterous consequences in human clinical trials (3):

  • TGN1412, a monoclonal antibody was tested as a treatment for leukemia in mice, rats, rabbits and non-human primates. However, when human volunteers were given only 1/500th of the dose given to monkeys, they suffered a severe reaction within minutes, including organ failure.

  • BIA-102474, a drug tested for neurological problems, produced brain haemorrhages and 1 death in human volunteers at a dose 1/500th of that found safe in dogs.

  • Fialuridine, a treatment for hepatitis B, produced 5 deaths in human volunteers, while 2 others only survived after a liver transplant, even though the dose they were given was much lower than that found safe in mice, rats, dogs and monkeys.

These are a few extreme examples of a general trend – 89% of new drugs that pass animal tests fail clinical tests, in about half the cases due to unexpected toxicity (3). A lot of time, money and animal lives have been wasted without producing an effective and safe treatment.

It may also be the case that potentially effective drugs never reach human trials because they fail animal tests. Any dog owner knows that their pooch can’t tolerate chocolate, although humans have no such problem. Dogs and cats can’t tolerate the widely used analgesic paracetemol. Guinea pigs are allergic to the wonder drug penicillin. Ibuprofin and warfarin are toxic to rodents, but used in human medicine (7). Tamoxifen is used in the treatment of some breast cancers, but causes liver tumours in rats (6). Gleevac is used to treat a form of leukeumia. It causes liver damage in dogs and serious adverse effects in 4 other species, but not in humans (6). It is impossible to know how many potentially useful drugs have been missed because they failed animal tests.

Replacement of animal experiments

Options for conducting reearch with human tissues are becoming increasingly sophisticated, and avoid the problems of extrapolating results from one species to another.

Organoids are simplified versions of an organ grown in vitro from human stem cells. They can be used to study normal biological processes, as well as modelling diseases and studying the effectiveness and safety of drug treatments (8). Here are some examples:

  • A brain organoid was able to show how the Zika virus affects brain development in utero (7). This virus causes microcephaly, an abnormally small brain and many neurological problems in unborn children, as seen in an outbreak in Brazil in 2015. It is impossible to study the effect of the virus in animals because their brain development is quite different to that in humans.

  • With human airway organoids it is possible to study how infective newly emerging strains of influenza are (7).

  • Organoids can be created from a patient’s own cancer cells to study which treatments are most effective (7).

  • A liver organoid correctly predicted the toxicity of Fialuridine, a drug developed to treat hepatitis B. It killed 5 volunteers in a clinical trial, after appearing safe in animal studies (2).

Organs-on-a-chip (OOAC) are flexible polymer devices about the size of a memory stick. Minute channels in the chip are lined with human blood vessel and organ cells. The aim is to simulate the structure and function of human organs. OOACs are able to mimic blood, air, and nutrient flow to and from the organ. They allow the study of biological processes, disease development and the effect of drugs (2,9).

For example, a liver-on-a-chip could explain why the experimental type 2 diabetes drug Rezulin caused liver damage in human trials, which was not predicted by animal studies (2).

The brain-in-a-box is a 3D network of human neurons that can be used to test medications for brain disorders (8). The structure includes electrodes that can be used to simulate seizures and to test the effectiveness of drugs in stopping them.

Strategies for change

Although the methodology of using human tissues in reseach is rapidly advancing, and some examples have been used in Australia (8), there is much more that needs to be done to overcome obstacles in the way research is funded and the attitudes of researchers (10,11).

A survey by NH&MRC identified insufficient funding as a barrier to replacing animal experiments (8). Another barrier is the attitude of researchers themselves. In an interview study, researchers showed little awareness of the problem of extrapolating results from animals to humans (12). Another study investigating researchers’ knowledge and application of the 3Rs found that they focused on refinement and reduction, that is, modifying animal experiments, rather than replacement of animals (10). In fact, they expressed little confidence in the possibility of replacing animals, and therefore would be unlikely to adopt new methods.

In order to make progress in the adoption of more human-relevant methods, a change in funding priorities is needed (2, p. 436): “Funding incentives could disrupt the current institutional lock-in to animal research by prioritisinig funding for human-based biomedical research over funding for ‘improved’ animal models.”

A change in the attitude of researchers is also needed. Academics at the prestigious Johns Hopkins University, advocate targeting educational efforts at young scientists in training as the most effective way of advancing human-based research (12). Along the same lines, the National Centre for the 3Rs in the UK offers PhD scholarships and early career fellowships “to ensure that the 3Rs are established in the minds and practices of the new generation of research leaders .” (10, p.199).

References

  1. Perel, P., Roberts, I., Sena, E. et al (2007). Comparison of treatment effects between animal experiments and clinical trials: a systematic review. British Medical Journal, 334 197-200

  2. Archibald, K., Tsaioun, K., Kenna, G. & Pound, P. (2018). Better science for safer medicines: the human imperative. Journal of the Royal Society of Medicine, 111 (12) 433-438

  3. Van Norman, G. (2019). Limitations of animal studies for predicting toxicity in clinical trials Part 1. Journal of the American College of Cardiology: Basic to Translational Science, 4 (7) 845-854

  4. Van Norman, G. (2020). Limitations of animal studies for predicting toxicity in clinical trials Part 2. Journal of the American College of Cardiology: Basic to Translational Science, 5 (4) 387-397

  5. Wyss Institute. Human organs on chips, at https://wyss.harvard.edu/technology/human-organs-on-chips/

  6. Akhtar, A. (2015). The flaws and human harms of animal experimentation. Cambridge Quarterly of Healthcare Ethics, 24 407-419

  7. Kim, J., Koo, B. & Knoblich, J. (2020). Human organoids: model systems for human biology and medicine. Nature Reviews: Molecular Cell Biology, 21 571-584

  8. NH&MRC (2019). Information paper: The implementation of the 3Rs in Australia. Downloaded from https://www.nhmrc.gov.au/about-us/publications/information-paper-implementation-3rs-australia

  9. Wu, Q., Liu, J., Wang, X. et al (2020). Organ-on-a-chip: recent breakthroughs and future prospects. Biomedical Engineering Online, 19 (9) downloaded from https://biomedical-engineering-online.biomedcentral.com/track/pdf/10.1186/s12938-020-0752-0.pdf

  10. Burden, N.. Chapman, K., Sewell, F. & Robinson V. (2015). Pioneering better science through the 3Rs: an introduction to the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Journal of the American Association for Laboratory Animal Science, 54 (2) 198-208

  11. Franco, N., Sandoe, P. & Olsson, A. (2018). Researchers’ attitudes to the 3Rs – an upturned hierarchy?. PloS ONE, 13 (8) downloaded from https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200895

  12. Herrmann, K., Pistollato, F. & Stephens, M. (2019). Beyond the 3Rs: expanding the use of human-relevant replacement methods in biomedical research. ALTEX, 36 (3) 343-352