Could the Next Blockbuster Drug Be Lab-Rat Free?

In 1937, an American drug company introduced a new elixir to treat strep throat — and unwittingly set off a public health disaster. The product, which had not been tested in humans or animals, contained a solvent that turned out to be toxic. More than 100 people died.

The following year, Congress passed the Federal Food, Drug and Cosmetic Safety Act, requiring pharmaceutical companies to submit safety data to the U.S. Food and Drug Administration before selling new medications, helping to usher in an era of animal toxicity testing.

Now, a new chapter in drug development may be beginning. The F.D.A. Modernization Act 2.0, signed into law late last year, allows drug makers to collect initial safety and efficacy data using high-tech new tools, such as bioengineered organs, organs on chips and even computer models, instead of live animals. Congress also allocated $5 million to the F.D.A. to accelerate the development of alternatives to animal testing.

Other agencies and countries are making similar shifts. In 2019, the U.S. Environmental Protection Agency announced that it would reduce, and eventually aim to eliminate, testing on mammals. In 2021, the European Parliament called for a plan to phase out animal testing.

These moves have been driven by a confluence of factors, including evolving views of animals and a desire to make drug development cheaper and faster, experts said. But what is finally making them feasible is the development of sophisticated alternatives to animal testing.

It is still early for these technologies, many of which still need to be refined, standardized and validated before they can be used routinely in drug development. And even advocates for these alternatives acknowledge that animal testing is not likely to disappear anytime soon.

But momentum is building for non-animal approaches, which could ultimately help speed drug development, improve patient outcomes and reduce the burdens borne by lab animals, experts said.

“Animals are simply a surrogate for predicting what’s going to happen in a human,” said Nicole Kleinstreuer, director of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods.

“If we can get to a place where we actually have a fully human-relevant model,” she added, “then we don’t need the black box of animals anymore.”

Animal rights groups have been lobbying for a reduction in animal testing for decades, and they have found an increasingly receptive public. In a 2022 Gallup poll, 43 percent of Americans said that medical testing on animals was “morally wrong,” up from 26 percent in 2001.

Reducing animal testing “matters to so many people for so many different reasons,” said Elizabeth Baker, the director of research policy at the Physicians Committee for Responsible Medicine, a nonprofit group that advocates for alternatives to animal testing. “Animal ethics is actually quite a big driver.”

But it is not the only one. Animal testing is also time-consuming, expensive and vulnerable to shortages. Drug development, in particular, is rife with failures, and many medications that appear promising in animals do not pan out in humans. “We’re not 70-kilogram rats,” said Dr. Thomas Hartung, who directs the Johns Hopkins Center for Alternatives to Animal Testing.

Moreover, some cutting-edge new treatments are based on biological products, such as antibodies or fragments of DNA, which may have targets that are specific to humans.

“There’s a lot of pressure, not just for ethical reasons, but also for these economical reasons and for really closing safety gaps, to adapt to things which are more modern and human relevant,” Dr. Hartung said.

(Dr. Hartung is the named inventor on a Johns Hopkins University patent on the production of brain organoids. He receives royalty shares from, and consults for, the company that has licensed the technology.)

In recent years, scientists have developed more sophisticated ways to replicate human physiology in the laboratory.

They have learned how to coax human stem cells to assemble themselves into a small, three-dimensional clump, known as an organoid, that displays some of the same basic traits as a specific human organ, such as a brain, a lung or a kidney.

Scientists can use these mini-organs to study the underpinnings of disease or to test treatments, even on individual patients. In a 2016 study, researchers made mini-guts from cell samples from patients with cystic fibrosis and then used the organoids to predict which patients would respond to new drugs.

Scientists are also using 3-D printers to produce organoids at scale and to print strips of other kinds of human tissue, such as skin.

Another approach relies on “organs on a chip.” These devices, which are roughly the size of AA batteries, contain tiny channels that can be lined with different kinds of human cells. Researchers can pump drugs through the channels to simulate how they might travel through a particular part of the body.

In one recent study, the biotech company Emulate, which makes organs on chips, used a liver-on-a-chip to screen 27 well-studied drugs. All of the drugs had passed initial animal testing, but some had later turned out to cause liver toxicity in humans. The liver-on-a-chip successfully flagged as many as 87 percent of the toxic compounds, the researchers reported in Communications Medicine last December.

Researchers can also link different systems together, connecting a heart-on-a-chip to a lung-on-a-chip to a liver-on-a-chip, to study how a drug might affect the entire interconnected system. “That’s where I think the future lies,” Dr. Kleinstreuer said.

Not all the new tools require real cells. There are also computational models that can predict whether a compound with certain chemical characteristics is likely to be toxic, how much of it will reach different organs and how quickly it will be metabolized.

The models can be adjusted to represent different types of patients. For instance, a drug developer could test whether a medication that works in young adults would be safe and effective in older adults, who often have reduced kidney function.

“If you can identify the problems as early as possible using a computational model that saves you going down the wrong route with these chemicals,” said Judith Madden, an expert on “in silico,” or computer-based, chemical testing at Liverpool John Moores University. (Dr. Madden is also the editor in chief of the journal Alternatives to Laboratory Animals.)

Some of the approaches have been around for years, but advances in computing technology and artificial intelligence are making them increasingly powerful and sophisticated, Dr. Madden said.

Virtual cells have also shown promise. For instance, researchers can model individual human heart cells using “a set of equations that describe everything that’s going on in the cell,” said Elisa Passini, the program manager for drug development at the National Center for the Replacement, Refinement and Reduction of Animals in Research, or NC3Rs, in Britain.

In a 2017 study, Dr. Passini, then a researcher at the University of Oxford, and her colleagues concluded that these digital cells were better than animal models at predicting whether dozens of known drugs would cause heart problems in humans.

Scientists are now building entire virtual organs, which could eventually be linked together into a sort of virtual human, Dr. Passini added, though some of the work remains in early stages.

In the short term, a virtual lab animal might be more achievable, said Cathy Vickers, the head of innovation at NC3Rs, which is working with scientists and pharmaceutical companies to develop a digital model of a dog that could be used for drug toxicity testing.

“It’s still a big push to develop a virtual dog,” Dr. Vickers said. “But it’s about building that capacity, building that momentum.”

Many potential animal alternatives will require more investment and development before they can be used widely, experts said. They also have limitations of their own. Computer models, for instance, are only as good as the data they are built on, and more data is available on certain types of compounds, cells and outcomes than others.

For now, these alternative methods are better at predicting relatively simple, short-term outcomes, such as acute toxicity, than complicated, long-term ones, such as whether a chemical might increase the risk of cancer when used over months or years, scientists said.

And experts disagreed on the extent to which these alternative approaches might replace animal models. “We’re absolutely working toward a future where we want to be able to fully replace them,” Dr. Kleinstreuer said, although she acknowledged that it might take decades, “if not centuries.”

But others said that these technologies should be viewed as a supplement to, rather than a replacement for, animal testing. Drugs that prove promising in organoids or computer models should still be tested in animals, said Matthew Bailey, president of the National Association for Biomedical Research, a nonprofit group that advocates for the responsible use of animals in research.

“Researchers still need to be able to see everything that happens in a complex mammalian organism before being allowed to move to the human clinical trials,” he said.

Still, even this more conservative approach could have benefits, said Nicole zur Nieden, a developmental toxicologist at the University of California, Riverside, who said that she thought the wholesale replacement of animal testing was unrealistic.

In particular, she said, the new approaches could help scientists screen out a greater number of ineffective and unsafe compounds before they ever get to animal trials. That would reduce the number of animal studies researchers need to conduct and the limit the chemicals lab animals are exposed to, she said, adding, “We will be able to reduce the suffering of test animals quite tremendously.”



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