The history of animal experimentation is sprinkled with bouts of controversy. Unquestionably, there are multiple valid concerns (animal sentience, ethical justification, what are acceptable harms given which circumstances and goal?) that arise from using animals for research purposes ranging from disease modeling, drug or safety testing, to the advancement of knowledge. Yet researchers had and have to rely on animal testing to advance science, especially medical science devising novel drugs and treatments for human patients had first to be tested on animals.
Since 1938, the FDA has required all new drugs to be tested on animals before entering clinical trials, and eventually the U.S. market.
This made sense, because systemic effects can sometimes only be assessed in living organisms. A drug candidate might have brilliant anti-tumor efficacy, but if it also harms the liver, kidney, heart or brain at therapeutic doses, it can not be used in humans. Consider also any therapy or vaccine that requires a host immune system to assess. Impossible to do in cell culture. Often, there is just no way around animal testing to deliver safe and effective treatments for humans.
Yet the current legal and regulatory requirements are not without contention. Especially for drug testing, decades of data have shown that animal models can be unrepresentative or even bad predictors of human responses (Greek & Menache, Int J Med Sci, 2013). Some studies suggest that more than nine in 10 drugs that enter human clinical trials fail because they are unsafe or ineffective (Seyhan AA, Translational Medicine communications, 2019), even after preclinical animal testing.
Although animal models have been the gold standards for preclinical drug testing, animal models often do not predict human response effectively — Greek & Menache, Int J Med Sci, 2013
The lack of alternatives perpetuated a sometimes uncomfortable status quo in drug testing until today, where animal experimentation was legally required and yet did not always yield relevant results. The last two decades however seem to have changed this equation. With the rise of human-derived stem cells, organoid technologies, and organ-on-chip systems, researchers are pushing hard to make model systems better and animal testing redundant.
That’s why on December 19th, 2022, a new law was passed that enables the FDA to remove the absolute requirement for animal testing before human drug trials. Now the law stipulates that it might be permissible to allow human drug trials also after non-animal preclinical model testing.
Why did the FDA make this change? Does that mean drugs could be less safe?
I think it is worth looking into the ethical principles that guide animal experimentation today, and how currently developing new technologies might fit into this larger framework.
Replace, reduce, refine
In 1959, scholars and animal welfare organizations have defined the ethical framework for when scientific research on animals is permissible, known as “The Three Rs”:
Replacement: The substitution for conscious living higher animals of insentient material;
Reduction: Reduction in the number of animals used to obtain information of given amount and precision;
Refinement: Any decrease in the severity of inhumane procedures applied to those animals, which still have to be used. — Hubrecht & Carter, Animals, 2019
The three Rs have been a staple in research practices all around the world and that basically state that sentient animals should not be used if non-sentient alternatives are available; that if animals do have to be used, a minimal amount are to be used that still allows to obtain useful information, and that experimental design should reduce negative experiences and harm as much as possible to animals.
The order is no coincidence either. The first priority is always with replacement, then reduction, then refinement, because bringing as few animals as possible into the position of testing is paramount to the eventual decoupling of our medical needs from animal sacrifice.
So how can new technologies replace animal models?
A glimpse into animal-free drug testing of the future
One of the fundamental issues with classical cell culture in vitro models is that they can not reproduce the complexity of whole tissues, organs or larger organisms. From the diversity of cell types to intricate 3D cytoarchitecture, from varied nutrient supply to complex multi-organ interactions, our cells are embedded in systems bigger than themselves.
Recent scientific advances in creating more complex in vitro model systems have been transforming basic biological research, it is reasonable to assume that drug discovery and safety testing are next to follow.
“I believe the biggest impact to date of induced pluripotent stem cell technology is not regenerative medicine, but in making disease models, drug discovery, and toxicology testing,” — Shinya Yamanaka, stem cell pioneer & Nobel Prize winner
Take for example stem cells, which are currently used in predictive toxicology (Kim TW et al., Regul. Toxicol. Pharmacol., 2019) or the increasing role of tissue-engineered 3D model systems as alternatives to animal models (Bédard P. et al., Bioengineering, 2020)
Maybe the most dramatic reduction of animal use for drug discovery purposes might however come from microphysiological systems (MPS), including organ-on-chip, microfluidics, and other hybrid or biointerface technologies.
Microphysiological systems (MPS) offer several advantages, such as recapitulation of tissue architecture, diffusion kinetics of drugs and signaling factors, and physiological flow conditions.
MPS systems offer controlled, high-throughput environments that are increasingly capable of recapitulating the complexity of multi-organ systems. This does not mean that they will be able to address every question.
We have previously written about the complexity barrier at the heart of brain research, and how new model systems (brain organoids) and technologies (neural biointerfaces) might finally be able to spur new discoveries and insights.
What these innovations imply for animal welfare is however often overseen: a dramatic reduction in animal testing
Just take this example below of how better biosensors can dramatically reduce (albeit not yet replace) the number of animals needed to gain useful information (Mapelli L. et al, biorxiv, 2022). (Disclaimer: 3Brain was involved in this work and thus holds a conflict of interest)
[…] increasing the efficiency of the technical apparatus will determine, as a consequence, a reduction in the number of tests (and therefore animals) needed for obtaining statistically relevant results. Such technological advancements are crucial in realizing the 3Rs principles. — Mapelli L. et al, biorxiv, 2022
At the moment, there is a rich tapestry of different technologies developed to address different questions, a sign of innovation and disruption that needs to come first before eventual consolidation in standardized operating procedures.
But stem cells, organoids, and MPS systems are not the only advances that further the ethical prescription of the “Three Rs” and rethink animal testing in the 21st century. For example, there are several ongoing EU projects using human cell cultures in combination with sophisticated in silico approaches to replace or reduce the use of animals in research.
Science is not a point where we can replace animals completely, but we are on the right track.
New technologies offer new opportunities to rethink, replace or renew currently existing toxicology, drug discovery, and safety testing pipelines.
The recent changes in law reflect a positive change that has been in the making for decades, and decades will still be the time horizon to continue that arc toward phasing out animal testing.
Still, it remains unclear just how much the new law will change things at FDA. Although the legislation allows the agency to clear a drug for human trials without animal testing, it doesn’t require that it do so. What’s more, FDA’s toxicologists are famously conservative, preferring animal tests in part because they allow examination of a potential drug’s toxic effects in every organ after the animal is euthanized. — Meredith Wadman for ScienceInsider
New microphysiology systems are already waiting in the wings to reduce and replace a lot of animal testing.
Personally, I believe using ethical frameworks like the “Three Rs” to guide our developments does not have to come as a detriment to innovation but can be a powerful force driving it.
The long road out of using animals for science might still be ahead of us, but it is worth turning back and appreciating how far we have come.
Ahktar A., Camb Q Healthc Ethics, 2015
Hubrecht & Carter, Animals, 2019
Sung JH. et al., Anal. Chem., 2019
Kim TW et al., Regul. Toxicol. Pharmacol., 2019
Bédard P. et al., Bioengineering, 2020
Mapelli L. et al, biorxiv, 2022
Meredith Wadman for ScienceInsider
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Declaration of interest:
The author is an employee at 3Brain.