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Can we end animal testing?
We find out whether innovative techniques using stem cells, computer modelling and 3D-printing could reduce the number of animals used in medical research.
Alla Katsnelson
There are many disagreements in the world of research, but few debates will get as heated as those surrounding animal testing. Many scientists and research advocates contend that animal experiments are crucial for learning about basic biology and disease mechanisms, and are necessary for testing the safety and efficacy of new medicines and chemicals. They point to many potent medicines that exist thanks to animal testing. Opponents, meanwhile, contend that subjecting animals to experiments for human gain is ethically unjustified. What’s more, many argue, such research is often misleading because it compares apples and oranges: results from animal studies often don’t translate to humans because the animals are just too different.
New methods
Animal welfare activists have long insisted that researchers jettison research on animals for alternative methods, such as human stem cells grown in a dish, computer modelling, or expanded clinical trials. But it’s only in the past few years that most of these tools have become truly good enough for prime-time use. Now, many researchers are embracing these alternatives. As Dr Donald Ingber, director of Harvard University’s Wyss Institute for Biologically Inspired Engineering, says, “It’s coming to a tipping point.”
Tallying the precise number of animals used in research is difficult, because countries record animal experiments differently. But estimates suggest that the count is more than 100 million animals each year worldwide. The majority are used in basic research and breeding to create specific genetic modifications. A smaller percentage of animals are used to test the effects of drugs or chemicals. More than 95 per cent of all animals used in research are mice, rats, birds and fish, but other species enter the mix, too. For example, some 60,000 monkeys like macaques are used in experiments in the US, Europe and Australia.
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It’s hard to deny that research on animals has advanced human health. In the 19th Century, for example, French biologist Louis Pasteur used animal experiments to understand how microorganisms can cause disease, and later to develop a vaccine for rabies. Animal studies were also crucial in understanding how insulin is produced and in developing ways to supplement it in people with diabetes. Penicillin was proven effective in mice, blood transfusions were perfected in rabbits, and kidney transplants were tested in dogs and pigs.
There’s no shortage of recent examples, either. Experiments in which macaques were infected with SIV, the monkey version of the AIDS-causing HIV virus, were crucial in creating antiretroviral medicines and in developing strategies for a potential HIV vaccine. Deep brain stimulation, used by some 20,000 people with Parkinson’s disease, relied on rat and monkey models to understand how the disease affects a part of the brain called the basal ganglia and how surgically implanting a stimulator could improve patients’ motor symptoms. And brain-machine interfaces that allow paralysed people to perform everyday tasks, such as bringing a coffee cup to their lips, are being developed with the help of experiments in monkeys.
A dying breed?
Yet many scientists would now agree that for some studies, animal experiments are no longer the best way forward. “Animal testing is an important tool – it has made our world safer and it has helped to develop certain drugs – but at the same time it has very often been misleading,” says Prof Thomas Hartung, a toxicologist and the director of the Center for Alternatives to Animal Testing at Johns Hopkins University in Baltimore, Maryland. He says that in just the past few years, there has been more agreement on the limitations of animal testing and “the belief that this is some type of gold standard is fading”.
Among researchers and the public, support for limiting animal research where possible seems to be growing. In the past few years, the European Union, Israel and India have banned animal testing for cosmetics, and other countries are considering similar laws. (The UK led the way with the first such ban back in 1989.) Countries throughout the world have largely phased out research on Old World primates such as chimpanzees, and in many regions the use of other non-human primates – as well as some other mammalian species – is also on the decline. Meanwhile, regulatory bodies like the US Food and Drug Administration (FDA), which have long insisted on animal studies, are beginning to evaluate whether alternative technologies can show similar or better results, says Ingber, and companies are trying to implement these tools into their pipeline.
Changing times
It’s not just ethical concerns spurring this change. Switching to studies that use human tissue instead of animals may often make for better science. Experimental medicines that seem to be effective in animals (usually rodents) often fail in human trials; 9 out of 10 cancer drugs, and 98 out of 100 neurological and psychiatric drugs that show promise in animal tests don’t turn out to work when tested in humans. Animal studies certainly don’t deserve the full blame for this disconnect, but finding better and more predictive disease models might help, researchers say.
There are also cases where a human disease simply can’t be modelled in animals. For example, Alysson Muotri, a neuroscientist at the University of California, San Diego, studies a rare but devastating neurological disease called Aicardi-Goutieres Syndrome (AGS). The mutations causing AGS are well-known, but when Muotri studied mice that had been genetically engineered to carry these mutations, he found that they had no symptoms. When his team grew cell structures called organoids from stem cells derived from tissues of patients with the disease, they recreated the nerve cells’ glitch. They learned that what causes the disease is an immune response to an element of DNA that is specific to humans. “It’s a case where we have a truly human disorder,” Muotri says. “We couldn’t see it in the mouse, and very likely we wouldn’t see it in a primate.”
One especially promising human cell-based alternative to animal research is so-called ‘organ-on-a-chip’ technology, in which specific types of human stem cells are grown with membranes on a microchip to mimic the function of specific organs. “There are lots of things you can do on these chips that you can’t do in animal testing,” says Ingber, who has developed about 15 such devices, along with his colleagues, for mimicking the function of organs including the lungs, intestine, kidney and bone marrow. Each chip, the size of a computer memory stick, is engraved with tiny channels that are lined with human cells and artificial blood vessel tissue. The tools also capture physiological features such as blood pressure and mechanical forces that act on cells. Researchers can link up to 10 chips together with vascular channels containing human blood in order to study how organ systems interact.
“We’ve been able to mimic amazing things – diseases of all types, pulmonary oedema, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, viral infection, drug toxicities – and we’ve been able to make chips with cells from patients,” Ingber says. These devices reveal drug toxicities that don’t show up in animal models, and can also probe questions that can’t be asked in clinical trials for ethical reasons. His team is using them to model the effects of radiation exposure, as well as childhood illnesses and malnutrition.
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But organs-on-a-chip aren’t just for university scientists. Roche Pharmaceuticals, one of the top five drug companies worldwide, embraced the technology three years ago and already uses it to test the safety of new compounds. “It opens a totally new field of opportunities to us in biology and drug discovery, and all of them are much better than an animal ever can be,” says Thomas Singer, Roche’s global head of pharmaceutical sciences. As this and other tools improve further, more companies have adopted them, banking on them being more reproducible and predictable than animal tests. “In the beginning we were very much on our own,” Singer says. “But I am convinced this technology will see a huge boost in development.”
Tiny organs
Other human cell-based alternatives to animal models are becoming available too. Prof Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in North Carolina, is creating tissues and organs such as bladders and kidneys using a 3D printer that spits out different types of human cells. “You are miniaturising a human organ, really,” he says. Initially, his team built these organs for surgical use in the body, but he soon realised that they could be standardised and mass-produced in minutes – ideal specs for screening new medicines and testing their safety. Initially, he says, such technologies will just supplement the animal studies, but eventually they can replace them.
Toxicology studies, for medicines as well as for all sorts of other chemicals, are a low-hanging fruit for switching to alternative methods, explains Hartung. Many animal tests are particularly bad at predicting toxicity in humans, not to mention slow and expensive to conduct, and in many cases, more modern, cell- or computer-based assays have been developed. Pushing the issue, a European law passed a decade ago requires thousands of chemicals to be assessed for safety. Hartung and other toxicologists in academia and industry have developed a computer model that can predict the toxicity of a compound based on its similarity to others. “This is astonishingly powerful,” he says.
But despite the promise of all these techniques, experts say, change will probably come slowly, and it’s likely that some forms of animal models will never be eliminated at all. As Ingber puts it, “I think we are going to replace animal testing one model at a time.”
- This article was first published in February 2018
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- 16 July 2024
Animal research is not always king: researchers should explore the alternatives
You have full access to this article via your institution.
Key differences between the immune responses of humans and mice make mice poor models for treating diseases such as sepsis in humans. Credit: Philippe Merle/AFP/Getty
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 .
Octopuses used in research could receive same protections as monkeys
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 species 1 , 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 humans 2 .
Can lab-grown brains become conscious?
Even among humans, responses to vaccines can vary by age, sex and geographical region in ways that are often difficult to model using animals 3 . 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 t ake 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.
Nature 631 , 481 (2024)
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