Response to Soliciting ideas for new NIH Common Fund

programs-2022

Human embryonic stem cell (hESC) research breakthrough innovations have provided much-needed
hESC model systems to bridge the knowledge gap in human embryogenesis, and present innovative, more
effective solutions for the therapeutic needs of a wide range incurable or hitherto untreatable neurological
and heart disorders by providing novel regenerative medicine advanced therapy products in large quantity
and high quality as safe and effective therapeutic cell sources adequate to regenerate the lost nerve tissues
and contractile heart muscles, thus overcoming the major bottlenecks in the regenerative medicine
market. hESC research breakthroughs cannot be replaced by iPSC, an adult stem cell Ponzi scheme.

Transformational Science and Discovery

In regenerative medicine, human embryonic stem cell (hESC) research holds huge promise for treating
major human diseases challenging traditional medicine. Millions of people are pinning their hopes on
hESC research. Human embryonic stem cell (hESC) research breakthrough innovations have provided
much-needed hESC model systems to bridge the knowledge gap in human embryonic neurogenesis and
cardiogenesis, and facilitate translational research and therapy development for a wide range of
neurological and heart diseases that affect millions and cost billions. The technology breakthroughs of
hESC research present innovative, more effective solutions for the therapeutic needs of a wide range
incurable or hitherto untreatable neurological and heart disorders by providing novel regenerative
medicine advanced therapy (RMAT) products in large quantity and high quality as safe and effective
therapeutic cell sources adequate to regenerate the lost nerve tissues and contractile heart muscles, thus
overcoming the major bottlenecks in the regenerative medicine market, potentially shifting current
research and clinical practices and creating new scientific paradigms for CNS and cardiac repair.
Please note hESC research breakthroughs do not apply to or cannot be replaced by induced pluripotent
stem cells (iPSC), a scientific Ponzi scheme or adult stem cell lie by the Bush administration. iPSC are in
fact pluripotent cancer cells, or adult cells reprogrammed with oncogenes (commonly-known as flawed
reprogramming or oncogenesis or the origin of cancers in the scientific world). It is common knowledge
for anyone with a doctor degree in science or medicine (PhD or MD) that iPSC contain oncogenes, have
oncogenic potential, are in fact cancer cells, but not stem cells. hESC are called pluripotent stem cells
(PSC) because hESC have unlimited differentiation potential. Growing evidence indicates that iPSC do
not even have unlimited differentiation potential, the definition of pluripotency, and it is completely false
to call such cells PSC. hESC have unlimited differentiation potential, genomic/epigenomic/cell-line
homogeneity, highly-acetylated and unmethylated, across all hESC lines. iPSC have different
differentiation potential, genomic heterogenicity, cell line variations, because the different tissues they
used for reprogramming have different genomic imprints and are highly-methylated that cannot be
reversed by genes, causing their cell line variations, genomic heterogenicity, different differentiation
potential, and also, most importantly, genomic instability and oncogenic potential. iPSC are not at
embryonic stage and do not respond to developmental signals at embryonic stage as hESC do. One
essential aspect of stem cells is their long-term genetic stability. Stem cells can maintain long-term,
stable growth in culture, while cancer cells grow abnormally crazy and mutate fast. The initial cluster of
iPSC papers was actually published in top scientific journals, such as Nature, Cell, and Science, in
lightning speed, or only a few weeks, without any scientific evidence or data to show the long-term
genetic stability of iPSC or iPSC could maintain long-term stable growth. And over a decade later, there
is still absolutely no scientific data to show the long-term genetic stability of iPSC or iPSC could maintain
long-term stable growth. Without the data of long-term genetic stability, the line between stem cells and
cancer cells is bleared. In fact, iPSC have been reportedly associated with abnormal gene expression,
accelerated aging, and immune-rejection following transplantation owing to introducing foreign
oncogenes and instability/abnormality to the adult genome, and serious spontaneous mutations, the sign
of cancer cells, have been identified in human iPSC clinical trials.
1. Lineage-specific differentiation of hESC at the pluripotent stage by small molecule induction
opens the door to investigate molecular embryogenesis in human development
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 embryogenesis.
Development and utilization of hESC models of human embryonic development will facilitate rapid
progress in identification of molecular and genetic therapeutic targets for the prevention and treatment of
human diseases. Technology breakthroughs of hESC research enable neuronal or cardiac lineage-specific
differentiation direct from the pluripotent state of hESC with small molecule induction, providing much-
needed in vitro model systems for investigating molecular neurogenesis and cardiogenesis in human
embryonic development. It opens the door for further unveiling genetic and epigenetic programs
embedded in the human CNS and heart formation using genome-wide high-throughput high resolution
profiling approaches. These studies will not only contribute tremendously to our knowledge regarding
molecular embryogenesis in human development, but also allow direct control and modulation of the
pluripotent fate when deriving an unlimited supply of clinically-relevant lineages for therapies.
2. Direct conversion of nonfunctional pluripotent cells into a large supply of functional cardiac
derivatives provides life-saving treatments or cures for heart disease and failure
To date, the lack of a scalable human cardiac stem cell source with sufficient myocardium regenerative
potential remains a major setback in developing safe and effective cell-based heart therapy. So far, there
is no evidence that any traditional stem cells, such as bone marrow cells, cord blood cells, umbilical cord
cells, mesenchymal stem cells, cells isolated from fat tissue, cells isolated from placenta, adult stem cells
isolated from heart, or any reprogrammed adult cells, are able to give rise to the contractile heart muscle
cells following transplantation into the heart, thus achieving graft-dependent myocardium regeneration.
Technology breakthrough of hESC research enables well-controlled high efficient direct conversion of
non-functional hESC at the pluripotent stage by small molecule induction into a large supply of high
quality human cardiac precursor cells as a novel, potent cardiac therapeutic product for heart muscle
regeneration. Future studies, including further assessment of the therapeutic stem cell behavior for
myocardium repair and demonstration of the in vivo efficacy for myocardium regeneration in animal
models of heart disease and failure using clinically relevant outcome measures, will provide necessary
preclinical data of safety and efficacy for IND-enabling preclinical development, IND-filing, and moving
into clinical trials as FDA RMAT designation for accelerated approval and entry into the therapeutic
market for heart disease and failure. The outcome of such stem cell research will enable clinical
translation of hESC technology and IP for heart muscle regeneration and contractile function restoration
as a much-needed solution for heart disease and failure, having a groundbreaking impact on the advance
of medicine.
3. Direct conversion of nonfunctional pluripotent cells into a large supply of functional neuronal
derivatives provides life-saving treatments or cures for a wide range of incurable or hitherto
untreatable neurological disorders
To date, the available source for clinically-suitable engraftable human stem/progenitor/precursor cells
with adequate CNS regenerative potential remains lacking, which has been a major setback in developing
safe and effective cell-based neuronal therapies. Technology breakthrough of hESC research enables
well-controlled high efficient direct conversion of non-functional hESC at the pluripotent stage by small
molecule induction into a large supply of high quality human neuronal progenitor cells as a novel, potent
neuronal therapeutic product for CNS regeneration. Future studies, including further assessment of the
therapeutic stem cell behavior for neuron circuitry repair and demonstration of the in vivo efficacy for
CNS regeneration in animal models of neurological disorders using clinically relevant outcome measures,
will provide necessary preclinical data of safety and efficacy for IND-enabling preclinical development,
IND-filing, and moving into clinical trials as FDA RMAT designation for accelerated approval and entry
into the therapeutic market for a wide range of incurable or hitherto untreatable neurological disorders.
The outcome of such stem cell research will enable clinical translation of hESC technology and IP for
CNS regeneration and neurological function restoration as a much-needed solution for a wide range of
incurable or hitherto untreatable neurological disorders, including Parkinson’s disease, Amyotrophic
lateral sclerosis, Alzheimer disease, Spinal muscular atrophy, motor neuron diseases, neurodegenerative
diseases, brain and spinal cord injuries, and stroke.
4. Neuronal/myocardial tissue engineering/biofabrication
Technology breakthroughs of hESC research provide scale-up capability for further reconstitution/
reconstruction of complex multi-cellular 3D human CNS/heart models or products from hESC
derivatives in reliable tissue-specific complex biomimetic culture systems. Future progress will lead to
the development and commercialization of multi-cellular 3D human CNS/heart-related models or
products, which can be used for rapid and high fidelity safety and efficacy evaluation of human
therapeutic candidates, thus leading to advances in technologies used in the regulatory review of medical
products; and will be readily adaptable in drug efficacy and toxicity testing; and for commercialization
and therapeutic development of replacement tissue and organ products. These studies will provide
powerful tools to increase the biological complexity of human-based in vitro models and assays to
mimic the in vivo structure, behavior, and function of the human CNS/heart, which are controllable,
reproducible, and scalable, and can be monitored and validated against responses on multiple
hierarchical levels. It will pave the way for further development of cutting-edge automated high-content
systems for systematic functional assembly of the in vitro replacement tissues and organs from
pluripotent hESC in a 3D setting that reflect the biological complexity, microenvironment niche, and
function of the in vivo human organ system, enabling automated high content and high-throughput
analysis of CNS or heart circuitry and dynamics, and systems developmental biology models of the
complex human embryonic development.