researchers should explore the alternatives

It’s been more than a year since US President Joe Biden signed a law allowing researchers to test drug candidates on human tissue or computer models before moving to trials in people. This challenged a regulatory dogma, accepted since the 1930s, that vaccines and drugs need to be tested on one rodent species and one non-rodent, such as a primate.

Researchers such as Ofer Levy, a vaccinologist at Boston Children’s Hospital in Massachusetts, rejoiced. Levy has long advocated that studies in human tissue can, in some cases, be more informative than those done on animals. But the number of researchers who don’t know about the law, which was signed in December 2022, stuns him: “I mention it, and they look at me like I fell from the sky,” he says.

Animal studies are still important and often necessary, especially in the latter stages of vaccine and drug development. Moreover, researchers and funders need to be cautious and establish a way to carefully validate disease models based on human tissue. The changed mandate for the US Food and Drug Administration (FDA) is a reminder for researchers to reduce their reliance on animals, particularly in early-stage research.

Global data on animals in research are incomplete, but there are signs that the number of scientific procedures performed on live animals is falling in some countries. According to UK government data for example, 2.76 million such procedures were performed in the country in 2022. This is the lowest number since 2002, and markedly lower than the 4.14-million peak in 2015.

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What, then, are the alternatives? Induced pluripotent stem cells — which have been ‘reprogrammed’ so that they can turn into any cell type — offer a way to generate human cells from skin or blood samples. Organoids, 3D cultures that can comprise multiple cell types, take such Petri-dish systems to the next level. They allow researchers to evaluate the interplay between cell types and the importance of their spatial organization on drug responses. Researchers are innovating in other ways, too. Small tissue samples can yield a wealth of data, which means human biopsies taken using very fine needles, which minimize the risk of harm, can be used for such studies.

Such approaches will never completely replace animal research. An organoid is not a full substitute for a mouse when evaluating, for example, how an experimental drug is absorbed and metabolized throughout the body. But these techniques allow for more initial hypotheses to be based on human-tissue responses to the environment or a disease, rather than beginning with observations of the animal model and looking for parallels in humans.

An important application has been in immunology. Although much has been learnt about the human immune system by studying mice, there are key differences between biological processes in the two species¹, so a particular mouse immune response might not be replicated in a human. For example, differences in how mice respond to infection have generally made them poor models of sepsis, a life-threatening condition in which the body’s reaction to infection can damage organs. As a result, treatments for sepsis developed in rodents have translated poorly to humans².

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Even among humans, responses to vaccines can vary by age, sex and geographical region in ways that are often difficult to model using animals³. And it is difficult to discover the molecular basis of longevity in a human centenarian while rifling through the genome of a rodent that reaches old age within two years. Around 90% of therapies tested in early-stage clinical trials fail to make it to market — a failure rate thought to result partially from a heavy reliance on animal models in preclinical research. Cancer cures in mice rarely translate to approved drugs in humans.

And then there are animal-rights concerns. Researchers must have a strong justification for using animals in their studies, and even then, there are rules limiting their use. For example, according to NIH guidance, it is inhumane to keep a mouse alive in a lab after some of the painful and debilitating consequences of ageing begin to take hold.

Experiments involving animals can also take an emotional toll on the researchers who carry out the work. And studies on captive primates raise extra ethical concerns, particularly when the work is outsourced to countries with relatively few restrictions on primate research.

Replacing animals in studies with human tissue brings its own challenges, which need to be mitigated if the practice is to become widespread. Correlations found in human-tissue biopsies, for example, might require subsequent experiments in animals to establish causality. Conducting such studies in humans could be complex, expensive and ethically fraught.

And just because a technique is based on human cells, that doesn’t make it necessarily superior. Funders and researchers will need to invest in the validation of these methods, by comparing results of computer predictions or tests using organoids with the results of clinical trials of the same experimental drug. Even Levy emphasizes that animals are also crucial for parts of his team’s research. “We still make use of animal models — just 70–80% less than the average research group,” he says.

The FDA policy allowing non-animal data to be used to support drug approvals needs to be much better communicated and amplified by the agency, funders and research institutions. And more researchers need to embrace the change. The outcome will be more-rigorous evaluation of experimental medications, and more-meaningful results.