Could the next successful medicine be made without guinea pigs? – 03/14/2023 – Science

In 1937, a US pharmaceutical company introduced a new sore throat remedy and unwittingly caused a public health disaster. The product, which had not been tested on humans or animals, contained a solvent that turned out to be toxic. More than a hundred people died.

The following year, Congress passed the Federal Food, Drug, and Cosmetic Safety Act, requiring pharmaceutical companies to submit safety data to the Food and Drug Administration (FDA) before selling new drugs. This helped usher in an era of animal toxicity testing.

Now, a new chapter in medicinal drug development may be beginning. The FDA’s Modernization 2.0 Act, passed late last year, allows drugmakers to gather initial safety and efficacy data using new high-tech tools, such as bioengineered organs, organs on chips and even computer models. , instead of live animals. Congress has also allocated $5 million to the FDA to accelerate the development of alternatives to animal testing.

Other agencies and countries are making similar changes. In 2019, the US Environmental Protection Agency announced that it would reduce and, over time, eliminate testing on mammals. In 2021, the European Parliament called for a plan to phase out animal testing.

Those moves were driven by a confluence of factors, including evolving views on animals and the desire to make drug development cheaper and faster, experts said. But what finally makes them viable is the emergence of sophisticated alternatives to animal testing.

It is still early days to use these technologies, many of which need to be refined, standardized and validated before they can be used routinely in drug development. And even advocates of these alternatives acknowledge that animal testing is unlikely to end anytime soon.

But the movement against animal testing is growing, which could help speed drug development, improve patient outcomes and reduce the suffering of laboratory animals, experts said.

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

“If we can get to a place where we actually have a fully relevant model for humans,” she added, “we don’t need the animal black box anymore.”

Attitudes about animals

Animal rights groups have lobbied against animal testing for decades and have found an increasingly receptive audience. In a 2022 Gallup poll, 43% of Americans said medical testing on animals was “morally wrong”, up from 26% in 2001.

Reducing animal testing “is important to a lot of people for a lot of different reasons,” said Elizabeth Baker, director of research policy for the Physicians Committee for Responsible Medicine, a nonprofit group that advocates for alternatives to animal testing. “Animal ethics is actually a great stimulus.”

But it’s not the only one. Animal testing is also time-consuming, expensive and subject to shortages. Drug development, in particular, is riddled with flaws, and many drugs that look promising in animals don’t work in humans. “We are not 150-pound rats,” said Thomas Hartung, director of the Johns Hopkins Center for Alternatives to Animal Testing.

In addition, some new cutting-edge treatments are based on biologics, such as antibodies or DNA fragments, which can have specific targets in humans.

“There’s a lot of pressure, not just for ethical reasons but also for economic reasons and to really close the security gaps, to adapt to things that are more modern and relevant to the human being,” Hartung said.

(Hartung is the inventor named in a Johns Hopkins University patent on brain organoid production. He receives royalties and consults for the company that licensed the technology.)

Brave new biology

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

They learned how to coax human stem cells into a small, three-dimensional cluster known as an organoid, which exhibits some of the same basic characteristics as a specific human organ, such as a brain, lung or 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-bowels from cell samples from cystic fibrosis patients and then used the organoids to predict which patients would respond to new drugs.

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

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

computational models

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

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

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

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

Virtual cells have also shown promise. For example, 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, drug development program manager at the National Center for Animal Substitution, Refinement, and Reduction. in Research, or NC3Rs, in Great Britain.

Reduce or replace

Many potential animal alternatives will require further investment and development before they can be used widely, experts said. They also have their own limitations. Computer models, for example, are only as good as the data they are built upon, 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 complex, long-term ones – for example, whether a chemical might increase cancer risk when used over months or years – , the scientists said.

And experts disagree on the extent to which these alternative approaches can replace animal models. “We are absolutely working towards a future where we want to replace them entirely,” Kleinstreuer said, although he acknowledges that this could take decades, “or even centuries.”

But others said these technologies should be seen as a complement to, not a replacement for, animal testing. Drugs that show promise in organoids or computer models have yet to 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 they are allowed to move on to human clinical trials,” he said.

Translated by Luiz Roberto M. Gonçalves