A miniature heart beating in a petri dish is quietly changing the way we assess drug safety, bringing a silent revolution to the global pharmaceutical industry.
During drug development, cardiotoxicity is a leading cause of drug failure. Approximately 27% of drugs are eliminated in the preclinical research stage due to cardiac safety concerns 1 .
Traditional testing methods often fail to accurately predict human cardiac responses, which has been a major challenge for the pharmaceutical industry.
With the advent of induced pluripotent stem cell (iPS cell) technology, scientists can now reprogram blood or skin cells to generate beating human cardiomyocytes, bringing unprecedented precision and reliability to drug safety testing.
Cardiovascular diseases are among the leading causes of death worldwide, with nearly 18 million people dying from cardiovascular diseases each year 1 . Drug-induced cardiotoxicity not only threatens patients' lives but also significantly increases the cost and risk of new drug development.
Effects on electrophysiology and contractility, including QT interval prolongation 1 .
QT interval prolongation leading to arrhythmia is one of the most common drug-related cardiac adverse reactions 1 . Traditional testing methods, primarily relying on animal experiments and engineered cell lines expressing specific ion channels (such as hERG channels), have significant limitations as animal hearts differ substantially from human hearts in physiology and electrophysiology 1 .
In 2006, the Japanese scientist Shinya Yamanaka's team successfully developed iPS cell technology, a breakthrough that brought revolutionary changes to human disease modeling and drug testing 7 .
iPS cells are created by introducing specific genes into somatic cells, reprogramming them into pluripotent cells 5 . These cells can differentiate into any cell type in the human body, including cardiomyocytes.
The emergence of iPS cell-derived cardiomyocytes means researchers can now obtain human-derived cardiomyocytes for testing drug safety and efficacy.
They retain the physiological characteristics of the human heart, more accurately predicting drug responses in human hearts 5 .
iPS cells can continuously differentiate into cardiomyocytes, providing stable, abundant experimental materials 5 .
iPS-CMs can be derived from specific patient populations (including those with heart diseases) to study individual differential responses to drugs 5 .
With the development of iPS-CMs technology, Japanese scientists are at the forefront of applying this technology to improve cardiac safety assessment.
In 2016, led by the Japanese National Institute of Health Sciences (NIHS), researchers from academia and industry formed the JiCSA (Japanese iPS Cardiac Safety Assessment) Consortium 6 .
The consortium's goal is clear - to develop and standardize protocols for cardiac safety testing using iPS-CMs, providing scientific evidence for revising the ICH S7B guidance 6 .
Researchers use multi-electrode array (MEA) systems to detect the electrophysiological activity of iPS-CMs 6 .
Japanese iPS Cardiac Safety Assessment consortium established in 2016 6
When iPS-CMs beat in a culture dish, MEA can non-invasively record their field potentials, similar to clinical electrocardiograms, providing key information about cardiac electrical activity 6 . By analyzing these data, researchers can detect potential drug-induced cardiac electrophysiological abnormalities, such as QT interval prolongation or other arrhythmia risks 6 .
The JiCSA consortium conducted a large-scale validation study to evaluate the accuracy and reliability of iPS-CMs in predicting drug cardiotoxicity 6 .
The table below shows representative results from testing three different types of drugs:
| Drug Type | Known Cardiac Risk | iPS-CMs Test Results | Prediction Accuracy |
|---|---|---|---|
| Antihistamine A | High (arrhythmogenic) | Significantly prolonged field potential duration | Correct |
| Antibacterial B | Low (no known risk) | Minimal or no effect | Correct |
| Antipsychotic C | Medium (potential risk) | Moderately prolonged field potential duration | Correct |
Further analysis showed that iPS-CMs testing could identify risks that traditional hERG testing might miss. For example, some drugs showed lower risk in single hERG channel tests but demonstrated significant arrhythmogenic effects in iPS-CMs, possibly because iPS-CMs contain complete cardiomyocyte electrophysiological activity, not just a single ion channel 6 .
The work of the JiCSA consortium not only demonstrated the scientific value of iPS-CMs testing but also promoted international cooperation. They shared experimental protocols and evaluation metrics with the "Cardiomyocyte Working Group" of the CiPA (Comprehensive in vitro Proarrhythmia Assay) initiative led by the US FDA 6 .
This collaboration facilitated the implementation of international validation studies, paving the way for the revision of the ICH S7B guidance 6 .
Meanwhile, Japanese researchers have made progress in other aspects of iPS cell technology. The RIKEN Institute, in collaboration with the Kyoto University iPS Cell Research Foundation and Kaneka Corporation, developed suspension culture technology for iPS cells 3 .
This new technology successfully inhibits spontaneous differentiation of iPS cells in suspension culture by adding two specific inhibitors - PKC(β) signaling inhibitor and WNT signaling inhibitor 3 .
This allows iPS cells to be established and scaled up entirely under suspension conditions, greatly increasing the yield and quality of iPS cells and their differentiated cardiomyocytes 3 .
Although iPS-CMs testing shows great promise, it still faces some challenges. One major issue is the maturity of iPS-CMs - those cultured in the laboratory are structurally and functionally more similar to fetal cardiomyocytes than adult cardiomyocytes 5 .
Allowing iPS-CMs more time to develop and mature 5
Such as "biowire" technology using electrical stimulation to promote structural and functional maturation 5
Better simulating the natural cardiac microenvironment 1
Another challenge is the population heterogeneity of iPS-CMs - they may contain mixed populations of atrial-like, ventricular-like, and pacemaker-like cells 5 . Scientists are attempting to guide iPS cells to differentiate into specific cardiomyocyte subtypes by modulating retinoic acid and Wnt signaling pathways 5 .
| Application Area | Specific Use | Progress Status |
|---|---|---|
| Drug Safety Testing | Assessing drug arrhythmogenic risk |
International validation stage
85%
|
| Disease Modeling | Studying genetic heart disease mechanisms |
Used for long QT syndrome, HCM
75%
|
| Personalized Medicine | Customizing drug tests for specific patient groups |
Research stage
45%
|
| Regenerative Medicine | Cell therapy for heart failure patients |
Early clinical trials
25%
|
The safety testing technology using iPS cell-derived cardiomyocytes is gradually moving from research laboratories to global regulatory standards. The research team at Osaka University has made iPS cell-differentiated cardiomyocytes into cardiomyocyte sheets and begun early clinical trials to evaluate their therapeutic effects on patients with severe heart failure 7 .
As regulatory agencies consider revising the ICH S7B guidelines, the tiny hearts beating in petri dishes may soon become the new global standard for drug safety testing - these rhythms of life created by iPS cell technology are guiding us toward a future of safer drug treatments.