Tech to Replace Animal Testing Is Almost Ready. Scientists Are Not

Seventeen years ago, cell biologist Donald Ingber and his colleagues at Harvard University’s Wyss Institute for Biologically Inspired Engineering submitted a paper to the journal Science describing their model human lung. It was smaller than a USB stick and made of a clear polymer slab containing narrow channels, which were lined with the type of cells that line a lung’s air sacs and blood vessels. When air was pumped through hollow chambers beside the channels, the device rhythmically expanded and contracted—it “breathed.” This lifelike movement was a dramatic change from previous generations of lung models, which typically used static cultures of lung tissue that were unable to simulate the movements essential to lung function. When exposed to inflammatory proteins and bacteria, Ingber’s artificial lung reacted much as living lungs would. And exposure to silica nanoparticles used to model the effects of ultrafine particulates revealed that movement affected how tissues absorbed them. Donald Ingber led the team that developed the first human lung-on-a-chip at Harvard University’s Wyss Institute. Sam Ogden It was a powerful proof-of-principle demonstration of a system that could be used to test drugs and other chemicals, providing a complement and even an alternative to testing in tissue cultures or in animals. Even so, the editors at Science were hesitant. They rejected the paper and suggested that Ingber’s team also run the tests in mice. It wasn’t an unreasonable request: Harvard’s lung system was new and comparing the results it generated to results from mice would help validate it. Ingber’s team ran the suggested experiments and resubmitted their study a year later, in 2010, at which point it was published. (It has since been cited by nearly 5,400 other papers.) Still, the incident spoke to how animal models have been the default of modern biomedical research. An early lung-on-a-chip developed at Harvard’s Wyss Institute used microfluidic channels lined with human cells to reproduce key features of lung function. Wyss Institute at Harvard University A recent story told by Ilka Maschmeyer, a translational toxicology researcher and executive at the German biotech company TissUse, shows how much things have changed. TissUse specializes in building organ-on-a-chip systems—the conversational name for systems like Ingber’s lung—that are used by pharmaceutical companies for research. A few months ago, says Maschmeyer, a pharmaceutical company approached TissUse after being denied permission by the U.S. Food and Drug Administration to run a clinical trial of a new drug. The problem: It had presented animal data, but the FDA wanted data from organs-on-a-chip or some comparable alternative. The standards had come full circle. A Breathing Lung-on-a-Chip The moment spoke to a trend, perhaps even the early days of a fundamental shift, away from the use of animals in toxicology and drug development. “It’s rare still,” says Maschmeyer, “but I think it’s going to be more and more frequent.” A host of these kinds of alternatives to experiments on animals have been developed over the years. Collectively they’re known as NAMs, an acronym that stands, depending on whom you’re talking to, for new approach methodologies, novel alternative methods, or nonanimal methods. Most NAMs have yet to be rigorously tested, but early studies suggest their potential. As NAMs have become more sophisticated, the question of how they will be implemented has become less about their technical qualities and more about the practical next steps needed to realize their potential. Validating NAMs—standardizing the systems, conducting head-to-head comparisons with animal experiments—is an enormous challenge. Moreover, simply outperforming animal models is necessary but not sufficient. The adoption of NAMs will require changes in policy, training, and culture. “This transition process is much more complicated than you would think,” says Thomas Hartung, a toxicologist and director of the Center for Alternatives to Animal Testing at Johns Hopkins University. “It is more about change management than it is about the technology.” The Technologies Replacing Animal Testing For decades, animal advocates and many scientists have criticized both the morality and usefulness of experimenting on animals. An estimated 92 percent of all drugs that enter U.S. clinical trials fail to reach the market, sometimes for business reasons but often because the drugs prove ineffective or unsafe in ways that were not predicted by animal experiments. Failure rates are even higher in drugs for heart disease, cancer, and diseases of the brain. These statistics don’t automatically mean that a reliance on animals is to blame. Flawed study designs are a problem too, and also the sheer confounding complexity of disease. But there’s little question that animals have made poor surrogates for many conditions. And just as animal experiments may mistakenly suggest efficacy or fail

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