What can animal models tell us about human health?
Avid readers of medical news will be familiar with the widespread use of animal models in biomedical research.
However, problems can arise when researchers make predictions about human health based on the results of such studies.
Scientists refer to this concept as clinical relevance. Many biomedical grant funding agencies require researchers to justify the use of animal models by predicting how likely the results are to make an impact on human health.
Meanwhile, journalists write catchy news headlines to draw our attention, sometimes failing to critically assess how clinically relevant a study is; or worse, they leave out the fact that scientists performed the work in animals, not humans.
The debate about the clinical relevance of animal models is ongoing, and a Twitter account called @justsayinmice — which encourages social media users to retweet news stories that do not clearly state if results are from an animal model or human volunteers with the caption "IN MICE" — recently fuelled it.
Can we assume that conducting research in animal models will reveal insights about our own health, and who is to blame when a news story includes sweeping statements about clinical relevance?
In this tale of mice and men (in lab coats), we explore how animal studies have contributed to biomedical advances, and why some scientists maintain that animal models harbor no clinical relevance.
Animal models date back to '2000 BC'
Before we delve into the early days of animal studies, I am going to add in a disclaimer. During my time as a research scientist, before joining Medical News Today, I was involved in several studies that used a large pig model of wound healing.
Although I have made every effort to approach this topic factually, I cannot guarantee that my experiences have not left me without some level of bias.
Back to the topic at hand.
Kirk Maurer, from the Center for Comparative Medicine and Research at Dartmouth College in Lebanon, NH, and Fred Quimby, from Rockefeller University in New Durham, NH, discuss the history of animal models in biomedical research at length in a chapter in the 2015 book Laboratory Animal Medicine.
"The earliest written records of animal experimentation date to 2000 BC when Babylonians and Assyrians documented surgery and medications for humans and animals," they write.
Through the centuries, animals revealed much of the information we assume as factual today.
From Galen's discovery in the second century AD that blood, not air, flows through our arteries to the identification in 2006 of four genes that, when activated, can revert any cell into an embryonic stem cell-like state, animal models are at the heart of scientific progress in the biosciences.
The key term here is animal model. Maurer and Quimby describe the efforts of several authors to define the "ideal" animal model. "Perhaps the most important single feature of the model is how closely it resembles the original human condition or process," they explain.
Yet any model will only go so far, they admit: "A model serves as a surrogate and is not necessarily identical to the subject being modeled."
Animal models in modern medicine
Françoise Barré-Sinoussi and Xavier Montagutelli, from the Institut Pasteur in Paris, France, discuss the contribution that studies in animals have made to medicine in a 2015 article in the journal Future Science OA.
"The use of animals is not only based on the vast commonalities in the biology of most mammals, but also on the fact that human diseases often affect other animal species," they explain.
"It is particularly the case for most infectious diseases but also for very common conditions such as type 1 diabetes, hypertension, allergies, cancer, epilepsy, myopathies, and so on," they continue.
"Not only are these diseases shared but the mechanisms are often also so similar that 90% of the veterinary drugs used to treat animals are identical or very similar to those used to treat humans."
Both Maurer and Quimby, as well as Barré-Sinoussi and Montagutelli, highlight a long list of Nobel Prize winners whose scientific insights in animal models led to the development of new treatments critical to modern medicine.
This includes the work by Frederick G. Banting and John Macleod on isolating insulin from dogs, Emil von Behring's work on vaccines in guinea pigs and rabbits, and James Allison and Tasuku Honjo's work in mice and mouse cell lines in the field of cancer immunotherapy, which won them the 2018 Nobel Prize.
There is no doubt that animal models have made a huge contribution to the medical care that we benefit from today. That said, Barré-Sinoussi and Montagutelli also point out that "it is, however, noticeable that the results obtained on animals are not necessarily confirmed in further human studies."
In part, they put this down to the fact that although we share a significant proportion of our genetic code with the various animal models that scientists use in research, there are clear genetic differences.
"While some people [...] use these differences to refute the value of animal models, many including ourselves strongly advocate for further improving our knowledge and understanding of these differences and for taking them into account in experimental designs and interpretation of observations," they explain.
Questioning clinical relevance
Not all scientists echo Barré-Sinoussi and Montagutelli's sentiment.
In a 2018 paper in the Journal of Translational Medicine, Pandora Pound, from the Safer Medicines Trust in the United Kingdom, and Merel Ritskes-Hoitinga, from Radboud University Medical Center in Nijmegen, the Netherlands, argue that "preclinical animal models can never be fully valid due to the uncertainties introduced by species differences."
Their article has a particular focus on the pharmaceutical industry, which has a significant requirement for animal studies at the stage before a drug enters clinical trials. Without such preclinical models, it is not currently possible to test new drugs in humans.
"While many factors contribute to the poor rates of translation from bench to bedside (including flawed clinical trials), a predominant reason is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety," they write.
Pound and Ritskes-Hoitinga cite a particularly poignant example from 2006, when despite preclinical studies showing the experimental drug TGN1412 to be safe, the participants of a phase I trial suffered severe life-threatening reactions.
Others do see value in animal models but advise caution when choosing a model and interpreting study results.
Dr. Vootele Voikar, from the University of Helsinki in Finland, uses mice in his neurobehavioral research.
In a recent article that he published alongside his colleague Johanna Åhlgren in the journal Lab Animal, Dr. Voikar showed that genetically related substrains of mice from difference vendors showed significant differences in their basic behavioral profile.
When I asked Dr. Voikar how relevant animal models are to human health, he told me that "some of the fundamental rules, when using animals in basic research, [are] to avoid anthropomorphizing and to take species-specific differences into account as much as possible."
"With careful design of the experiments, understanding the validity issues at different levels, and appropriate critical interpretation of the results, the relevance and some confidence can be achieved."
Dr. Vootele Voikar
Less 'hype,' more 'objective discussion'
I asked Dr. Voikar whether he thinks that journalists often misinterpret or misrepresent what scientists publish when they write news stories. He puts the onus on scientists.
"I think the main problem is with scientists and their press releases — how they sell the data and results, how strong [the] evidence [is] they find in relation to some devastating disease, promises that are not yet there, although based on their interesting and important but often preliminary findings," he explained.
"Usually it means that more research needs to be done, to find out if the findings are reproducible and applicable to the other conditions. The care or treatment does not become available overnight, unfortunately, in [the] majority of cases. However, (over)selling is often needed for attracting new grants for the research."
Dr. Vootele Voikar
He advocates "multidisciplinarity dialogue between clinic and basic, preclinical work — too often the biologists studying disease models have a very limited knowledge of the respective clinical condition and spectrum for differential diagnosis."
When I asked him what he thought news outlets could do to improve how they communicate science news that includes studies in animals, he suggested the following:
"To be critical, avoid hype, ask and present different views to promote objective discussion, [and] consider applicability and generalization of the findings — for that specialized science writers are needed."
Although the debate about the clinical relevance of animal models continues and enthusiastic scientists and non-scientists alike delight in retweeting headlines with the "IN MICE" caption on a daily basis, I firmly believe that many scientists use animals to model human diseases with the hope of improving our health.
Along the way, all parties involved — including the researchers who pick the model, the senior scientists who oversee the interpretation and communication of results, the press officers, and the news outlets — bear a level of responsibility.
At all times, clear communication on the relevance of any animal model and the likelihood of the results having an impact on human health are key.