For decades, scientists have relied on animal research to propel modern medicine forward, with animal testing being involved in routine vaccinations as well as cancer therapies. However, the status quo is now changing.
“For many years, the pharmaceutical industry, the Food and Drug Administration, and many scientists have known that animal models are not accurate at predicting results in humans, particularly when it gets to clinical trials,” said Donald Ingber, a bioengineer and pioneer in organs-on-chips research at Harvard University. “In fact, they're usually wrong more often than they're correct.”
Indeed, only about five percent of animal-tested therapies obtain regulatory approval for humans.1
Recognizing these gaps, the National Institutes of Health (NIH) announced last year that it will no longer develop new funding opportunities focused exclusively on animal models of human disease. Last month, building on this further, the NIH announced funding of more than $150 million to develop research methods that reduce reliance on animal models. As part of this, a few researchers across the US received grants to create models that capture essential aspects of human biology such as organoids, organs-on-chips, and in silico approaches, often called New Approach Methodologies (NAMs).
“NIH is focused on advancing new technologies and research models that best reflect human biology and disease, ensuring the strongest possible science to improve human health,” an NIH spokesperson wrote in an email to The Scientist. “As scientific capabilities evolve, NIH is committed to supporting approaches that most accurately model human pathogenesis and biological systems, regardless of the specific methodology.”
With this announcement, NIH joins the FDA in a push for phasing out animal testing.
“It’s a turning point,” said Ingber, who hopes this motivates scientists to explore experimental systems other than animals. “It will make them begin to think about not just continuing to go by reflex and do what they [have] always done,” he said.
NIH Funds Support Development, Validation, and Standardization of NAMs
One of the recipients of the NIH funding is James Wells, whose lab at Cincinnati Children’s Hospital Medical Center uses gastric organoids to study gastrointestinal development and congenital defects of the digestive tract.
“The grant allows us to try to develop several disease models of the gastrointestinal tract, and the team here will be studying…inflammatory diseases of gastrointestinal organs,” said Wells. According to him, organoids fill a critical gap between the extremes of studying one organ within an animal and relying on cell lines.
Having generated gastric organoid models of some diseases, Wells and his team aim to study how closely they capture disease biology in humans and use the system to test therapies. “The ultimate goal is that we will have organoids from multiple different patients who respond differently,” said Wells. Patient-specific in vitro models combined with in silico bioinformatics studies of patient samples could help clinicians predict the efficacy of different treatments better, Wells noted.
According to both Ingber and Wells, NAMs also help overcome crucial limitations of using animal models in isolation to study human diseases and design treatments against them.
“In these organ-chips, you can control every potential parameter individually or in combination,” said Ingber. These include cell types, extracellular matrix, fluid flow, mechanical motions, and even the microbiome. “We again and again get insights into disease mechanisms and drug targets that you couldn't do other ways,” explained Ingber.
Is the Scientific Field Ready to Move Away from Animal Research?
Despite the push to move away from animal models, Wells does not believe that the field can completely do away with animal testing. Organoids are valuable in studying some aspects of diseases and drug testing, but they cannot replicate every aspect of an animal’s biology, he explained.
Some aspects that organoids may not accurately mimic are drug toxicity and safety. While a liver-on-a-chip model developed by Ingber and his team identified drugs known to be toxic to the liver, he noted that this was just replicating one organ.2 “So, [drug developers] are still going to do animal tests for a long time until you have every organ represented,” Ingber said.
Wells agreed. “There is now, and in my opinion, probably will always be a need for some animal testing of new therapeutics,” he said. Despite this, he believes that organoids have come a long way in significantly reducing dependence on animal models and the number of animals required for research.
“We still need animal models, but the idea is to really progressively reduce them and to give incentives, not to keep doing the status quo, which is demanding animal [experiments],” said Ingber.
Progressing Away from Animal Models
Ingber, who is also the scientific founder of Emulate, Inc., which commercially develops organs-on-chips, added that creating such models is not straightforward. “It's taken a long time and a lot of investment to figure out how to mass-produce these chips so that they're the same,” he said. He added that while this may be difficult to do in an academic environment, commercialization of these platforms—which is already in progress for some of them—will be required to overcome this hurdle.
Lindy Fishburne, founder and managing partner of Breakout Ventures, a venture capital firm that invests in biology and technology startups, believes that a funding push toward NAMs could drive efficiency in biotechnology and pharmaceutical company pipelines. “We will be able to use those models to kill bad options that we don’t need to move forward,” she explained.
Despite this, she said that these do not offer an end-to-end solution in pharmaceutical workflows culminating in regulatory filing. So just relying on NAMs may not be enough to obtain approval for drug development, clinical trials, and commercialization of products.
According to Wells, organoids are a valuable tool in scientists’ toolbox to answer bigger questions. However, developing better organoids does not mean that an existing tool needs to be completely replaced, he added. “It just means we have more tools to play with,” he said. “It's a good thing.”
However, he is skeptical about the rush to move away from animals, especially as researchers still uncover the capabilities and limitations of NAMs. “We need to, as scientists, remind the funding bodies how important these animal model systems are,” he said.
For instance, studying embryonic development in animals has laid the groundwork in developing organoid models that self-assemble and replicate physiological systems to a significant extent. “We wouldn't know how to do it if we didn't have all that foundational knowledge,” he said. “We absolutely have to keep funding this foundational science on animal models as we also move into more human models.”
- Ineichen BV, et al. Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications. PLoS Biol. 2024;22(6):e3002667.
- Ewart L, et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med. 2022;2(1):154.
