Scientists grow tiny human livers that predict toxic drug reactions

The results were published online on September 26, 2025 Advanced scienceDescribes a complete, miniature human liver system developed from a patient’s stem cells and immune cells. This advanced model provides a new way to study why some people develop severe immune-related liver injury from drugs considered safe. The research was led by co-first author Fadwa Al-Abdalawi Al-Sousi, and corresponding author Magdalena Cassindra, both from the Center for Stem Cell and Organic Medicine (CuSTOM) at Cincinnati Children’s Hospital.

“Our goal was to create a human system that captures how patients’ liver and immune systems interact,” says Al-Abdalawi Al-Soussi. “By integrating patient-specific genetics and immune responses, we can finally begin to explain why some drugs cause liver injury in only a small subset of individuals.”

A model replicating immune-related liver injury

Some drugs that pass traditional safety tests can still lead to idiopathic drug-induced liver injury (iDILI), a rare but serious immune reaction that can cause severe illness or force drug withdrawal. Standard laboratory and animal models have long struggled to reproduce these complex immune responses that vary from person to person.

The new platform bridges this gap by combining liver organoids made from induced pluripotent stem cells (iPSCs) with each donor’s own CD8⁺ T cells, which are immune cells that target injured or damaged tissue. The result is a complete human immunocompetent system that reflects the genetic and immunological diversity found in real patients.

As a proof of concept, the researchers recreated liver damage caused by the antibiotic flucloxacillin, which only occurs in individuals who carry the HLA-B*57:01 risk gene. Their model accurately reproduced biological markers of immune-related liver injury, including T cell activation, cytokine release, and liver cell damage, closely mirroring what happens in susceptible people.

“Our goal has always been to bring human biology to the laboratory in a way that is scalable, reproducible, and meaningful to patients,” says Cassindra, who serves as director of research and development at CuSTOM. “By linking foundational stem cell science with applied toxicology, this model pushes organoid research one step further toward changing how drugs are developed and tested.”

Building on the foundation of organic innovation

This new platform expands on previous work by co-author Takanori Takebe, MD, PhD, whose laboratory has developed methods to reliably produce human liver organoids from iPSCs. By optimizing these techniques into a matrix-free microarray system and pairing them with a patient’s own immune cells, the CuSTOM Accelerator team at Cincinnati Children’s Hospital has turned a scientific breakthrough into a scalable precision toxicology tool.

Collaboration with Roche played a key role in the success of the project, as it combined the hospital’s scientific expertise with Roche’s expertise in translational toxicology.

“This partnership demonstrates the power of combining academic innovation with industry expertise,” says Adrian Roth, Ph.D., chief scientific director for personal healthcare safety at Roche. “Together, we are building predictive human models that can improve patient safety and accelerate the development of new medicines.”

A growing ecosystem for organic medicine

Cincinnati Children’s Hospital has been a world leader in organoid medicine since 2010, when its scientists created the first functional human intestinal organoids.

Under Cassandra’s leadership, the CuSTOM Accelerator is collaborating with biopharmaceutical and technology companies to translate these scientific advances into real-world solutions for drug safety, precision medicine, and regenerative therapy.

What’s the next step?

The CuSTOM Accelerator team continues to work to automate organoid screening and enable high-throughput screening across large, genetically diverse donor populations. This next phase will allow researchers to capture the full range of human diversity – an essential step towards developing more effective, comprehensive and personalized treatments.

Learn more about CuSTOM’s ongoing collaboration with Molecular Devices and Danaher: Collaboration to Develop Liver Organoids for Drug Toxicity Screening – Research Frontiers

“This work reflects CuSTOM’s vision – to transform human physiology into practical tools that improve health,” Cassandra says. “This is just the beginning – by connecting biology, engineering, and clinical insight, we are getting closer to predicting how real patients will respond to new treatments before they reach the clinic.”

About the study

Cincinnati Children’s Hospital and University of Cincinnati co-first author Michael Brusilovsky, PhD (now with Sanofi), Emma Buck, MS (now at Emanis Life Sciences), W. Clark Bacon, MS, Sina Dadgar, PhD, Ricardo Baril, PhD, and Michael Helmrath, MD, included co-first author Michael Brusilovsky, MD (now with Sanofi). Collaborators also included experts from Genentech, Inc. and Molecular Devices LLC.

Funding sources for this research include Roche, Danaher, and the Farmers Family Foundation.