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Animal testing is crucial for measuring the efficacy and safety of new treatments. It's also a step that everyone would like to avoid as much as possible for economic, regulatory, and ethical reasons. But what are the alternatives, and can they really reduce the use of animals in drug development? Before drug developers let a treatment anywhere near human testing, they need evidence that it’s likely to be both safe and effective. This has historically been done by testing the drug on living animals (in vivo), and more recently in human cells or tissue in a dish (in vitro). In general terms, in vitro testing is cheaper and quicker than in vivo, but testing in animals, most commonly mice, is thought to give a better picture of how a treatment behaves in a living organism. While the predictive value of animal models does vary depending on the diseases and treatments in question, a company must always show that its treatment is safe and effective in animal models to get past regulatory hurdles. With advances in biotechnology, we’re now able to better mimic human organs and physiology. If these technologies prove better than animal testing at predicting the effects of a drug on the human body, they could eventually replace some of the animal testing currently required in drug development. While it's unlikely that animal disease models can ever be replaced fully, these technologies are changing the face of drug development and reducing our reliance on animal models. This could make it cheaper and quicker to get new disease treatments into the clinic and eventually to patients. Tissue bioprinting 3D printing has revolutionized the tech world for its potential to produce complex machine parts from a digital file. The same is starting to be done using bioinks that carry cells to make living tissues. Tissue bioprinting can be used to replicate the 3D structure of a human tissue, which provides a lot more information about a drug’s effect than just using human cell cultures. For example, the French bioprinting company Poietis is working with the pharma Servier to develop a bioprinted liver model to test the likelihood that a drug will cause liver toxicity. “Few companies in the world use bioprinted tissues in the drug discovery process,” said Kevin Fournier, Sales Manager at Poietis. “But every year more and more companies choose to use bioprinting technology for their applications. Some experts are betting on a huge explosion of this technology over the coming years.” One particular area of interest for the bioprinting field is cosmetics. Since the EU banned animal testing in cosmetics research back in 2013, the French giant L’Oreal has been working with the US biotech Organovo to bioprint human skin for testing. Aside from traditional drug development, tissue bioprinting could also enable personalized medicine. One example of this is a collaboration between Swedish company Cellink and French biotech CTIBiotech to bioprint tumor tissue derived from cancer patients to test which specific drug will help each patient best. However, tissue bioprinting is still at a very early stage. “At the moment, there are no studies that compare animal models to bioprinted models,” Fournier told me. “We bet that, over the next 10 years, bioprinting technologies will offer alternatives that are closer to native human tissues and that are also more ethical, responsible, and affordable than animal models. We all have a lot to win by changing our models.” Organoids While cell cultures are tried and tested methods for screening drugs, how human cells behave in a dish is not necessarily how they behave in the body. One alternative could be miniature organs, called organoids. These 3D organoids are grown using stem cells, which, with the right cocktail of nutrients and treatments, can become the organ of choice. Like with bioprinting, organoid research is still in its early stages, but there are several companies developing the technology. For example, Sun Bioscience in Switzerland is using organoids to model the intestine and study how it is affected by the genetic condition cystic fibrosis. In the Netherlands, OcellO develops organoids to model different types of cancer. “Colorectal cancer is the most advanced organoid field scientifically,” said Leo Price, CEO of OcellO. “Development still needs to occur in immuno-oncology, immunology, neurodegeneration, diabetes, obesity, and fibrosis -- all areas where the tissue architecture is going to be critical. Simple cultures of cells on plastic aren't going to cut it.” There is also an active academic community developing organoids, with at least two groups modeling the placenta, and even efforts to develop brain organoids for modeling neurological diseases. Like bioprinting, organoids could have big uses in advanced in vitro testing in early drug development, and even in personalized medicine. According to Price, the first stages of preclinical testing could be done in organoids, with only a final validation needed in the animal. One drawback of organoids is that it’s still hard to manufacture them reliably for the commercial scale. Another is that it’s currently tricky to include a diverse set of cell types within the organoid, which is what one would find in real organs. There’s work being done to overcome this, but there’s still a long way to go. Organ-on-a-chip Organ-on-a-chip technology consists of growing cells inside of tiny chips that mimic the structure and behavior of human organs. Because of the small size of the chips, researchers can test drugs more quickly and cheaply than in animals. “The organ-on-a-chip field is only maybe six or seven years old,” said Jos Joore, CEO of the Dutch organ-on-a-chip company Mimetas. “It has a huge promise on its shoulders, and is actually coming up with good predictive disease models.” These organs-on-a-chip are being used to model all sorts of organs, including liver, kidney, intestines, heart, and even the brain. The chips can then be connected to each other to model how a drug affects different organs as it travels through the bloodstream. This is what UK company CN Bio is doing with a system that incorporates 10 organs on a single chip. However, Joore believes that this system cannot replace animal testing fully. In fact, mixing too many organs-on-a-chip may be missing the main strength of the technology, which is making simple disease models in human tissues easy and quick. “When you start connecting these tissues, the complexity increases exponentially,” he told me. “I don’t even want to think about connecting ten tissues because at the end of the road, you’re making, I would say, a Frankenstein’s monster, which you can hardly control anymore.” The future of animal testing in research Bioprinting, organoids, and organs-on-a-chip are all early stage technologies with the potential for making in vitro research better predict the effects that a drug will have on humans. While they represent a big improvement over traditional cell cultures in the drug development process, they are still limited in regards to predicting the behavior of a drug. This means that, while these technologies may reduce animal testing, animals will still likely be used to validate the results before testing in humans. Still, one big issue remains with animal research, which is that animal testing doesn’t represent human patients perfectly. This is particularly the case in neurodegenerative diseases such as Alzheimer’s, where many drugs have failed in clinical trials after showing promise in animal testing. “Animal models, on a general level, are not very predictive,” remarked Joore. “If animal models worked perfectly, you wouldn’t have 90% attrition when you start doing a clinical trial.” Chris Magee, Head of Media and Public Affairs at the organization Understanding Animal Research, told me that animal models are actually great at predicting the safety of a drug. However, they tend to be less predictive of drug efficacy, often because experiments have been oversold or badly designed in the past. This has improved over the years, though. “Scientists know that mice aren’t tiny humans,” Magee commented. “In recent years there’s also been less of a tendency to over-promise on the basis of animal studies.” So, can biotechnology reduce animal testing in medicine? In the near future, it seems animal models are here to stay. But their use should decrease a lot, due both to the rise of new techniques and to better experimental design. As we reduce animal testing, drug development gets cheaper, faster, and more ethical, so everyone's a winner. Cover illustration by Elena Resko, images from Shutterstock, NIH Flickr, and Cellesce. This article was originally published in April 2019 and has since been updated.

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