The end of animals-only testing brings both opportunities and challenges

The National Institutes of Health announced last week that it will no longer issue funding calls for grant proposals that rely solely on animal testing.

Moving forward, all such calls must also incorporate New Approach Methodologies, or NAMS—alternatives such as artificial intelligence, computer modeling, or "organs-on-a-chip"—to be considered for support. The Food and Drug Administration announced similar parameters in April.

Here, Thomas Hartung, an expert on organoids—lab-grown tissue cultures that mimic human organs, including the brain—discusses the implications of this new approach for policy, science, and human health. Hartung is a professor at Johns Hopkins University's Bloomberg School of Public Health, Whiting School of Engineering, and School of Medicine, as well as  Georgetown University and the University of Konstanz in Germany. He directs the Johns Hopkins Center for Alternatives to Animal Testing and is the field chief editor of Frontiers in AI.

How do organoids compare to traditional animal testing for predicting drug safety and effectiveness in humans? And where do they still fall short of what animal models provide?

Let's take our field of work, brain toxicity and diseases. One out of every four new medicines in development that fail do so because they cause side effects on the brain that didn't show up when tested in animals. For drugs meant to treat diseases of the brain, 95% don't work. Brain organoids—tiny clusters of human brain cells grown in the lab from stem cells that act like miniature versions of how our brains grow and work—are rapidly becoming powerful new tools in drug development. Because they are made from human stem cells, these brain organoids are much better at showing us what will actually happen in people compared to animal testing.

You could make the same case for any essential human organ. Organoids have already proven their value in studying viral infections such as COVID-19 and catching the toxic effects that animal studies missed. In our field, they help us understand what is happening at the cellular level in autism spectrum disorders and Parkinson's disease. They can also be made from individual patient's cells, giving us personalized insights into the way diseases affect different people—a major step toward personalized medicine.

However, brain organoids are not yet perfect copies of real human brains or other organs. They typically represent what organs look like in developing fetuses rather than in adults. They don't have full blood vessel networks or immune responses, and different laboratories sometimes get different results using the same methods. Scientists are working hard to actively address these gaps.

Given that the NIH is now requiring alternatives to animals-only testing, what would it take to convince other regulators that organoids are reliable enough to replace animal testing for brain-related medications? Are we close to that point?

We are at a tipping point. To fully move toward replacing animal testing altogether, organoid and microphysiological systems (MPS) technologies—an umbrella term that includes organoids and organ-on-chip technologies—must prove they give reliable, consistent results that regulators can trust. We have started an international society and World Summits to bring together and advance this community.

MPS platforms that combine brain organoids with fluid flow, real-time sensors, and immune components are now being used to test how chemicals affect developing brains and how drugs cause brain inflammation. While they can't replace completely animal testing yet, these systems are increasingly seen as valid alternatives for specific kinds of testing. The continued development of specialized validation centers and global data-sharing—as proposed by the International MPS Society—will accelerate this transition.

You've spoken previously about the ethical considerations of organoid research. As we reduce animal testing, how do we handle the new ethical questions that come with growing more sophisticated mini-brains in labs?

Using fewer animals in research is a major ethical step forward, but it introduces new questions as we create increasingly complex brain organoids that exhibit human-like features such as organized layers, spontaneous electrical activity, and even responses to external stimuli. While these lab-grown systems currently don't have the structure and connections needed for consciousness, scientists are taking seriously the possibility that they might develop sentient-like behavior in the future.

Ethics in organoid research must evolve proactively and ahead of the science. This means defining levels of complexity that might require additional oversight, improving informed consent for people who donate stem cells, and ensuring transparency about research goals and data use. Several efforts, including those at Johns Hopkins and through the Center for Alternatives to Animal Testing, have called for establishing ethical review frameworks akin to Institutional Animal Care and Use Committees—but adapted to address the unique concerns of human-derived in vitro systems.

We shouldn't wait for public backlash or sensational headlines to force us to think about ethics. As brain organoid research advances—and especially as applications like organoid intelligence emerge—the field must integrate ethical standards, and incorporate patient perspectives and cross-disciplinary governance into its core structure.