Human embryonic stem cells remain indispensable for research and therapy

A recently closed request for information (RFI) from the US National Institutes of Health (NIH) has reopened a question many in the stem cell science community thought had been largely settled: whether human embryonic stem cell (hESC) research should receive federal support. The RFI, coupled with a pause on submissions of new lines to NIH's hESC Registry, represents the agency's most significant policy action in this area since the issuance of the NIH Guidelines for Human Stem Cell Research in 2009.

hESCs represent a foundational platform in stem cell science. Their capacity for sustained self-renewal and pluripotency – the ability to differentiate into all cell types in the body – has informed our understanding of cell differentiation and human development, supported disease modelling and drug screening platforms, and enabled the development of new regenerative medicines.

Because hESCs are derived from early-stage embryos, their use raises ethical questions, which is why hESC research has long been subject to strict oversight. The existing legal and ethical framework for research with hESCs in the USA has allowed this research to proceed without interference for nearly two decades, but NIH's RFI is a signal that this period of policy stability may be nearing an end.

In explaining the rationale for issuance of the RFI, NIH points to a decline in the number of cell lines submitted to its hESC Registry and a plateau in funding for hESC research (while noting that funding for induced pluripotent stem cell (iPSC) research has steadily risen). The agency also suggests that 'newer, more advanced' biotechnologies have the potential to replace hESCs, highlighting adult stem cells and iPSCs as examples.

However, the conversations that informed the International Society for Stem Cell Research's (ISSCR's) response to the RFI pointed in a different direction. Investigators working with these platforms in laboratories around the world emphasised that hESCs remain an integral, often irreplaceable, part of the scientific toolkit, and they continue to drive discoveries while offering immense therapeutic potential (see BioNews 1338).

The slowing pace of submissions to the hESC Registry should not be mistaken for evidence that hESC research is no longer needed. Rather, it reflects the success of nearly two decades of public investment in well-characterised lines, standardised methods, and extensive engineered cell libraries that provide a foundation for rigorous and reproducible research.

New lines are not submitted simply to expand the Registry; they are submitted when there is a clear scientific need. Preserving that submission pathway is therefore essential. Future hESC lines may be necessary to model newly identified disease mechanisms, to expand the representation of genomic profiles not currently available on the Registry, and to capitalise on advances in methodology that could improve the stability and scalability of lines for future therapeutic development.

Nor should a modest decline in funded projects be taken as evidence that hESCs can be replaced by iPSCs or adult stem cells. hESCs are still the 'gold standard' for naturally occurring, unmodified human pluripotency. As a result, they are used to assess whether other pluripotent stem cell systems have achieved pluripotency, development potential, differentiation capacity, and reproducibility. Newer platforms like iPSCs hold tremendous research promise but they are not a substitute for hESCs because they are not fully biologically equivalent.

Genome-wide epigenetic analyses show that iPSCs frequently retain epigenetic signatures associated with their cell of origin, and these differences can affect gene expression, differentiation potential, and reproducibility. hESCs serve in a complementary role to iPSCs, providing a benchmark against which newly generated iPSC lines can be evaluated. And while adult stem cells have their place in the research toolkit, they are not a substitute for hESCs either. In most human tissues adult stem cells are rare and difficult to isolate, and their differentiation potential is confined to their tissue of origin. Unlike hESCs, adult stem cells eventually senesce in culture limiting their usefulness in, eg, biomanufacturing.

For many research uses hESCs are not just complementary, they are an indispensable scientific tool, especially for studying human development and reproductive biology. Technological progress is happening rapidly in this space, with hESC-derived models shedding light on the fundamental biological mechanisms underlying development in ways that cannot be replicated by animal models due to species differences. With continued support these models may provide insight into the establishment and maintenance of a healthy pregnancy and the developmental origins of disease, as well as aid researchers in investigating the genetic and environmental causes of infertility.

These models also have the potential to improve outcomes from the use of IVF. Because hESCs are derived directly from embryos, these cells provide the most suitable building blocks for generating these novel models of human development.

In clinical research, hESCs are the most established and best characterised source of pluripotent stem cells for the development of cellular therapies. The well-characterised biology, stability, and track record in translational research of hESCs has enabled multiple hESC-derived products to advance into clinical trials, including late-stage clinical trials for type 1 diabetes, Parkinson's disease, and epilepsy.

Additional promising clinical studies are under way for indications like age-related macular degeneration and spinal cord injury. To date, cellular therapies that use hESCs as starting material are the furthest along in the clinic, further than iPSCs, and offer the most near-term promise for patients with unmet medical needs. And because the clinical applications of iPSCs are not far behind, access to hESCs will be necessary for rigorous comparative research between the two platforms to ensure that the safest and most effective therapeutic approaches can be delivered to patients.

hESCs also contribute to the development of new approach methodologies (NAMs), including organoids and microphysiological systems intended to provide more human-relevant models for drug discovery, toxicology and regulatory decision-making. This is especially important because the development and validation of NAMs is a priority of NIH and other federal agencies seeking to reduce reliance on animal models.

Many NAMs platforms were first established or validated using hESCs, and newer systems still require comparison against well-characterised hESC lines to assess reproducibility and biological relevance. Computational models and AI-assisted methods offer promise for future research directions and may further expand this field, but they too will rely on biological reference points for training and validation. A limitation on the use of hESCs may undercut and delay this key priority of NIH.

Finally, the ethical questions posed by hESC research are real, but they are addressed by the aforementioned legal and ethical framework, a framework supported by the National Academies, the ISSCR, and leading scientific, medical, and patient advocacy organisations. This well-established framework permits the use of hESC lines derived from embryos originally created for clinical use by IVF, but deemed surplus to the clinical need and provided for research purposes with informed consent from donors. Because these embryos are routinely discarded during IVF care, any new restrictions on the use of hESC lines would not rescue a single embryo from destruction. Rather, such limitations will only constrain the ability of researchers and patients to derive scientific and medical value from materials already designated for disposal.

For these reasons, the ISSCR concluded in its RFI response that the available scientific and translational evidence does not support reducing NIH's reliance on hESC research. hESCs remain uniquely informative for many areas of basic, translational, and clinical research and are contributing to the advancement of emerging technology platforms that depend on hESCs as reference standards. It is why we urged, and continue to urge, the NIH to lift its pause on submissions to the hESC Registry and continue its commitment to supporting scientifically meritorious hESC research conducted under rigorous ethical oversight.

This Comment is adapted in substantial part from ISSCR's response to the NIH RFI on reducing reliance on hESC research. The authors are grateful to the members of the ISSCR working group whose expertise informed the response, and to ISSCR manager of policy Dr Andrew Bremer for guiding the development of the submission.