By Nina Bauer, PhD

When US and European regulators acted in recent years to support the use of animal model alternatives for drug development, reactions were mixed. There is broad acknowledgement regarding the limitations of animal-based disease models and their inability to fully recapitulate human biological complexity, contributing to a high clinical failure rate, and so there was true excitement for the possibilities.

There were also concerns that the necessary technology doesn’t yet exist to form the basis for widespread changes. This partly reflects decades of development that have flown under the radar. In fact, there has been a consistent push for such new approach methodologies (NAMs) within industry and academia, even in the absence of a consistent pull from regulators.

One particular technology crucial to the future of NAMs, which has been steadily if quietly progressing for decades, is induced pluripotent stem cells (iPSCs). iPSCs are the utility player and workhorse of the NAMs movement, underpinning everything from organoids to microfluidic chips and even AI models.

Today, as NAMs take center stage and biopharmaceutical companies explore scalable alternatives to animal testing that are more human relevant, economical, faster and ethical, iPSCs are coming of age.

A Brief History

One of the reasons for our reliance on animal models is an embedded history. Animal testing for biological research dates back at least to the ancient Greeks, and it ultimately enabled the foundational understandings that shape drug development today. However, about 30 years ago, advances including Dolly the Sheep and the Human Genome Project began to open new doors.

In the mid-2000’s, we began to see a shift away from animal use for toxicity testing, culminating with the launch of the Toxicology in the 21st Century (Tox21) program in 2008 by multiple US agencies.

In parallel, scientists were laying the groundwork for the iPSC revolution, starting with the creation of the first mouse iPSCs in 2006 and human ones a year later. By the time Shinya Yamanaka and John Gurdon won the Nobel Prize in 2012 for their initial iPSC discoveries, significant scientific progress had been made.

One landmark initiative launched in 2013 evolved into an international collaboration that resulted in the development of the Comprehensive in Vitro Proarrhythmia Assay (CiPA), combining the use of iPSC-derived cardiomyocytes and in silico modeling. Once researchers demonstrated CiPA modeling was more accurate than animals, the integrated cardiac tox screening approach paradigm was incorporated into international regulatory expectations. CiPA demonstrated a convergence of the progress seen with iPSC technologies and NAMs more broadly, effectively serving as a proof-of-concept for the NAMs field that exists today.

Soon thereafter, gene editing technology such as CRISPR expanded their potential utility, supported by the growth of HLA-matched iPSC cell banks. iPSC banks were generating limitless numbers of human cells like cardiomyocytes, neurons, hepatocytes, and more, to be used for disease screening and tox testing. This led to combinations of iPSC-based cell types for use in more complex combinations for microphysiological systems, including microfluidic organs-on-chips and organoids.

Commercialization accelerated into the 2020’s, followed by regulatory modernization pushes in the US and Europe to encourage a move towards more human-relevant models. This public pressure escalated as large-scale iPSC manufacturing took root.

Overcoming Practical Obstacles

As a manufacturer of iPSCs that are frequently utilized in a variety of NAMs, our teams had been hearing a frustrating refrain for several years: biopharmaceutical companies were recognizing the predictive capability of NAMs, even expressing a preference over animal models in certain instances, but regulators, investors, and funding agencies still maintained an expectation that certain benchmarks of the drug development cycle would be demonstrated in animal models.

Some drug developers still found it worthwhile to effectively duplicate research on both systems, given the advantages of NAMs, but overall, the existing regulatory atmosphere continued to disincentivize investment in their usage.

As a young field, the NAMs industry also had yet to standardize, often limiting reproducibility. iPSCs in particular began as an academic endeavor, and labs produced cells with different protocols, making material inconsistent and workflows difficult to validate.

Recent regulatory changes that allow or even encourage use of NAMs have begun to change industry perspectives, creating new opportunities. These did not happen in a vacuum: iPSC-based NAMs were already starting to prove their worth, with commercial utility in cardiotoxicity testing and safety pharmacology.

With the advent of commercial-grade iPSC manufacturing, the field now has the scalable basis for broader use of NAMs, and uptake is increasing. iPSC-derived cells and related organoid systems have become standardized and industrialized.

Integration, Not Replacement

Ultimately, the most pertinent question isn’t “why have NAMs taken so long to arrive” or even “when will NAMs replace animal testing” – replacement is not the goal. The crucial point is about how and when iPSC-based NAMs can begin improving drug development, and the answer is, effectively, now.

The range of NAMs make it possible to begin reducing animal usage in specific scientific contexts. As the field matures, iPSC-derived cells will be a cornerstone of NAMs that better recapitulate full human tissue complexity. Off-the-shelf, GLP-compliant products will require increasingly robust QC and standardized manufacturing protocols to ensure consistency and replicability.

To support the next phase of growth, we expect that the recent regulatory enthusiasm for NAMs will mature into an international harmonization effort, hinging on validation efforts that clearly connect in vitro readouts with clinical outcomes.

Despite the rapid growth of iPSC capabilities, there is no short-term expectation that animal usage will shrink to zero, or NAM uptake will become universal. Animal modelling matured over the course of centuries and, despite its limitations, has a track record that NAMs have not yet secured.

To achieve the universal goal of better, safer, drug development that gets new medicines to patients faster, we expect to see steady growth and integration of new models that leverage in vitro, iPSC-based testing with AI and other new technologies.

Reference

Thomas R. The US Federal Tox21 Program: A strategic and operational plan for continued leadership. ALTEX. 2018;163–8.

Nina Bauer is Executive Vice President, Strategy and Commercial, FUJIFILM Cellular Dynamics. She works on iPSC manufacturing and clinical translation programs, collaborating with therapy developers to move iPSC-derived products from research-grade processes to GMP manufacturing, and enabling NAMs through an extensive catalogue of off-the-shelf cell types for screening and testing.