SDRMI Response to NOT-OD-26-031 “NIH Pause on New Submissions to the NIH Human Embryonic Stem Cell (hESC) Registry and Request for Information on Reducing Reliance on Human Embryonic Stem Cells in NIH-Supported Research”

1. Research areas in which currently approved hESC lines sufficiently meet the needs of the research community as well as research areas for which new hESC lines are needed

All the NIH-approved human embryonic stem cell (hESC) lines currently on the NIH hESC Registry are research-grade for research purposes only, only suitable for preclinical research. The NIH hESC Registry has no clinical-grade hESC lines suitable for therapeutic purposes, clinical applications, human trials, or patient uses.

All the currently approved hESC lines on the NIH hESC Registry are research-grade exclusively for preclinical research only, but none of those hESC lines eligible for Federal finding are biologics-free, clinical-grade hESCs suitable for therapeutic purposes, clinical applications, human trials, or patient uses. Because all the NIH-approved hESC lines were initially derived and maintained on mouse feeder cells and proteins, therefore, such hESC lines have been contaminated with animal cells, biologics, and genetic materials, unsuitable for clinical applications to patients or not clinically compatible. Using mouse feeder cells and foreign biologics for derivation, maintenance, and differentiation of these hESC lines currently on the NIH hESC Registry has compromised their therapeutic potential because of the risk of transmitting xeno-biologics and xeno-pathogens, altering genetic background, and promoting the expression of immunogenic proteins.

Although the NIH hESC registry currently has approximately 486 approved hESC lines, only a few, about 4-6 hESC lines, are commercially available for research purposes only, all from the Wicell Research Institute. Due to early improper handlings during passaging, most of the hESC lines currently on the NIH hESC registry are in extremely low quality or already dead, and therefore, could not be used for research anymore. For example, some of these NIH-approved hESC lines could not even be thawed alive from cryo-freezers. Even though some of these hESC lines could be grown back from cryo-freezers, they were found no longer at the pluripotent stage (e.g., no longer express pluripotent markers like Oct-4, SSEA-4), and therefore, no longer useful to get any hESC research going. All the NIH-approved hESC lines were initially derived and maintained using mouse supporting cells. Mouse cells grow much faster than human cells and survive harsh handlings during passaging much better than hESCs too. As a result, some of these NIH-approved hESC lines (e.g., Doug Melton’s lines of Harvard) have apparently been contaminated or altered by mouse cells, because those cells actually express mouse cell markers (e.g., SSEA-1), but not hESC markers (e.g., SSEA-4), and behave more like mouse cells too. Therefore, it is essential for NIH to authenticate all the NIH-approved hESC lines and assess the quality of all the hESC lines currently on the NIH hESC Registry to ensure they are actually pluripotent hESC lines and in good quality for hESC research.

High-quality, biologics-free, clinical-grade new hESC lines are needed for clinical translation of hESC research and therapeutic applications, such as developing hESC-based stem cell therapies for tissue and function restoration and bio-fabrication of human replacement tissues/organs. Breakthroughs and advances in the last 20 years of hESC research have established defined hESC culture platforms to provide biologics-free (e.g., feeder-free, xeno-free, conditioned-medium-free, serum-free), defined culture systems for well-controlled, efficient derivation, maintenance, and differentiation of clinical-grade, high quality, cGMP compatible, stable hESC lines [e.g., Parsons. 2025, Directing pluripotent hESCs towards lineage-specific cell therapy derivatives for regenerative medicine. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Chapter 31:795-818; Parsons. 2016, Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2016;1307:299-318; Parsons, et al. 2012, Defining conditions for sustaining epiblast pluripotence enables direct induction of clinically-suitable human myocardial grafts from biologics-free hESCs. J. Clinic. Exp. Cardiology 2012;S9-001]. Defined hESC culture platforms allow all poorly-characterized and unspecified biological components and substrates in the culture system, including those derived from animals, to be removed, substituted, and optimized with defined human alternatives for de novo derivation and long-term maintenance of cGMP-quality, xeno-free, stable hESC lines and their human cell therapy derivatives, which have never been contaminated with animal cells and proteins, thus suitable for therapeutic development and clinical applications. Such breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy to the clinic, enabling de novo derivation of clinical-grade, cGMP compatible, stable hESC lines from human blastocysts that have never been contaminated by animal cells and proteins, and direct conversion of such pluripotent hESCs into a large supply of clinical-grade, functional human neurons and cardiomyocytes to be translated to patients for mending the damaged CNS and heart.

In 2009, President Obama lifted Bush administration’s restriction on NIH. As a result, the NIH registry has been expanded to include hundreds of hESC lines since. So far, those hESC lines on NIH registry are exclusively for research purposes only, but none of the hESC lines eligible for Federal funding are biologics-free, clinical-grade hESCs suitable for patient uses or clinical trials. hESC research has been surrounded by decades of social and legal controversy. The central ethical concern and controversy surrounding hESC research is the derivation of hESC lines, because it involves the destruction of human embryos to obtain stem cells, raising questions about the moral status of an early embryo and whether it constitutes a human life, with proponents arguing for the potential medical benefits of stem cell research while opponents believe it is morally wrong to destroy embryos for research purposes. So far, all the hESC lines on the NIH registry eligible for Federl funding were derived from surplus embryos with funding from private sector or the State (e.g., CIRM), that were in excess from IVF procedures and otherwise destined for destruction, and that were donated under IRB-approved guidelines that mandated informed consent, protection of the donor’s identity, and strict ethical research practices. Despite some progresses, Federal funding remains barred from any activities associated with the derivation of hESC lines from IVF leftover embryos for research purposes by the Dickey-Wicker Amendment, a federal law that prohibits the use of federal funds to support research that destroys or harms human embryos, or prohibits the use of federal funds for the creation, destruction, or discarding of human embryos for research purposes, and also prohibits subjecting human embryos to a greater risk of injury or death than is allowed for research on fetuses in utero. Basically, Federal funding could not be used to derive hESC lines from human embryos for research purposes only.

However, breakthroughs and advances in the last 20 years of hESC research have changed the premise of the Dickey-Wicker Amendment, the federal law that prohibits the use of federal funds to derive hESC lines from human embryos for research purposes only.

In August, 2001, when President Geroge W. Bush announced the restriction of Federal funding to hESC lines derived before his announcement, he basically provided a compromised solution to both pros and cons. To those who supported hESC research, he allowed hESC research continue with NIH funding in the hope that it would provide scientific evidence of medicinal uses of hESCs for many diseases to warrant continued Federal funding and public support for hESC research in future. To those who were against hESC research, he also ended derivation of more hESC lines by destroying embryos. 25 years later, his policy to invest Federal funding in hESC research has paid off. Breakthroughs and advances in the last 20 years of hESC research have provided scientific evidence of medicinal uses of hESCs for many life-threatening and devastating diseases to warrant continued Federal funding and public support for hESC research. Those original hESC studies in the last 20 years have presented hESCs as a novel, advanced therapeutic strategy for a host of chronic diseases that destroy lives. The IVF techniques offer a small portion of the millions of excess embryos currently stored in the IVF clinics worldwide, which are otherwise destined for destruction, to be an unlimited source that could potentially deliver in future a whole range of therapeutic treatments or cures to patients with life-threatening and devastating diseases for tissue and function restoration. The breakthroughs and advances in the last 20 years of hESC research have laid the foundation for relaxing Federal policy to allow Federal funding to be used to derive biologics-free, clinical-grade hESC lines from human embryos for therapeutic purposes, clinical applications, patient uses, or human trials. Such deregulation efforts will dramatically increase the overall turnover of investments in biomedical research, deliver urgently-needed treatments or cures for a host of incurable or hitherto untreatable disorders that destroy lives, speed hESC medical breakthroughs to patients, and drive real progress on ending the chronic disease epidemic.

2. Research areas for which hESCs are the gold standard and could not be pursued if hESCs were unavailable

2.1. Human embryonic stem cells (hESCs) are the gold standard of regenerative medicine in restoring vital tissue and function for a wide range of incurable or hitherto untreatable chronic diseases. hESCs offer the only scalable health solution to address the unmet medical needs of many costly and devastating chronic diseases. Those life-threatening chronic diseases are major health problems, cost trillions in healthcare, affect millions of people, and could not be pursued or solved if hESCs were unavailable.

Chronic diseases are major causes of morbidity and mortality in US and leading drivers of health care costs. Many chronic diseases, including heart disease and failure, stroke, Parkinson’s disease (PD), Alzheimer disease (AD), spinal cord injury (SCI), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Type 1 diabetes, liver diseases, lung diseases are caused by damage or loss of tissue that leads to impairment or loss of function. Those devastating and life-threatening diseases are leading causes of death or permanent disability and major health problems that cost trillions in healthcare annually and affect millions of people in the US, but there is no effective treatment or drug that can restore the damaged or lost tissue and function. The limit capacity of cardiomyocytes (the mature contracting heart muscle cells) of the heart as well as neuron circuitries of the brain/spinal-cord for self-repair constitutes a significant challenge to traditional medicine for tissue and function restoration in seeking cures for those serious life-threatening diseases and injuries. To date, the need to restore vital tissue and function for a wide range of chronic diseases remains a daunting challenge to the conventional mode of drug development.

The successful derivation of hESC lines from the in vitro fertilization (IVF) leftover embryos is considered as one of the major breakthroughs of the 20th century life sciences. Pluripotent hESCs can maintain long-term, stable growth and differentiate into clinically-relevant lineages, providing an inexhaustible source of replacement cells for human tissue and function restoration. It is public consensus that hESC research holds huge promise for treating major human diseases that have been challenging for traditional medicine, such as a wide range of incurable or hitherto untreatable chronic diseases. Millions of people are pinning their hopes on hESC research. Despite these devastating and life-threatening chronic diseases are leading causes of death or permanent disability, yet, there is no effective treatment or drug available. hESCs are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. Therefore, they have been regarded as an ideal source to provide an unlimited supply of large-scale, well-characterized human specialized cell types for cell-based therapies to resolve some worldwide major health problems, such as neurodegenerative diseases, paralysis, diabetes, and heart diseases. So far, hESCs are the gold standard of regenerative medicine in restoring vital tissue and function for a wide range of incurable or hitherto untreatable chronic diseases. hESCs offer the only scalable health solution to address the unmet medical needs of many costly and devastating chronic diseases. Those life-threatening chronic diseases are major health problems, cost trillions in healthcare, affect millions of people, and could not be pursued or solved if hESCs were unavailable.

The rising prevalence of chronic diseases, coupled with increased healthcare costs, has fueled the exponential growth of the cell-based regenerative medicine market over the last 2 decades, to address the need to repair, replace, or regenerate the damaged or lost tissue or organ for many incurable or hitherto untreatable chronic diseases that have been challenging to traditional medicine. Although stem cell therapy represents a promising regenerative medicine approach closest to provide a cure for those diseases, demonstrating stem cell production at the scale and product purity adequate to heal the damaged or lost tissues that have naturally limited capacity for repair, such as the human heart and brain, has been a big challenge for traditional adult stem cell sources or products, including the prototypical heart/CNS tissue-derived epithelial-like Nestin+ human cardiac/neural stem cells (hCSC/hNSC), mesenchymal stem cells (MSC), bone marrow-derived stem cells (BMSC), and the so-called adult cell alternative to hESCs --- induced pluripotent adult/stem cells (iPSCs) that are in fact adult cells reprogrammed with oncogenes or cancer cells harboring oncogenes. iPSCs contain oncogenes because the process of creating them often involves using oncogenes or genes that are linked to tumorigenesis. Key reprogramming factors like c-Myc, Klf4, Oct4, Sox2 are well-known oncogenes and have links to tumor formation. It is common scientific knowledge that gene reprogramming is in fact oncogenesis. While these genes are necessary for reprogramming, their presence means iPSCs inherently carry an oncogenic risk that must be addressed, particularly for clinical applications.

Adult cell therapy products currently in clinical trials or on the market for heart and neurological indications, if any, have not demonstrated production at scale as well as any regenerative potential for heart muscle or neuron circuitry repair. So far, there is no evidence that any traditional adult stem cells are able to give rise to the contractile heart muscle cells (cardiomyocytes [CM]) or functional neurons following transplantation into the heart/CNS, thus achieving graft-dependent myocardium/CNS regeneration. Despite significant research efforts, the overwhelming majority of human trials with such traditional adult stem cells have failed to demonstrate clinical efficacy and benefit. Those clinical studies have revealed that most cell types are safe, but exert their therapeutic effects primarily through anti-inflammatory and protective actions to prolong the survival and function of existing cardiomyocytes/neurons, rather than mediate graft-dependent cardiomyocyte/neuron cell regeneration/replacement, suggesting that such therapeutic effects that primarily produce trophic or protective factors to rescue endogenous host cardiomyocytes/neurons or enhance endogenous cardiac/neural repair provide no substantial improvement in clinical end points and have no effect on overall survival. The over 2 decades of clinical studies have identified the urgent need for safe and effective therapeutic stem cell sources adequate to regenerate the damaged/lost myocardium/nerve tissues.

Technology breakthroughs and advances in hESC research over the last 2 decades have provided innovative, scalable, and reproducible platforms to ensure high degrees of efficacy and safety of the hESC-derived regenerative medicine advanced therapy (RMAT) products, thus robust clinical benefit leading to therapies, which not only constitutes clinically representative progresses in both human neuronal and cardiac therapeutic products for treating a wide range of incurable or hitherto untreatable neurological and cardiovascular diseases, but also offers manufacturing innovation for production scale-up and creation or bio-fabrication of replacement tissue/organ products, such as the human heart and brain [e.g., Parsons. 2025, Directing pluripotent hESCs towards lineage-specific cell therapy derivatives for regenerative medicine. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Chapter 31:795-818; Parsons XH. Direct conversion of pluripotent hESC under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2016;1307:299-318. DOI: 10.1007/7651_2014_69. PMID: 24500898].

Due to lack of a scalable human neuron source, the need to restore vital tissue and function for a wide range of neurological diseases and injuries remains a daunting challenge to conventional drug development. Technology breakthrough in hESC research enables direct conversion of non-functional, clinical-grade hESCs at the pluripotent stage by small molecule induction uniformly into a large supply of human neuronal progenitor cells and functional neurons [e.g., patent: USPTO# 8,716,017; Parsons. 2025, Directing pluripotent hESCs towards lineage-specific cell therapy derivatives for regenerative medicine. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Chapter 31:795-818; Parsons. 2016, Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2016;1307:299-318], providing the scalable manufacturing capability for large scale production of high quality clinical-grade human neuronal cells adequate for neuron circuitry repair and nerve tissue bio-fabrication to fill the capability gap in nerve tissue and neurological/motor function restoration for a wide range of incurable or hitherto untreatable neurological diseases. So far, hESCs offer the only scalable source of human neurons adequate for neuron regeneration and neurological function restoration to treat serious, life threatening, progressive or fatal neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and strokes. hESCs offer a novel, advanced therapeutic strategy for a wide range of incurable or hitherto untreatable neurological disorders that destroy lives, and those urgently needed cutting-edge stem cell therapy solutions could not be pursued if hESCs were unavailable.

Lack of a scalable human cardiac stem cell source with adequate heart muscle regeneration potential remains a major setback for heart replacement, and fabricating a human heart is still beyond reach. Technology breakthrough in hESC research enables direct conversion of non-functional clinical-grade hESCs at the pluripotent stage by small molecule induction uniformly into a large supply of human cardiac precursor cells and contractile cardiomyocytes [e.g., patent: USPTO# 9,428,731; Parsons. 2025, Directing pluripotent hESCs towards lineage-specific cell therapy derivatives for regenerative medicine. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Chapter 31:795-818; Parsons. 2016, Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2016;1307:299-318], providing the scalable manufacturing capability for large-scale production of high-quality clinical-grade human heart muscle cells adequate for heart muscle regeneration and bio-fabrication to fill the capability gap in myocardial tissue and contractile function restoration for heart disease and failure. So far, hESCs offer the only scalable source of human cardiomyocytes adequate for heart muscle regeneration and contractile function restoration to treat heart disease and failure. hESCs offer a novel, advanced therapeutic strategy for cardiovascular diseases (CVD), and those urgently needed cutting-edge stem cell therapy solutions could not be pursued if hESCs were unavailable.

Despite false claim that “the adult alternative iPSCs and hESCs are identical”, iPSCs and hESCs are actually not identical, but distinctly different. The so-called adult alternative iPSCs are not pluripotent stem cells, but bioengineered pluripotent cancer cells reprogrammed from adult cells with oncogenes, distinctly different from embryo-originated hESCs that are the real, natural pluripotent stem cells. hESCs derived from embryos are highly acetylated and unmethylated, genetically stable with unlimited expansion ability and unrestricted plasticity, sustaining epiblast pluripotency, maintaining genomic/epigenomic/cell-line homogeneity across all hESC lines, and respond to developmental signals at embryonic or epiblast stage. In contrast, the so-called adult cell alternative iPSCs are in fact reprogrammed from different adult cells or different tissues with different oncogenes, deacetylated and highly-methylated, having different differentiation potential and cell line variations, displaying genomic heterogenicity and instability because the different tissues they used for reprogramming have different genomic imprints that could not be simply reversed by genes, not responding to developmental signals at embryonic or epiblast stage, displaying uncontrolled growth, just like cancer cells. hESC discoveries and breakthroughs do not apply for iPSCs, and hESC technologies and platforms do not work for iPSCs either.

Ironically, most of the Federal funding for stem cell research during the Obama, Trump, and Biden Administrations has been allocated to waste on the false promise --- so-called adult alternative iPSCs, which, despite well-funded, have generated neither intended public interests nor promised medicinal benefits to really push the regenerative medicine field forward. hESC research is irreplaceable in developing innovative regenerative medicine technologies for a host of chronic diseases that destroy lives and improving our understanding of the dynamics and complexity of the human tissue and organ function in development and disorders. Future efforts to relax Federal policy and prioritize funding to support such cutting-edge hESC research are crucial in order to dramatically increase the overall turnover of investments in biomedical research.

Today, cutting-edge hESC technology platforms have been developed, some even commercialized, for defined media and culture systems to derive high quality, clinical-grade, stable hESC lines suitable for human trials and patient uses, for large-scale production of clinical-grade hESC-derived CNS/heart-related human stem/progenitor/precursor cells, accessory cells, and functional human CNS/heart cell/tissue/organ products to support clinical trials of regeneration or replacement therapies as well as tissue/organ biofabrication for those most-costly and devastating chronic diseases. Innovative hESC technology platforms and products have broad applications for a wide range of chronic diseases that destroy lives, thus providing high-impact therapeutic solutions across a wide spectrum of life-threatening chronic diseases, and ultimately, relieving the high burdens of diseases, and generating high-yield return for public investment.

Current state of hESC research has provided much-need therapeutic solutions for a wide range of incurable or hitherto untreatable chronic diseases, and has laid the foundation for CNS/heart tissue and function restoration as well as for bridging the key knowledge gaps in human CNS/heart development. Despite the social and legal controversies constantly surrounding hESC research, advances in the last 20 years of hESC research have presented hESCs as a novel, advanced therapeutic strategy for a host of chronic diseases that destroy lives, thus warranting continued public support and Federal investment. It is crucial for the Federal government to prioritize such frontiers of regenerative medicine to ensure that these reachable, urgently-needed, better treatments and new cures brought by the breakthrough medical innovations of hESC research for those costly and devastating chronic diseases are near, thus ensuring taxpayer money be used to pave a successful path in the war against diseases.

2.2. hESCs are the gold standard for understanding human embryonic development, providing much-needed human model systems to unlock the mysteries of human development and disorders, and facilitating rapid progress in identification of molecular and genetic therapeutic targets for the prevention and treatment of childhood chronic diseases. Such research areas critical to ending the childhood chronic disease epidemic could not be pursued or solved if hESCs were unavailable.

Traditional drug development usually starts with drug leads discovered in non-human simple model organisms, thus requires lengthy and costly both demonstration in animal model testing and establishment of proof-of-concept and safety in human trials. As a result, millions of drug leads have vanished before even reach clinical trials, and for few lucky ones, have encountered the very high drug failure rate in human trials. Among those very few drugs that eventually obtained their market approvals, there were not any cures, or even meaningfully effective treatments, for Parkinson’s disease, Alzheimer disease, stroke, spinal cord and brain injuries, heart disease and failure, or a host of other chronic diseases that destroy lives. The difficulty of crossing the gulf between finding a promising new agent and demonstrating its safety and efficacy in humans in biomedical research has been referred as “the valley of death”.

The difficulty of crossing “the valley of death” in drug development is the pounding consequence of a vast amount of Federal and private investments only go to maintain the status quo of mainstream biomedical research in the non-human, lower organism models or systems that do not reflect the complexity of humans, thus have little implications for the prevention and treatment of human diseases. Without a readily accessible and effective human model system to unlock the mysteries of human development and disorders, the road of desperately seeking cures has become all but a dead end to real world remedy.

Due to the restrictions on human embryonic and fetal materials that significantly limit their availability for study, there is a fundamental gap in our knowledge regarding the molecular networks and pathways underlying human embryogenesis. Derivation of hESCs provides powerful in vitro model systems to remove limitations at the cellular or biological systems levels that stymie progress towards developing human-based tools and platforms that can apply to a broad range of human diseases. Development and utilization of hESC models of human embryonic development facilitate rapid progress in identification of molecular and genetic therapeutic targets for the prevention and treatment of human diseases. Technology breakthroughs in the last 20 years of hESC research enable neuronal or cardiac lineage-specific differentiation direct from the pluripotent state of hESCs with small molecule induction, which have provided much-needed in vitro model systems for bridging the key knowledge gaps in human CNS (central nervous system) and heart development [e.g., Parsons. 2025, Directing pluripotent hESCs towards lineage-specific cell therapy derivatives for regenerative medicine. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Chapter 31:795-818; Parsons. 2016, Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2016;1307:299-318]. It opens the door for further unveiling genetic and epigenetic programs embedded in the human CNS and heart formation during human embryogenesis using genome-wide high-throughput high resolution profiling approaches. Therefore, hESCs are gold standard for understanding human embryonic development, providing much-needed human model systems to unlock the mysteries of human development and disorders, and facilitating rapid progress in identification of molecular and genetic therapeutic targets for the prevention and treatment of childhood chronic diseases. Such research areas critical to ending the childhood chronic disease epidemic could not be pursued or solved if hESCs were unavailable.

2.3. hESCs are the gold standard for developing human-based risk testing systems for rapid and high-fidelity safety evaluation of health risks, particularly cumulative health risks, of developmental toxins with sensitivity equivalent to vulnerable children, infants, and fetuses, thus uncovering the root causes of childhood chronic diseases. Such research areas critical to ending the childhood chronic disease epidemic could not be pursued or solved if hESCs were unavailable.

In order for a drug to be approved in the US, the FDA typically requires preclinical toxicity tests and animal model studies on small and large animals to provide sufficient evidence of proof-of-concept for the prospect of safety and efficacy to justify an Investigational New Drug (IND) application for the proposed clinical investigation of a new drug. Companies use tens of thousands of animals for such tests each year. Yet more than nine in 10 drugs that enter human clinical trials fail because they are unsafe or ineffective.

Thus far, testing potential therapeutic strategies has largely relied on animal models for evaluating the behavior, safety, and efficacy of therapeutic candidates and human cell therapy products. However, because of interspecies differences, conventional studies using animal models are often poor predictors of human efficacy and safety. Animal models are xeno-hosts for the transplantation of human cells, not ideal for testing the behavior, safety, and efficacy of therapeutic outcomes of human stem cells. Large primate models are very costly and often taken years to obtain results. In addition, the results of animal studies can be highly variable and difficult to reproduce, making them unreliable as benchmarks for decisions on humans in clinical trials. Preclinical data using animal models, even results of large animal models, do not necessarily provide the benchmarks or indicators for safety and efficacy in human trials.

Children are still in a sensitive developmental stage, uniquely vulnerable to environmental chemical exposures, including pesticides, microplastics, dioxins, flame retardants, BPA, PFSA, fluoride, EMR, Phthalates, Bisphenols, herbicides, and insecticides. Since President Clinton’s executive order 13045 in 1997, childhood health has largely worsened, and the chemicals children are exposed to have grown. There is a growing concern about the link between environmental health risks, particularly cumulative health risks, and chronic diseases. The emerging crisis of overmedication and the growth of childhood vaccine schedule also compound the health risks, particularly cumulative health risks, of childhood environmental chemical exposures, drugs, and vaccines to vulnerable children who are still in a sensitive developmental stage. Such health risks, particularly cumulative health risks, could be the root causes of childhood chronic disease epidemic that warrant scientific investigations.

However, scientific inquiry into the links between the health risks of childhood environmental chemical exposures, drugs, and vaccines to chronic diseases, has been hindered by the lack of a human-based risk testing system with sensitivity equivalent to that of vulnerable children, infants, and fetuses. In the US, federal regulations do not allow research that presents “greater risks than minimal” on children. In addition, federal restrictions on human embryonic and fetal materials significantly limit their availability for study. As a result, there are significant gaps in available data regarding the effects of developmental toxins that may play a crucial role in the rising prevalence of childhood chronic diseases.

The advances in pluripotent hESC research have provided the unique opportunity to develop human-based risk testing systems for rapid and high-fidelity safety evaluation of developmental toxins with sensitivity equivalent to that of vulnerable children, infants, and fetuses. Human embryo-originated hESC and their cell/tissue/organ products/models offer viable, adequate, timely, cost-effective, sensitive, and superior alternatives that meet higher quality and safety standards than current animal testing systems and other human adult cell/tissue/organ-based testing systems. hESCs are derived from human embryos, negating the species-species differences observed in animal testing. hESCs and their derivatives have a very low tolerance threshold and are highly sensitive to any toxic chemicals/drugs/products/vaccines, providing scalable, more timely, predictive, reliable alternative methods to current animal testing systems and other human adult cell/tissue/organ-based testing systems, ensuring higher quality and safety standards, and reducing the time and cost. hESC-based human cell/tissue/organ products or models offer rapid, cost-effective, and high-fidelity safety evaluation of developmental toxins with sensitivity equivalent to that of vulnerable children, infants, and fetuses.

FDA Modernization Act 2.0 legitimizes alternatives to animal testing for advancing a drug or product to human trials. Enacting such a law for a drastic change in FDA regulation, passed by Congress and welcomed by animal welfare groups, was only made possible by advances in hESC research that have begun to offer increasingly viable alternatives to animal testing. However, many of the new approach methodologies (NAMs) proposed by the FDA in the “Roadmap to Reducing Animal Testing in Preclinical Safety Studies”, such as adult-cell/tissue/organ-based organ-on-a-chip systems, computational modeling, and advanced in vitro assays, are unable to provide higher quality and safety standards than animal testing. For example, organ chips and organoids based on adult stem/cancer cells (e.g., iPSCs that are in fact adult cells reprogrammed with oncogenes or actually cancer cells) have proven to be inadequate as alternatives to animal toxicity testing because the tolerance threshold of adult/cancer cells/iPSCs to toxic chemicals/drugs is much higher than the tolerance threshold of normal human tissues or organs. Such as, the drugs screened by the liver chips of Emulate based on iPSCs either failed in clinical trials because they were toxic to the liver or were approved for market but then withdrawn or scaled back because of liver damage (see the New York Times report “Could the next blockbuster drug be lab-rat few?”).

The hESC-based innovative platforms provide scale-up capability for the creation of human replacement CNS and heart, such as micro-brains, micro-spinal-cords, and micro-hearts, thereby increasing the biological complexity of human-based in vitro models and assays to mimic the in vivo structure, behavior, and function of the human CNS and heart. These hESC-based in vitro models and assays are controllable, reproducible, and scalable, and can be monitored and validated against responses on multiple hierarchical levels. Development and utilization of complex 3D multi-cellular models of human embryogenesis and organogenesis using hESCs provide a highly-sensitive, authentic, and reliable in vitro tool for rapid and high-fidelity safety evaluation of developmental toxins that may play a crucial role in the rising prevalence of childhood chronic diseases, thus uncovering the root causes that will lead to better prevention strategies and evidence-based therapeutic solutions to end the childhood chronic disease epidemic. Therefore, hESCs are the gold standard for developing human-based risk testing systems for rapid and high-fidelity safety evaluation of health risks, particularly cumulative health risks, of developmental toxins with sensitivity equivalent to vulnerable children, infants, and fetuses, thus uncovering the root causes of childhood chronic diseases. Such research areas critical to ending the childhood chronic disease epidemic could not be pursued or solved if hESCs were unavailable.

3. Research areas in which the robustness of emerging biotechnologies such as induced pluripotent stem cells (iPSCs), adult stem cells, etc., can replace the use of hESCs

There is no research area in any emerging biotechnologies that can replace the use of hESCs.

Any efforts to replace the use of human embryonic stem cells (hESCs) would only result in additional waste of a staggering amount of taxpayer money on false promises and frauds, just like hundreds of billions of taxpayer money have been wasted on the fruitless efforts of iPSC fraud in the last 20 years.

hESC research holds the greatest benefit to humankind and has overwhelming public support. Prioritizing hESC research is vital to addressing childhood chronic diseases and ending the chronic disease epidemic. It is bad policy to ban hESC research or replace hESC research with adult stem cell scams and scientific frauds that would result in enormous waste of taxpayer money just like the massive fraud and waste iPSCs did in the last 20 years, stall any progress on life-saving solutions for many chronic diseases, deny access of millions of patients to life-saving treatments or cures brought by the breakthrough medical innovations of hESC research, cause public outrage, and push scientific research back to a dark era even worse than the Bush administration.

hESC research holds huge promises for treating major chronic diseases that have been challenging for traditional medicine, such as a wide range of incurable or hitherto untreatable neurological and heart diseases, including Parkinson’s disease, Alzheimer disease, stroke, spinal cord and brain injuries, heart disease and failure that cost trillions and affect millions. Millions of people are pinning their hopes on hESC research. Even President Bush didn’t ban hESC research 25 years ago, but allowed hESC research continue with Federal Funding, so someday, we could find lifesaving treatments and cures for a host of chronic diseases that destroy lives. There is no alternative for hESC research. And the so-called adult alternative to hESCs --- induced pluripotent stem cells (iPSCs) of ISSCR endorsed by the Nobel Foundation with Nobel Prize --- are in fact cancer cells reprogrammed with oncogenes, a massive scientific fraud and adult stem cell scam that has wasted a lot of government research funding in staggering amounts of hundreds of billions of taxpayer dollars, but produced absolutely nothing hopeful for any diseases. Adult stem cells and iPSCs have not created any life-saving treatments for any diseases and conditions, and iPSCs have failed safety tests in clinical trials by causing serious spontaneous mutations and harming patients just like cancer cells would do. Please see sdrmi.org for more.

The so-called adult cell alternative to hESCs --- induced pluripotent adult/stem cells (iPSCs) that are in fact adult cells reprogrammed with oncogenes or cancer cells harboring oncogenes. iPSCs contain oncogenes because the process of creating them often involves using oncogenes or genes that are linked to tumorigenesis. Key reprogramming factors like c-Myc, Klf4, Oct4, Sox2 are well-known oncogenes and have links to tumor formation. It is common scientific knowledge that gene reprogramming is in fact oncogenesis. While these genes are necessary for reprogramming, their presence means iPSCs inherently carry an oncogenic risk that must be addressed, particularly for clinical applications.

Despite false claim that “the adult alternative iPSCs and hESCs are identical”, iPSCs and hESCs are actually not identical, but distinctly different. The so-called adult alternative iPSCs are not pluripotent stem cells, but bioengineered pluripotent cancer cells reprogrammed from adult cells with oncogenes, distinctly different from embryo-originated hESCs that are the real, natural pluripotent stem cells. hESCs derived from embryos are highly acetylated and unmethylated, genetically stable with unlimited expansion ability and unrestricted plasticity, sustaining epiblast pluripotency, maintaining genomic/epigenomic/cell-line homogeneity across all hESC lines, and respond to developmental signals at embryonic or epiblast stage. In contrast, the so-called adult cell alternative iPSCs are in fact reprogrammed from different adult cells or different tissues with different oncogenes, deacetylated and highly-methylated, having different differentiation potential and cell line variations, displaying genomic heterogenicity and instability because the different tissues they used for reprogramming have different genomic imprints that could not be simply reversed by genes, not responding to developmental signals at embryonic or epiblast stage, displaying uncontrolled growth, just like cancer cells. hESC discoveries and breakthroughs do not apply for iPSCs, and hESC technologies and platforms do not work for iPSCs either.

Ironically, most of the Federal funding for stem cell research during the Obama, Trump, and Biden Administrations has been allocated to waste on the false promise --- so-called adult alternative iPSCs, which, despite well-funded, have generated neither intended public interests nor promised medicinal benefits to really push the regenerative medicine field forward. hESC research is irreplaceable in developing innovative regenerative medicine technologies for a host of chronic diseases that destroy lives and improving our understanding of the dynamics and complexity of the human tissue and organ function in development and disorders. Future efforts to relax Federal policy and prioritize funding to support such cutting-edge hESC research are crucial in order to dramatically increase the overall turnover of investments in biomedical research.

In 2009, President Obama lifted Bush administration’s restriction on NIH. As a result, the NIH registry has been expanded to include hundreds of hESC lines since. So far, those hESC lines on NIH registry are exclusively for research purpose only, but none of the hESC lines eligible for Federal funding are biologics-free, clinical-grade hESCs suitable for patient uses or clinical trials. hESC research has been surrounded by decades of social and legal controversy. The central ethical concern and controversy surrounding hESC research is the derivation of hESC lines, because it involves the destruction of human embryos to obtain stem cells, raising questions about the moral status of an early embryo and whether it constitutes a human life, with proponents arguing for the potential medical benefits of stem cell research while opponents believe it is morally wrong to destroy embryos for research purposes. So far, all hESC lines in NIH registry eligible for Federl funding were derived from surplus embryos with funding from private sector or the State (e.g., CIRM), that were in excess from IVF procedures and otherwise destined for destruction, and that were donated under IRB-approved guidelines that mandated informed consent, protection of the donor’s identity, and strict ethical research practices. Despite some progresses, Federal funding remains barred from any activities associated with the derivation of hESC lines from IVF leftover embryos for research purposes by the Dickey-Wicker Amendment, a federal law that prohibits the use of federal funds to support research that destroys or harms human embryos, or prohibits the use of federal funds for the creation, destruction, or discarding of human embryos for research purposes, and also prohibits subjecting human embryos to a greater risk of injury or death than is allowed for research on fetuses in utero. Basically, Federal funding could not be used to derive hESC lines from human embryos for research purposes.

However, breakthroughs and advances in the last 20 years of hESC research have changed the premise of the Dickey-Wicker Amendment, the federal law that prohibits the use of federal funds to derive hESC lines from human embryos for research purposes only.

In August, 2001, when President Geroge W. Bush announced the restriction of Federal funding to hESC lines derived before his announcement, he basically provided a compromised solution to both pros and cons. To those who supported hESC research, he allowed hESC research continue with NIH funding in the hope that it would provide scientific evidence of medicinal uses of hESCs for many diseases to warrant continued Federal funding and public support for hESC research in future. To those who were against hESC research, he also ended derivation of more hESC lines by destroying embryos. 25 years later, his policy to invest Federal funding in hESC research has paid off. Breakthroughs and advances in the last 20 years of hESC research have provided scientific evidence of medicinal uses of hESCs for many life-threatening and devastating diseases to warrant continued Federal funding and public support for hESC research. Those original hESC studies in the last 20 years have presented hESCs as a novel, advanced therapeutic strategy for a host of chronic diseases that destroy lives. The IVF techniques offer a small portion of the millions of excess embryos currently stored in the IVF clinics worldwide, which are otherwise destined for destruction, to be an unlimited source that could potentially deliver in future a whole range of therapeutic treatments or cures to patients with life-threatening and devastating diseases for tissue and function restoration. The breakthroughs and advances in the last 20 years of hESC research have laid the foundation for relaxing Federal policy to allow Federal funding to be used to derive biologics-free, clinical-grade hESC lines from human embryos for therapeutic purposes, clinical applications, patient uses, or human trials. Such deregulation efforts will dramatically increase the overall turnover of investments in biomedical research, deliver urgently-needed treatments or cures for a host of incurable or hitherto untreatable disorders that destroy lives, speed hESC medical breakthroughs to patients, and drive real progress on ending the chronic disease epidemic.

4. Research areas in which additional investments should be made to bolster validated models to replace the use of hESCs

There is no research area in which additional investments should be made to bolster validated models to replace the use of human embryonic stem cells (hESCs).

Any additional investments made to bolster validated models to replace the use of hESCs would only result in additional waste of a staggering amount of taxpayer money on false promises and frauds, just like hundreds of billions of taxpayer money have been wasted on the fruitless efforts of iPSC fraud in the last 20 years.

hESC research holds the greatest benefit to humankind and has overwhelming public support. Prioritizing hESC research is vital to addressing childhood chronic diseases and ending the chronic disease epidemic. It is bad policy to ban hESC research or replace hESC research with adult stem cell scams and scientific frauds that would result in enormous waste of taxpayer money just like the massive fraud and waste iPSCs did in the last 20 years, stall any progress on life-saving solutions for many chronic diseases, deny access of millions of patients to life-saving treatments or cures brought by the breakthrough medical innovations of hESC research, cause public outrage, and push scientific research back to a dark era even worse than the Bush administration.

hESC research holds huge promises for treating major chronic diseases that have been challenging for traditional medicine, such as a wide range of incurable or hitherto untreatable neurological and heart diseases, including Parkinson’s disease, Alzheimer disease, stroke, spinal cord and brain injuries, heart disease and failure that cost trillions and affect millions. Millions of people are pinning their hopes on hESC research. Even President Bush didn’t ban hESC research 25 years ago, but allowed hESC research continue with Federal Funding, so someday, we could find lifesaving treatments and cures for a host of chronic diseases that destroy lives. There is no alternative for hESC research. And the so-called adult alternative to hESCs --- induced pluripotent stem cells (iPSCs) of ISSCR endorsed by the Nobel Foundation with Nobel Prize --- are in fact cancer cells reprogrammed with oncogenes, a massive scientific fraud and adult stem cell scam that has wasted a lot of government research funding in staggering amounts of hundreds of billions of taxpayer dollars, but produced absolutely nothing hopeful for any diseases. Adult stem cells and iPSCs have not created any life-saving treatments for any diseases and conditions, and iPSCs have failed safety tests in clinical trials by causing serious spontaneous mutations and harming patients just like cancer cells would do. Please see sdrmi.org for more.

The so-called adult cell alternative to hESCs --- induced pluripotent adult/stem cells (iPSCs) that are in fact adult cells reprogrammed with oncogenes or cancer cells harboring oncogenes. iPSCs contain oncogenes because the process of creating them often involves using oncogenes or genes that are linked to tumorigenesis. Key reprogramming factors like c-Myc, Klf4, Oct4, Sox2 are well-known oncogenes and have links to tumor formation. It is common scientific knowledge that gene reprogramming is in fact oncogenesis. While these genes are necessary for reprogramming, their presence means iPSCs inherently carry an oncogenic risk that must be addressed, particularly for clinical applications.

Despite false claim that “the adult alternative iPSCs and hESCs are identical”, iPSCs and hESCs are actually not identical, but distinctly different. The so-called adult alternative iPSCs are not pluripotent stem cells, but bioengineered pluripotent cancer cells reprogrammed from adult cells with oncogenes, distinctly different from embryo-originated hESCs that are the real, natural pluripotent stem cells. hESCs derived from embryos are highly acetylated and unmethylated, genetically stable with unlimited expansion ability and unrestricted plasticity, sustaining epiblast pluripotency, maintaining genomic/epigenomic/cell-line homogeneity across all hESC lines, and respond to developmental signals at embryonic or epiblast stage. In contrast, the so-called adult cell alternative iPSCs are in fact reprogrammed from different adult cells or different tissues with different oncogenes, deacetylated and highly-methylated, having different differentiation potential and cell line variations, displaying genomic heterogenicity and instability because the different tissues they used for reprogramming have different genomic imprints that could not be simply reversed by genes, not responding to developmental signals at embryonic or epiblast stage, displaying uncontrolled growth, just like cancer cells. hESC discoveries and breakthroughs do not apply for iPSCs, and hESC technologies and platforms do not work for iPSCs either.

Ironically, most of the Federal funding for stem cell research during the Obama, Trump, and Biden Administrations has been allocated to waste on the false promise --- so-called adult alternative iPSCs, which, despite well-funded, have generated neither intended public interests nor promised medicinal benefits to really push the regenerative medicine field forward. hESC research is irreplaceable in developing innovative regenerative medicine technologies for a host of chronic diseases that destroy lives and improving our understanding of the dynamics and complexity of the human tissue and organ function in development and disorders. Future efforts to relax Federal policy and prioritize funding to support such cutting-edge hESC research are crucial in order to dramatically increase the overall turnover of investments in biomedical research.

In 2009, President Obama lifted Bush administration’s restriction on NIH. As a result, the NIH registry has been expanded to include hundreds of hESC lines since. So far, those hESC lines on NIH registry are exclusively for research purpose only, but none of the hESC lines eligible for Federal funding are biologics-free, clinical-grade hESCs suitable for patient uses or clinical trials. hESC research has been surrounded by decades of social and legal controversy. The central ethical concern and controversy surrounding hESC research is the derivation of hESC lines, because it involves the destruction of human embryos to obtain stem cells, raising questions about the moral status of an early embryo and whether it constitutes a human life, with proponents arguing for the potential medical benefits of stem cell research while opponents believe it is morally wrong to destroy embryos for research purposes. So far, all hESC lines in NIH registry eligible for Federl funding were derived from surplus embryos with funding from private sector or the State (e.g., CIRM), that were in excess from IVF procedures and otherwise destined for destruction, and that were donated under IRB-approved guidelines that mandated informed consent, protection of the donor’s identity, and strict ethical research practices. Despite some progresses, Federal funding remains barred from any activities associated with the derivation of hESC lines from IVF leftover embryos for research purposes by the Dickey-Wicker Amendment, a federal law that prohibits the use of federal funds to support research that destroys or harms human embryos, or prohibits the use of federal funds for the creation, destruction, or discarding of human embryos for research purposes, and also prohibits subjecting human embryos to a greater risk of injury or death than is allowed for research on fetuses in utero. Basically, Federal funding could not be used to derive hESC lines from human embryos for research purposes.

However, breakthroughs and advances in the last 20 years of hESC research have changed the premise of the Dickey-Wicker Amendment, the federal law that prohibits the use of federal funds to derive hESC lines from human embryos for research purposes only.

In August, 2001, when President Geroge W. Bush announced the restriction of Federal funding to hESC lines derived before his announcement, he basically provided a compromised solution to both pros and cons. To those who supported hESC research, he allowed hESC research continue with NIH funding in the hope that it would provide scientific evidence of medicinal uses of hESCs for many diseases to warrant continued Federal funding and public support for hESC research in future. To those who were against hESC research, he also ended derivation of more hESC lines by destroying embryos. 25 years later, his policy to invest Federal funding in hESC research has paid off. Breakthroughs and advances in the last 20 years of hESC research have provided scientific evidence of medicinal uses of hESCs for many life-threatening and devastating diseases to warrant continued Federal funding and public support for hESC research. Those original hESC studies in the last 20 years have presented hESCs as a novel, advanced therapeutic strategy for a host of chronic diseases that destroy lives. The IVF techniques offer a small portion of the millions of excess embryos currently stored in the IVF clinics worldwide, which are otherwise destined for destruction, to be an unlimited source that could potentially deliver in future a whole range of therapeutic treatments or cures to patients with life-threatening and devastating diseases for tissue and function restoration. The breakthroughs and advances in the last 20 years of hESC research have laid the foundation for relaxing Federal policy to allow Federal funding to be used to derive biologics-free, clinical-grade hESC lines from human embryos for therapeutic purposes, clinical applications, patient uses, or human trials. Such deregulation efforts will dramatically increase the overall turnover of investments in biomedical research, deliver urgently-needed treatments or cures for a host of incurable or hitherto untreatable disorders that destroy lives, speed hESC medical breakthroughs to patients, and drive real progress on ending the chronic disease epidemic.