Re: NOT-OD-26-047 Request for Information (RFI): Inviting Comments and Suggestions on a Framework for the NIH-Wide Strategic Plan for Fiscal Years 2027-2031
Re: NOT-OD-26-047 Request for Information (RFI): Inviting Comments and Suggestions on a Framework for the NIH-Wide Strategic Plan for Fiscal Years 2027-2031
Priority 1: Research Areas (500 words)
For the namesake, NIH need to focus on human-based tools, methods, technologies, research relevant to human health. One of the biggest opportunities of advancing the frontier sciences in human development and disorders underlying medicine and public health is provided by human embryonic stem cell (hESC) research. Due to the restriction on human embryonic and fetal materials available for study, there is a fundamental gap in our knowledge regarding the molecular networks and pathways underlying human development. 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. Technology breakthroughs in 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 and heart development.
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, life-threatening, and devastating chronic diseases that cost trillions in healthcare and affect millions of people. 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, including heart disease and failure, Parkinson’s disease, Alzheimer’s disease, ALS, spinal cord injury, traumatic brain injury, and strokes, 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.
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 that will lead to better prevention strategies and scientific evidence-based therapeutic solutions to end the childhood chronic disease epidemic.
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 regeneration and biofabrication as well as for bridging the key knowledge gaps in human CNS/heart development. The hESC-based technology platforms and products have broad applications for a wide range of chronic diseases that destroy lives. Prioritizing such frontiers of human-based technologies is crucial to the mission of the NIH. It will speed medical innovations to patients, lead to treatments and cures, and dramatically increase the overall turnover of investments in biomedical sciences.
Priority 2: Research Capacity (500 words)
Human embryonic stem cell (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 in healthcare and affect millions of people, who are pinning their hopes on hESC research. NIH need to establish worldclass, clinical-grade hESC research resources and infrastructure to fill the capability gap in tissue and function restoration for a host of disorders that destroy lives.
Currently, all the 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.
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. 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.
To develop and maintain scientific and clinical capacity in hESC research, NIH need to establish a well-trained hESC research workforce; support training programs on hESC culture techniques and emerging technologies of regenerative medicine; support hESC innovative technology platforms and novel products moving forward; fund high-risk, high reward hESC research projects that are aligned with Secretary Kennedy’s MAHA priorities, address major unmet medical needs, provide urgently-need therapeutic solutions, uncover root causes of chronic diseases with NIH common fund; and develop urgently-needed state-of-the-art hESC research and clinical resources and infrastructure to streamline hESC research innovations, advance hESC research from bench to bedside, speed hESC medical breakthroughs to patients, and drive real progresses on ending the chronic disease epidemic.
Priority 3: Research Operations (500 words)
As a public funding agency, NIH should hold the highest standards of integrity and transparency. The root cause of the worsening replication crisis, skyrocketing biomedical paper retractions, and “valley of death” in drug development is the status quo of mainstream biomedical research that overwhelmingly employs non-human, lower or simple organism models or systems. Those simple or lower organism-based tools, methods, or technologies often don’t work for humans. And the ideas or leads generated from those non-human, lower or simple organism models or systems have little implications for the prevention and treatment of human diseases, some even fundamentally flawed. As a result, the "publish or perish" culture often forces many professors and researchers to fake their data in order to get funding or generate profits, which is compounded by the fact that government funding agencies, pharmaceutical companies, and academic institutions do not really look into scientific misconduct and replication crisis, often reluctant to denounce scientific misconduct, because of all the funding or profits tied to it, leading to the worsening replication crisis and skyrocketing biomedical paper retractions.
One of the massive frauds and wastes of NIH funding is the so-called adult alternative to hESCs --- induced pluripotent stem cells (iPSCs) that are in fact cancer cells reprogrammed with oncogenes --- a massive 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. 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. 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 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.
Despite false claim that “iPSCs and hESCs are identical”, they are actually not identical. iPSCs are not pluripotent stem cells, but pluripotent cancer cells reprogrammed from adult cells with oncogenes, distinctly different from embryo-originated hESCs that are the real 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 stage. In contrast, iPSCs are in fact reprogrammed from different adult cells or tissues with different oncogenes, deacetylated, highly-methylated, different differentiation potential, cell line variations, genomic heterogenicity, 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 stage, uncontrolled growth, like cancer cells. hESC discoveries or breakthroughs do not apply for iPSCs, and hESC technologies do not work for iPSCs either.