Editorial: Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration

San Diego Regenerative Medicine Institute and Xcelthera announce Dr. Parsons’ Editorial, titled “Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration” (doi: 10.4172/cpo.1000e110), published in current issue of The International Open Access Journal of Cardiovascular Pharmacology.

Given the limited capacity of the heart muscle for self-repair after birth, transplantation of cardiomyocyte stem/precursor/progenitor cells holds enormous potential in cell replacement therapy for cardiac repair. However, the lack of a clinically-suitable human cardiomyocyte stem/precursor/progenitor cell source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart, either by endogenous cells or by cell-based transplantation or cardiac tissue engineering. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing human embryonic stem cell (hESC)-based therapy for heart disease and failure. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. In addition, undefined foreign or animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic. Recent technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. Such milestone advances and medical innovations in hESC research enable direct conversion of pluripotent hESCs into a large supply of homogeneous populations of clinical-grade hESC neuronal and heart cell therapy products for developing safe and effective stem cell therapies. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting. This novel small molecule direct induction approach renders a cascade of neural or cardiac lineage-specific progression directly from the pluripotent state of hESCs, providing much-needed in vitro model systems for investigating the genetic and epigenetic programs governing the human embryonic CNS or heart formation. Please read Dr. Parsons’ editorial at http://www.esciencecentral.org/journals/ArchiveCPO/currentissueCPO.php.

Direct Conversion of Pluripotent Human Embryonic Stem Cells into Functional Cell Therapy Derivatives Brings Cell-Based Regenerative Medicine to a Turning Point

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ review article, titled “Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine”, in British Biotechnology Journal at http://www.sciencedomain.org/issue.php?iid=243&id=11. In this review article, Dr. Parsons gives an insight view on recent advances and breakthroughs in human embryonic stem cell (hESC) research that have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-based regenerative medicine to a turning point.

Human stem cell therapy derivatives are extremely attractive for therapeutic development because they have direct pharmacologic utility in clinical applications, unlike any cells originated from animals and other lower organisms that are only useful as research materials. The human stem cell is emerging as a new type of pharmacologic agent of cellular entity in cell-based regenerative medicine, because human stem cell therapy derivatives have the potential for human tissue and function restoration that the conventional drug of molecular entity lacks. The ability of a human stem cell, by definition, to both self-renew and differentiation makes it a practically inexhaustible source of replacement cells for many devastating or fatal diseases that have been considered as incurable, such as neurodegenerative diseases and heart diseases. The pharmacologic activity of human stem cell therapy derivatives is measured by their extraordinary cellular ability to regenerate the tissue or organ that has been damaged or lost. In this regard, the pharmacologic utility of human stem cells cannot be satisfied only by their chaperone activity, if any, to produce trophic or protective molecules to rescue existing endogenous host cells that can simply be achieved by a small molecule or a drug of molecular entity. There is a large unmet healthcare need to develop human embryonic stem cell (hESC)-based stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Clinical applications of hESC therapy derivatives provide the right alternative for many incurable diseases and major health problems that the conventional mode of drugs and treatments cannot.

We must bear in mind that the pluripotent hESC itself cannot be used for therapeutic applications. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, which yields embryoid body (EB) consisting of a mixed population of cell types that may reside in three embryonic germ layers and results in inefficient, incomplete, and uncontrollable differentiation that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. Growing evidences indicate that incomplete lineage specification of pluripotent cells via multi-lineage differentiation often resulted in poor performance of such stem cell derivatives and/or tissue-engineering constructs following transplantation. In addition, most currently available hESC lines were derived and maintained on animal feeder cells and proteins, therefore, such hESCs have been contaminated with animal biologics and unsuitable for clinical application. Without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies and profiling of hESC differentiating multi-lineage aggregates have compromised their implications to molecular controls in human embryonic development.

Recent advances and technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation of clinically-suitable 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 neuronal or cardiomyocyte therapy derivatives to be translated to patients for CNS or heart repair. Without an understanding of the essential developmental components for sustaining hESC pluripotence and self-renewal, hESC lines are at risk for becoming unhealthy and unstable after prolonged culturing under animal feeders, feeder-conditioned media, or artificially-formulated chemically-defined conditions. Resolving minimal essential requirements for sustaining embryonic pluripotence allows all poorly-characterized and unspecified biological additives, components, and substrates in the culture system, including those derived from animals, to be removed, substituted, or optimized with defined human alternatives for de novo derivation and long-term maintenance of GMP-quality xeno-free stable hESC lines and their human therapy derivatives. Formulation of minimal essential defined conditions renders pluripotent hESCs be directly and uniformly converted into a specific neural or cardiac lineage by small signal molecule induction. Such milestone advances and medical innovations in hESC research enable generation of a large supply of high purity clinical-grade hESC neuronal and heart muscle cell therapy products as powerful cellular medicines that can offer pharmacologic utility and capacity for CNS and heart regeneration that no conventional drug of molecular entity can. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting. The availability of human neuronal and cardiomyocyte therapy derivatives in high purity and large quantity with adequate potential for CNS and myocardium regeneration will facilitate CNS and myocardial tissue-engineering and accelerate the development of safe and effective cell-based therapy to resolve these major health problems. Further improving policy making and funding situation for hESC research would open up a new dimension of cell therapy-based future medicine to provide new medical treatments for many devastating and life-threatening diseases and injuries. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products, bringing cell-based regenerative medicine to a turning point. Please read Dr. Parsons’ full open access article at http://www.sciencedomain.org/issue.php?iid=243&id=11.

Embedding Lineage-Specific Developmental Programs into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells Offers Efficiency in Deriving Cell Therapy Products for the Future of Regenerative Medicine

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ review article, titled “Embedding the Future of Regenerative Medicine into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells”, in Annual Review & Research in Biology at http://www.sciencedomain.org/issue.php?iid=239&id=9. In this review article, Dr. Parsons gives an insight view on the human stem cell epigenomes in discerning the intrinsic plasticity and regenerative potential of human stem cell derivatives from various sources as well as recent advances on uncovering the developmental programs embedded in neural and cardiac lineage-specific differentiation of pluripotent human embryonic stem cells (hESCs) that lead to efficiency in deriving neural and cardiac elements for cell-based therapies.

Human stem cells are extremely attractive for therapeutic development because they have direct pharmacologic utility in clinical applications, unlike any cells originated from animals and other lower organisms that are only useful as research materials. The human stem cell is emerging as a new type of drug of cellular entity that can offer pharmacological utility and capacity for human tissue and function restoration that the conventional compound drug of molecular entity lacks. However, to date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost central nervous system (CNS) structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent hESCs, derived from the pluripotent inner cell mass or epiblast of the human blastocyst, have both the unconstrained capacity for long-term stable undifferentiated growth in culture and the intrinsic potential for differentiation into all somatic cell types in the human body, holding tremendous potential for restoring human tissue and organ function. Given the limited capacity of the CNS and heart for self-repair, transplantation of hESC neuronal and heart cell therapy derivatives holds enormous potential in cell replacement therapy for neurodegenerative and heart diseases that cost the healthcare system > $500 billions annually. There is a large unmet healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for normal tissue and function restoration in many major health problems. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by conventional approaches for generating functional cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation. Growing evidences indicate that incomplete lineage specification of pluripotent cells via multi-lineage differentiation often resulted in poor performance of such stem cell derivatives and tissue-engineering constructs following transplantation. The development of better differentiation strategies that permit to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to desired phenotypes is vital for realizing the therapeutic potential of pluripotent hESCs.

The eukaryotic genome is packaged into chromatin, a nucleoprotein complex in which the DNA helix is wrapped around an octamer of core histone proteins to form a nucleosomal DNA structure, known as nucleosome, that is further folded into higher-order chromatin structures with the involvement of other chromosomal proteins. Chromatin modifications, such as DNA methylation and histone modifications, serve as important epigenetic marks for active and inactive chromatin states, thus the principal epigenetic mechanism in early embryogenesis. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations reside in chromatin modifications that shape the respective epigenomes of their derivation routes. The broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin. The hESCs are not only pluripotent, but also incredibly stable and positive, as evident by that only the positive active chromatin remodeling factors, but not the negative repressive chromatin remodeling factors, can be found in the pluripotent epigenome of hESCs. The normality and positivity of hESC open epigenome also differentiate pluripotent hESCs from any other stem cells, such as the induced pluripotent stem cells (iPS cells) reprogrammed from adult cells with known oncogenes and the tissue-resident stem cells. Somatic cell nuclear transfer and transcription-factor-based reprogramming have been used to revert adult cells to an embryonic-like state with extremely low efficiencies. Although pluripotent, the iPS cells and ESC derived from cloned embryos by somatic nuclear transfer are made from adult cells, therefore, adult cell-originated pluripotent cells carry many negative repressive chromatin remodeling factors and unerasable genetic imprints of adult cells that pluripotent hESCs do not have. Somatic cell nuclear transfer and factor-based reprogramming are incapable of restoring a correct epigenetic pattern of pluripotent hESCs, which accounts for abnormal gene expression, accelerated senescence, not graftable, and immune-rejection following transplantation of reprogrammed cells. These major drawbacks have severely impaired the utility of reprogrammed or deprogrammed or direct or trans-differentiated somatic cells as viable therapeutic approaches.


Using hESCs to develop cellular medicine for the brain and the heart must first transform pluripotent hESCs into CNS or heart fate-restricted cell therapy derivatives. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. This technology breakthrough enables high efficient direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate pharmacologic capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate pharmacologic capacity to regenerate neurons and contractile heart muscles that no conventional drug of molecular entity or tissue-derived stem cells can. Embedding lineage-specific genetic and epigenetic programs into the open epigenomic landscape of pluripotent hESCs offers a new dimension for direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. Please read Dr. Parsons’ full open access article at http://www.sciencedomain.org/issue.php?iid=239&id=9.

CIRM Employs Negative Reviewers of No Scientific Integrity to Make Dishonest Comments and Scores to Block Prop71 Stem Cell Research for Funding and Cover Up COI

To understand why billions of Prop71 have flowed into conflicts of interest (COI) but not stem cell research from CIRM unobscurely, it may help to look into CIRM flawed review process, particularly the part that has been forbidden by CIRM internal COI to disclose to the public, covered up as CIRM pre-application or LOI. It is interesting to see CIRM president Alan Trounson’ very public demand for his $70 million alpha clinic proposal while, unseen by the public, he is so evidently negligent or even negative about stem cell research and therapy in handling CIRM flawed grant review process as CIRM president. The only problem is that, so far, CIRM has not had one FDA-approved stem cell therapy, not even any CIRM sponsored IND or clinical trials. Without clinically-suitable human stem cells or FDA-approved stem cell therapy, Alan Trounson’s alpha clinics would be no different from those stem cell con man’s clinics hunted by FBI. It would turn out to be just another way for Alan Trounson to get $70 million freebies for CIRM COI, while under the cover he has been deliberately blocking those real beneficial proposals that would provide stem cell therapy for his alpha clinics using CIRM COI flawed review process with his apparent consent.

If ICOC’s COI is only speculation in public, COI in CIRM grant review is monopoly, even to the extent of extortion. Therefore, it is no surprise CIRM has been very resistant to be transparent in its grant review. So far, it seems that CIRM reviewers have been only capable of making negative comments that are so full of false statement, factual error, bias or predisposition, COI that have comprised the integrity and credibility of any advices provided by the reviewers. It is quite shocking that CIRM reviewers of no scientific integrity usually could not note any strength of hESC research proposal and intentionally gave false or biased or dishonest comments and scores against scientific evidences that did not reflect the overall impact and scientific merit of hESC grant applications (see hESC grant title and summary below for example). Our proposal shown below is to understand molecular mechanism in human embryonic stem cell neuronal differentiation using novel lineage-specific differentiation technique in hESC research breakthrough. Such technique has never been described before us. Only RA effect on hESC differentiating multi-lineage embryoid body has been described before, but the effects are small, and molecular mechanism in human and mouse ESC is totally different. There is nothing in our proposal about iPS cells and some other irrelevant comments made by CIRM reviewers. We have written to CIRM president/vice president, CIRM, ICOC multiple times about such flawed reviews from CIRM reviewers before, however, it seems that CIRM president/vice president or chair or ICOC have never been able to address such serious issues as CIRM reviewers’ COI or scientific misconduct, deliberately brushed it off, never responded to our complaints about CIRM flawed reviews or COI in CIRM review, and covered it up by consent to reviewers’ COI or false statement or flawed review. Considering many of CIRM ICOC members are leaders, physicians, Deans, and Presidents who know more than anyone else how serious a issue of scientific misconduct is in their own institutions, particularly provided by CIRM review comments for unmistakenable evidences, it would be detrimental for us to think that CIRM or ICOC or CIRM president/vice president or chair have been actually behind CIRM reviewers’ COI, false statement, or scientific misconduct by deliberately avoiding to address CIRM flawed grant review process.

RFA 13-02, RB5-07199:

Molecular Controls in Human Embryonic Stem Cell (hESC) Neuronal Lineage Specification

The hESCs provide a powerful in vitro model system to investigate molecular controls in human embryonic neurogenesis as well as an unlimited source to generate the diversity of human neuronal cell types for CNS repair. However, realizing the potential of hESC derivatives has been hindered by conventional approaches for generating neuronal cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific neuronal or cardiac lineage by small molecule induction. This technology breakthrough enables well-controlled efficient neuronal lineage-specific differentiation direct from the pluripotent state of hESCs. In this project, this novel hESC model of neuronal lineage-specific progression will be characterized and used for genome-wide genetic and epigenetic profiling to generate a comprehensive knowledge of developmental regulators and networks for identification of molecular controls in hESC neuronal lineage specification. Fulfilling the goal of this project will be provide a comprehensive understanding of molecular neurogenesis in human embryonic development, thereby, reveal potential molecular and cellular therapeutic targets for the prevention and treatment of CNS disorders. The outcome of this project will have a transformative impact on a broad area of biomedical sciences and public health.  

From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, May 24, 2013 12:58 PM
To: parsons@sdrmi.org
Subject: CIRM Basic Biology V Awards

Dear Dr. Parsons:

Thank you for submitting your proposal under the CIRM RFA 13-02: Basic Biology V Awards. After careful consideration, your PreApp was not selected for further review under this RFA.

The goal of the PreApp process is to identify proposals that are the most responsive to the RFA objectives and likely to be competitive. For this competition we received over 340 PreApps and selected about 60 for a full application. The process was designed to handle a large volume of proposals and to ensure a rapid turn-around on the review. Reviewers may provide brief comments that highlight strengths and weaknesses where appropriate. The comments are not comprehensive and do not necessarily provide all the reasons for an invitation or denial. Each application is assigned to 3 independent reviewers and each reviewer assesses approximately 20-30 PreApps within their area of expertise and scores the applications on a scale of 1 to 100, 100 being the most meritorious. CIRM scientific staff further assesses proposals to ensure that projects meet eligibility requirements and are responsive to the RFA. CIRM invites the most highly ranked and responsive PreApps as determined by the external scientific reviewers and CIRM science officers.

The summary below shows the final score for your PreApp and comments provided by reviewers.

We thank you for your interest, and we encourage you to respond to future CIRM initiatives. We look forward to your future applications to CIRM. If you have any questions about the review please feel free to contact me.

Sincerely,

Gil Sambrano

Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107
Phone: 415-396-9103
gsambrano@cirm.ca.gov

SUMMARY OF REVIEW

Overall Scientific Score: 33.33

Comments provided by reviewers:

Comments 1:

Strengths:

            The use of an in-vivo assay in Milestone 3 is very significant as it validates the in-vitro results of all the other Milestones.

Weaknesses:

            The direct conversion of hESCs to neuronal derivatives has already been extensively described by many different laboratories. (our response: the reviewer’s statement is false & against scientific evidences. The fact is the direct conversion of hESCs from the pluripotent state to neuronal derivatives has never been done by any laboratories before us.)

            It has been shown that inhibition of the TGFB pathway by SB and LDN small compound is sufficient to robustly induce conversion to telencephalic. (our response: The reviewer did not provide the fact that it was induced from neuroepithelial cells isolated from embryoid bodies (EBs) in extremely low efficiency by University of Connecticut & groups connected to CIRM vice president/UC connect/Sanford/UC. Our study overcomes their shortcoming to generate neurons direct from hESCs in high efficiency and purity, not isolated from EB.  The fact the reviewer did not disclose shows that this review had conflicts of interest (COI) and intentionally gave false or biased or dishonest comments against scientific evidences, which has affected the integrity of advice provided by this reviewer).

            The use of RA is sub-optimum as it as it generates random sets of neurons, which will make collective data analysis useless. (Our response: the reviewer’s statement is false & against scientific evidences. RA is optimized to induce neuroectoderm and neuronal differentiation from hESCs to a large supply of neuronal cell type and subtypes, which is critical for collecting data for analysis of molecular mechanism in hESC neuronal lineage specification.)

Comments 2: (our response: our proposal is to investigate molecular mechanism in hESC neuronal lineage-specific differentiation and has nothing to do with iPS cells and the negative comments of this reviewer (see title & summary). The reviewers’ comments are false, which show COI since this review could not note any strength of this hESC proposal and intentionally gave false or biased or dishonest comments against scientific evidences, and which has affected the integrity of advice provided by this reviewer).

Weaknesses:

- This protocol for differentiating human iPSCs into neurons has not particular advantages respect to others already present in the literature, while having some substantial drawbacks:

1) this protocol is not designed to generate one particular neuronal subtype while generating a variety of very different neurons. It is not clear which relation is existing between DA and spinal cord neurons which are both generated by this same protocol.

2) it is not explained which particular type of DA or spinal cord neurons are generated with this protocol. Are DA neurons patterned as ventral mesencephalic Pitx3+ neurons? This is a crucial information for generating therapeutic relevant neurons.

3) Retinoic Acid (RA) it is a well-known inducer of caudal neuronal subtypes. It is therefore unclear how DA neurons can be specified in this particular regimen

4) Preliminary data are missing showing electrophysiological maturation and activity of iPSC-derived neurons

Considering these pitfalls, caution is required in employing this protocol in large extent and a better characterization of the differentiated neurons is necessary to validate the system.

Comments 3: (our response: our proposal is to investigate molecular mechanism in hESC neuronal lineage-specific differentiation using a novel technology by small signal molecule induction. The reviewer’s comments are vague, did not give any specifics. It is commonly known that miRNAs are governors of regulatory circuits. The reviewers’ comments are biased, which show COI since this review could not note any strength and apparent novelty of this hESC proposal and intentionally gave false or biased or dishonest comments against scientific evidences, and which has affected the integrity of advice provided by this reviewer).

novelty of this application not at all clear

many vague, sweeping statements about the transformative nature of the work, but very little focus

not at all clear how regulatory circuits will emerge from miRNA profiling

CIRM Comments:

NA

Gilberto R. Sambrano, Ph.D.

Associate Director, Review

California Institute for Regenerative Medicine

210 King Street

San Francisco, CA 94107

(415) 396-9103

CIRM Mediocre Leaders of No Leads --- Directors’ Sidekicks and Freebies

CIRM awarded leaders all bore one unmistakenable resemblance to the sidekicks of CIRM directors, such as Eric Ahrens and Robert Wechsler-Reya to Sanford Directors Larry Goldstein and Evan Snyder, Hiromitsu Nakauchi to Irv Weissman of Stanford U, Barry Stripp to Cleve Svendsen of Cedars-Sinai & UCLA, Kevin Parker to Deepak Srivastava of Gladstone & UCSF. Are any leaders in any societies, coalitions, or communities expected to have at least some sort of acceptable leadership activity or accomplishment to be a leader, if it is not up to the standard of outstanding?  However, CIRM awarded leaders are definitely exception to the meaning of leader in any languages. Besides their close relationship with CIRM directors, they all have one thing in common, they have absolutely no leadership activity nor accomplishment in the stem cell community to make them pass the standard of acceptable or outstanding to lead anyone but corruption. Therefore, it would be more appropriate to translate CIRM leaders as CIRM directors’ sidekicks or freebies for sneaking tens of millions of taxpayer money from stem cell research in CIRM’s own language that can only be found in the government corruption directory. To make it more obvious, CIRM ICOC directors and president Alan Trounson even went extra miles to sneak more millions of taxpayer money for stem cell research as freebies to CIRM vice chair/UC connect Duane Roth’s company Sangamo BioSciences for something that is neither new nor eligible for Prop 71 stem cell research. It makes us all wonder what those CIRM ICOC directors are wasting taxpayer money to meet together really for on a regular basis, how come CIRM directors’ requests for sidekicks and freebies have become commands to CIRM ICOC for hundreds of millions of taxpayer money, and how come CIRM directors’ interests and requests, and ONLY CIRM directors’ interests and requests, for sidekicks and freebies are CIRM president, chair, ICOC’s commands for money in a State government agency that is designated public money for stem cell research and fair competition by a law. 

Skating on Thin Ice --- The Bottled-Up Stem Cell Community Deceived by Dictating Interest and High Impact of Unquestionable Prestige

Today, with the world second largest economy and a new generation emerging from the 90^th, China’s culture revolution has been left behind in a bottled-up history. No one, not even those who were born into it, could make sense of culture revolution any more, could make sense of the insanity, brutality, and mass destruction committed by those who were so young so innocent. Only those who once lived in the bottle and had their life dictated by the unquestionable will and sugar-coated political interest of a single high power beyond their control could believe what had really happened was totally unavoidable. For the rest, reading culture revolution is like reading the consequence of irrationality. In my teenage years, not even through my aunt’s hilarious imitation, I could make sense that my young, handsome, intelligent, and kind parents, uncles and aunts, would leave their infant kids alone at home in the dark, voluntarily go to do their totally ridiculous duty dancing on the streets just to show their devotion to a dying old man. Until they finally got their own common sense back, just in time to catch the last nearby train flee out of the exploded conflict zone, leaving their toddlers behind to survive a war-torn city.

The recent wave of induced pluripotent stem cells (iPS cells) in the stem cell community is just as insane as the culture revolution, making no sense at all to anyone who has little bit of common sense, to anyone who has little bit of scientific integrity. Besides the Nobel committee’s golden framed words that need Karolinska Institute’s intelligence to understand, besides the perplexed news persons’ copied words that do not need Karolinska Institute’s intelligence to tell that it sounded very much like a scam, what has Yamanaka really accomplished? Yamanaka put not just one, not two, not three, but 4 oncogenes into skin cells, not even the skin of humans but lab rats, rationally or scientifically, he would not get anything coming out of it but cancer cells. If Yamanaka told the public in lay language what he really did, probably any ordinarily people would only think he was just some mad scientist. However, it was told through the high impact peer-reviewed prestigious scientific journal Cell, it was told in sugar-coated political interest by highly-trusted big names as the “safe” and “ethical” alternate for human embryonic stem cells (hESCs), it was copied by every major news agencies throughout the world as “the biggest breakthrough of stem cell research” without hearing a single critique or even precaution, like a man-made earthquake with the magnitude that could even shake the more than 100 years of unquestionable prestige of Nobel Assembly. Although Yamanaka’s Bernie Madoff scam in the stem cell community does not make any sense scientifically, it does make sense monetarily if simply check how much taxpayer money has gone into the epicenter of Yamanaka iPS cells from NIH and CIRM since.   

In 1989, James was in London, stayed in Margaret Thatcher’s old flat. He visited Berlin Wall without any speculation that someday it would come down. He had to memorize his passport number in case that the Berlin Wall might really prevent him from coming back to the free world. Then, a few months later, it was gone, forever. Danny was in Beijing, turned on the TV in his hotel room and saw CNN to his surprise. He thought Chinese people could actually watch CNN, how wonderful. I was in the same city, and like all the Chinese people only 100 feet away from his Westerner-only hotel, did not even know the existence of CNN and could only watch one single state-controlled news broadcast – China Central News. Nearly 20 years later, when I sit in front of my parents’ TV bigger than the one we had, that was still all I could watch. If talking enforced high impact, the Central News broadcast occupies the prime time, copying the same exact words with never-changed sugar-coated tone through every channel, every household, every neighborhood, and every dinner table of an entire country that I have never missed even a bit. A KFC and a large shopping mall erupted right next to my old elementary school that was still very much unchanged. I went into KFC to taste the chicken that looked and tasted just like a KFC, then went into the shopping mall to spend my parents’ money and brought a few pairs of pure gold earrings, then went by my old elementary school that looked just like what I remembered, having this incredible feeling that I was going through a time machine. Hong Kong, from where I flew in, was only 2 hours away. Their TV satellites could pick up the signals of some Hong Kong channels. However, the interfering signals to those channels were so bad, few minutes staying on those snowy channels would only make the Central News sound unbelievably wonderful. 

Although Berlin Wall had come down, without transparency, the peer-review system can be easily broken by the dictating interest and high impact of unquestionable prestige, and Berlin Wall can always be rebuilt by a privileged few to implement their own will and fence away fair competition and everything else that a democratic free country has stood for.

This piece is written in memory of Margaret Thatcher, the only woman and only scientist who had become a great politician of the world and had sailed through a stormy era in our time. 

NIH Response to Letter to NIH Director Francis Collins

Dear Dr. Gadbois,

Thank you for your response on behalf of Dr. Francis Collins. Although we do not have NIH actual award# for human embryonic stem cell (hESC) research, according to NIH online statistics at http://stemcells.nih.gov/research/funding/pages/Funding.aspx, in 2012, only 10% of total NIH fund to stem cell research (~ $1.468 billion) was gone into hESC research, while 56% (~ $822 million) was gone into non-human stem cells. The significance and benefit of hESC research should be in reverse with the fund supported by NIH. In the 10%, hESC research is often only a tiny fraction or small project of adult induced pluripotent stem (iPS) cell U grants or large center grant awards, so the actual NIH fund to hESC research is even much less than the 10%.

My hESC grant applications have encountered such non-peer reviewed processes or events in NIH CSR (Center for Scientific Review) peer review as that study section overridden the reviewers’ scores to outside of funding range or biased reviewers scored to as low as exclusive 9s or 8s (in a scale of 1 to 10 with 1 the strongest and 10 the weakest) for the scientific merits and overall impact of hESC research with significance and impact to understanding human embryonic development and finding a cure for PD, neurological and heart diseases as currently the most promised therapeutic approach closet to provide a cure. I have gone through NIH appeal system for at least 3 times (please see the appealed project title and summary below), the appeals were either not brought up for consideration, or concurred by NIH appeal system to reviewers’ biased recommendation. Therefore, it seems NIH appeal system did not work, at least for my hESC applications. Please do not hesitate to contact me should you have any questions, thanks,

R01 HD073109-01A, Parsons, Xuejun H.

Title: Preclinical study of a novel neuronal progenitor induced from human embryonic stem cells in spinal muscular atrophy model, in response to NIH funding opportunity Program Announcement (PAR) Number: PAR-11-038 Title: Preclinical Research on Model Organisms to Predict Treatment Outcomes for Disorders Associated with Intellectual and Developmental Disabilities (R01).

Project summary: Spinal muscular atrophy (SMA) is a devastating, untreatable, and one of the most common genetic neurodevelopmental diseases leading to infant mortality. Human stem cell transplantation represents a promising therapeutic approach closest to provide a cure to restore the lost nerve tissue and function for SMA. However, to date, lacking of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies. In spite of proffering cures, realizing the developmental and therapeutic potential of pluripotent human embryonic stem cells (hESCs) has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. To achieve uniformly conversion of pluripotent hESCs to a neuronal lineage, I have established a small molecule induction approach to generate a large supply of novel nurr1-positive human neuronal progenitors direct from the pluripotent state of hESCs (hESC-I hNuPs) in high efficiency, purity, and neuronal lineage specificity to support preclinical research. SMA, characterized by selective degeneration of spinal cord motor neurons, provides an ideal model for in vivo motor neuron dysfunction bioassay. In this project, hESC-I hNuPs will be transplanted into animal models of SMA to determine if the engrafted cells will extend life-span and improve the motor function by differentiation into motor neurons for nerve regeneration and reinnervation of host muscle to provide preclinical evidences of efficacy and safety against incurable motor neuron disease. Their therapeutic behavior, including engraftment/cell survival/integration, migration, differentiation into motor neurons, graft-dependent nerve regeneration and reinnervation of host muscle, and motor function recovery will be assessed for evidences of efficacy, and a lack of tumors and inappropriate cell type formation will be assessed for evidences of safety. Assessment of the potential of hESC-I hNuPs in disease models of SMA will offer critical insights into novel therapeutic strategies against incurable motor neuron disease as well as provide necessary and sufficient preclinical evidences of safety and efficacy to demonstrate their potential as stem cell therapy to be translated to SMA patients for motor neuron repair in clinical trials. The outcome of this proposal will have significant impact on the advance of medicine to provide treatment options for incurable motor neuron diseases in pediatric patient populations.

1 R43 TR000349-01      Parsons, Xuejun H

Title: Dopaminergic specification of human embryonic stem cells for cell-based therapy against Parkinson’s disease (Phase I), in response to NIH funding opportunity Program Announcement (PA) Number: PA-10-122 Title: SHIFT Award: Small Businesses Helping Investigators to Fuel the Translation of Scientific Discoveries [SBIR: R43/R44].

Project summary: To date, lacking of a large supply of clinical-grade human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies for restoring the damaged CNS. Pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the therapeutic potential of hESCs has been hindered by the current state of the art for generating neuronal cells from pluripotent cells through multi-lineage differentiation, which is uncontrollable, inefficient, instable, highly variable, difficult to reproduce and scale-up. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific lineage by small molecule induction. The goal of this project is to use a novel small molecule induction approach for well-controlled efficiently directing neuronal lineage-specific differentiation of hESCs from the pluripotent stage towards human neuronal progenitors and neurons at scale, purity, and DA regenerative potential suitable for preclinical development of cell-based therapy against Parkinson’s disease (PD), a prototypical age-related neurodegenerative disorder. Retinoic acid (RA) was found to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger progression to neuronal progenitors and neurons efficiently by promoting nuclear translocation of Nurr1. In the phase I of this project, the cascade of hESC neuronal lineage-specific differentiation by small molecule induction will be characterized. These characterizations will be used to optimize the hESC neuronal differentiation protocol and to define their homogeneity and dopaminergic (DA) potential. These studies in Phase I will be used to establish the feasibility of this approach prior to initiating Phase II for large-scale molecular profiling to define stage-specific human embryonic neurogenic factors and for preclinical studies of their therapeutic effect in vivo in the DA dysfunction models. These studies will lead to producing a large supply of well-characterized human neuronal progenitors and neurons in high purity and adequate DA regenerative potential for therapeutic applications. Further assessment of their potential in the PD models will offer critical insights into novel neuron replacement therapy as well as provide necessary and sufficient preclinical evidences of safety and efficacy for predicting stem cell therapy outcomes in clinical trials against PD. The outcome of this proposal will have significant impact on the advance of medicine to provide novel graft-dependent stem cell therapy for restoring the lost tissue and function in CNS disorders.

1 R43 HL114131-01A1      Parsons, Xuejun H

Title: Cardiomyocyte specification of human embryonic stem cells (hESCs) for cell-based therapy for myocardium regeneration (Phase I), in response to NIH funding opportunity Program Announcement (PA) Number: PA-09-249 Title: Directed Stem Cell Differentiation for Cell-Based Therapies for Heart, Lung, and Blood Diseases (SBIR),

Project summary: To date, lacking of a suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent human embryonic stem cells (hESCs) proffer unique revenue to generate a large supply of cardiac lineage-committed cells as human myocardial grafts for cell-based therapy. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. However, realizing the therapeutic potential of hESCs has been hindered by the current state of the art for generating cardiomyocytes from pluripotent cells through multi-lineage differentiation, which is uncontrollable, inefficient, instable, highly variable, difficult to reproduce and scale-up. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific lineage by small molecule induction. The goal of this project is to use a novel small molecule induction approach for well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human cardiac precursors and cardiomyocytes at scale, purity, and myocardium regenerative potential adequate for preclinical development of cell-based therapy for heart disease. Nicotinamide was found to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs and trigger progression to cardiac precursors and cardiomyocytes efficiently. The cascade of hESC cardiac lineage specific differentiation by small molecule induction will be characterized. These characterizations will be used to identify cardiac stage-specific markers and optimize hESC cardiac lineage-specific differentiation by small molecule induction to beating cardiomyocytes. These studies in Phase I will be used to establish the feasibility of this approach prior to initiating Phase II for large-scale molecular profiling and for preclinical studies of their therapeutic effect in myocardium regeneration in vivo. These studies will lead to producing a large supply of well-characterized human cardiac precursors and cardiomyocytes in high purity and adequate myocardium regenerative potential for commercial and therapeutic applications. This project is crucial to driving the advance of medicine to provide optimal treatment options for the damaged or diseased hearts that have been lacking. The outcome of this project will have a transformative impact on a broad area of biomedical sciences and public health.

From: Gadbois, Ellen (NIH/OD) [E] [mailto:gadboisel@od.nih.gov]
Sent: Wednesday, May 01, 2013 8:27 AM
To: 'parsons@SDRMI.org'; 'parsons@xcelthera.com'
Cc: HESCREGISTRY (NIH/OD)
Subject: your email to Dr. Francis Collins

Dear Dr. Parsons,

Your recent email dated April 17, to Dr. Francis Collins, Director of the National Institutes of Health (NIH), regarding stem cell research funding, was referred to me for reply. I appreciate the opportunity to respond to your email. 

Across NIH, stem cell research is a high priority. As you know, NIH funds a range of stem cell research, using human and non-human adult stem cells, embryonic stem cells, and induced pluripotent stem cells. NIH-funded research is exploring potential applications in regenerative medicine, drug screening, and the study of the molecular pathways in biological development and human disease. There is no budget set for stem cell research overall or in specific categories; the individual institutes and centers at NIH make their decisions on awarding grants and contracts based on considerations of scientific merit and relevance to their mission, programs, and priorities.

You state that NIH has cut funding for research with human embryonic stem cells under the current administration. That is not correct--NIH has actually increased support by $58.4 million between fiscal year 2008 ($88.1 million awarded) and fiscal year 2012 ($146.5 million awarded). You can find additional details about NIH stem cell research funding at http://stemcells.nih.gov/research/funding/pages/Funding.aspx. 

You may also be interested in reading the NIH Guidelines for Human Stem Cell Research (Guidelines), posted at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx. NIH has approved 209 human embryonic stem cell lines for use in NIH-funded research under the Guidelines. Information on these lines is available at http://grants.nih.gov/stem_cells/registry/current.htm. If you have human embryonic stem cell lines that you think meet the requirements of the Guidelines, I encourage you to submit your documentation for consideration by NIH.

Finally, it is of utmost importance to NIH to conduct high quality peer review. NIH has established a peer review appeal system (see NOT-OD-11-064) to provide investigators and applicant organizations the opportunity to seek reconsideration of the initial review results if, after consideration of the summary statement, they believe the review process was flawed as outlined below. Additional details of this appeals process can be found at http://grants.nih.gov/grants/peer_review_process.htm#Appeals. 

Thank you again for your interest in stem cell research.

Sincerely,

Ellen L. Gadbois, Ph.D.

Senior Policy Analyst

Office of Science Policy

Office of the Director

National Institutes of Health

Letter to NIH Director Francis Collins

Dr. Francis Collins
Director, National Institutes of Health

1 Center Drive, MSC 0148 (Room 126)
Bethesda, MD 20892-0148
Fax: 301-402-2700
Email: francis.collins@nih.gov

Subject: Urge NIH to increase funding and support for human embryonic stem cell research and new stem cell research investigator

Dear NIH Director,

Thank you for your recent visit to San Diego research & biotech community to promote increasing funding for NIH and finding a cure for Parkinson’s disease (PD). Human embryonic stem cell (hESC) cell therapy derivatives hold tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternative for many incurable diseases & major health problems that the conventional mode of drugs & treatments cannot, such as heart disease and failure, Parkinson’s diseases, ALS, Alzheimer disease, stroke, brain & spinal cord injuries. Each single one of those world-wide major health problems cost the health care system more than $10 billion annually. In particular, hESC neuronal & cardiomyocyte therapy derivatives are currently the only available human cell sources with adequate capacity to regenerate neurons & contractile heart muscles, vital for CNS and heart repair in the clinical setting. The loss of NIH funds to hESC research threatens the future of existing hESC projects and the ability for new investigators to get funding to continue hESC research and career or begin new studies, which are crucial to improving the human health and fighting human diseases, particularly those major health problems of US, such as PD and heart disease.

Recent advances and breakthroughs in San Diego Regenerative Medicine Institute (SDRMI) hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications. SDRMI & Xcelthera have established human stem cell technology platforms for defined culture systems for derivation and maintenance of clinical-grade pluripotent hESCs (PluriXcel-DCS) and lineage-specific differentiation of pluripotent hESCs by small molecule induction for direct conversion of pluripotent hESCs into neuronal cells or heart muscle cells for developing safe and effective stem cell therapies (PluriXcel-SMI). Such milestone advances and medical innovations in SDRMI & Xcelthera hESC research enable generation of a large supply of high purity clinical-grade hESC neuronal (Xcel-hNuP & Xcel-hNu) & heart (Xcel-hCardP & Xcel-hCM) cell therapy products for treating neurological & heart diseases & injuries. Please go to our websites at http://www.sdrmi.org & http://www.xcelthera.com to see SDRMI & Xcelthera stem cell research breakthrough publications, human stem cell therapy products and technology platforms, and watch videos of hESC heart beats (hESC-derived heart muscle cells) & slideshow of evolution of CNS neuron cells from hESCs by SDRMI & Xcelthera exclusive human stem cell technique PluriXcel-SMI.

Increasing current NIH funding for hESC research is vital to driving the advance of medicine to provide treatment options for many major world-wide incurable diseases, such as Alzheimer disease, Parkinson’s disease, ALS, heart disease. Given the limited capacity of the CNS & heart for self-repair, transplantation of hESC neuronal & heart cell therapy derivatives holds enormous potential in cell replacement therapy, representing most promising therapeutic approaches closest to provide a cure. Increasing funding for hESC research would be crucial to relieving health care burden, therefore, budget deficit in the future. However, although President Obama acted very quickly to relax the NIH policy on hESC research in March 2009, so far NIH under your directing have cut funding for hESC research to a level worse than that under pervious Bush administration by a Republican President or previous NIH director. During Obama administration led by a Democrat President, crucial hESC research and advances cannot proceed, and existing national hESC research labs and resources that had been open for research progress even in Bush administration have been shut down due to lack of funding. On the other hand, NIH under your directing have wasted hundreds of millions of taxpayer money on adult stem cell frauds and scams and fake science, such as on making very dangerous malicious cancer cells from skin by calling it as induced pluripotent stem cells (iPS cells, no scientific evidence for self-renewal by the definition of stem cells) to endanger public health. In last few years, NIH under your directing have wasted > $300 millions on iPS cells (putting oncogenes into the skin cells of lab rats by falsely claiming it as adult cell alternate for hESCs), examples include Deepak Srivastava of USF (NIH U01HL100406) ~ $ 7 million, George Daley of Harvard U. (NIH U01HL100001) ~ $ 7 million, Robert Robbins of Stanford U (NIH U01HL099776) ~ $ 7 million, Charles Murry of U. Washington (NIH P01HL094374) ~ $ 10 million, Alysson Muotri of UCSD (NIH 1DP2OD006495) ~ $5 million, John O'Shea of National Institute of Arthritis And Musculoskeletal And Skin Diseases (NIH 1ZICAR041190) ~ $ 14 million. While funding for hESC research has been reduced from ~ $80 millions in Bush administration to < 10 millions annually in Obama administration. Please see this website http://search.engrant.com for more information. As NIH new investigator, my critical hESC research projects relevant to understanding the human development and fighting human diseases & major US health problems, such as heart diseases and PD, have kept receiving NIH flawed reviews with apparent biases/COI and scores not reflecting the overall impact and scientific merit of hESC research grant applications. Therefore, we’d like to urge NIH to take action to have high level of transparency and high standard of review for NIH grants review processes in Center for Scientific Review, particularly for stem cell research projects, increase NIH funding for hESC research and new stem cell research investigator, and stop funding stem cell frauds & scams & fake science with taxpayer money. 

CIRM Continue to Cover Up Unlawful Practice By Using Biased Pre-Application to Deny Prop71 Funding for Stem Cell Research But Give Conflicts of Interest Preferential Treatment

If anyone wants to see hard core denial, California Institute for Regenerative medicine (CIRM) would be a very good example. Although evidences and signs of conflicts of interest (COI) in CIRM RFAs, grant reviews, and awards have been widespread and as red as monkey’s butt, the only people who cannot see their COI are CIRM themselves, the only people who think their red butt has been well covered are CIRM themselves. So far, CIRM president Alan Trounson has totally denied there were any COI in CIRM grant reviews and awards. Recently, it seems CIRM chair Jon Thomas finally stepped ahead of Alan Trounson to address potential conflicts within this agency to appeal to the press. However, for CIRM applicants who have long been tired of hearing ICOC and CIRM press releases to screw hundreds of millions of Prop 71 together with stem cell research and scientific integrity beyond the justification of any ethics and research integrity committee, nothing has changed. If anyone predicted that human embryonic stem cell (hESC) research would possibly lose competition to MSC junk cells, tissue adult cells, disease cells, iPS cell scam, and fake science in applying for funding from a Proposition for hESC research, probably no one would believe it. But that is the today’s reality, that is what CIRM did with their unfair competition practice to CA $1.5 billion awards of Prop 71 in front of an oversight committee that comprises Dean, President, CEO of CA most prestigious universities and research institutions who represent the best of a society can offer.

CIRM RFA 13-01 LOI: Application Number: DR3-07198

Project Title: Clinical Development of Human Embryonic Stem Cell (hESC) Neuronal Therapy Derivatives for Nerve Regeneration Following Spinal Cord Injury (SCI)

Project Summary: There is a large unfulfilled healthcare need to provide treatment to improve the neurologic and motor functions following SCI. Human stem cell transplantation represents a promising therapeutic approach closest to provide a cure to restore the normal nerve tissue and function. However, to date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost CNS structure and circuitry. Despite some beneficial outcomes, the prototypical neuroepithelial-like nestin-positive neural stem cells (hNSCs) appeared to exert their therapeutic effect primarily by their non-neuronal progenies through producing trophic and/or neuro-protective molecules to rescue endogenous host neurons, but not related to regeneration from the graft or host remyelination. Pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the therapeutic potential of hESC derivatives has been hindered by conventional approaches for generating functional cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. To overcome the major obstacles in therapeutic application of hESCs, we have established human stem cell technology platforms for defined culture systems for derivation and maintenance of clinical-grade pluripotent hESCs (PluriXcel-DCS) and lineage-specific differentiation of pluripotent hESCs by small molecule induction for direct conversion of pluripotent hESCs into neuronal progenitors and neuronal cells that are highly neurogenic in vitro and in vivo (PluriXcel-SMI), which dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. This technology breakthrough enables well-controlled efficient generation of a large supply of high purity clinical-grade hESC neuronal derivatives (Xcel-hNuP & Xcel-hNu) with adequate capacity for CNS regeneration as cell therapy products to be translated to patients in clinical trials for nerve regeneration and neuronal function restoration following SCI. The objective of this stem cell therapy development project is to file IND for hESC neuronal therapy derivatives as treatments for SCI to obtain FDA approval for first-in-human studies, and to complete early phase clinical trials designed to test safety and clinical efficacy of hESC neuronal therapy derivatives in treating SCI-resulted paralysis. Clinically-suitable hESC neuronal derivatives will be cGMP manufactured and transplanted into both acute and chronic paraplegic patients with complete SCI. Clinical trials will be designed to evaluate primarily safety in humans as well as provide preliminary evidences of effectiveness for nerve regeneration and motor function improvement that could lead to more definitive clinical efficacy studies. Fulfilling the goal of this project will lead to safe and effective hESC-based regenerative therapies as optimal treatment options for tissue and function restoration following SCI.  The outcome of this project will have a transformative impact on improving the function, wellness, and overall quality of life.

Our Response to CIRM: This CIRM RFA does not require PreIND meeting, part of the goal is to have the meeting and file an IND. San Diego Regenerative Medicine Institute (SDRMI) hESC neuronal & cardiomyocyte therapy derivatives are currently the only available human cell sources with adequate capacity to regenerate neurons & contractile heart muscles, vital for CNS and heart repair in the clinical setting. CIRM are giving CIRM board member applicants preferential treatment, such as they only need to file a IND (does not even matter what kind of IND, if the IND has anything to do with Prop 71, or if they are in CA or not, so long as they connect to somebody in CIRM), we have to have pre-IND meeting with our Prop 71 IND since we do not have any member on board to speak for us, not consistent with Prop 71 equal and fair competition review criteria. CIRM have been withholding Prop 71 from CA human embryonic stem cell (hESC) research and facility, such as deny consideration against Prop 71 for our grant applications targeting for heart and neurological diseases in accordance with Prop 71 pursuant to Prop 71 and consistent with Prop 71 (e.g., TR4-06762; DR2-05339; TR3-05505; RB4-06272). We have all our scientific data ready to file an IND, wait for CIRM to give us lawful Prop 71 fund to do that. We said in the LOI, whenever CIRM is going to dole out Prop 71 in accordance with Prop 71 pursuant to Prop 71 and consistent with Prop 71 to us, whenever we are planning to file an IND immediately. That CIRM continue to deny Prop71 funding for our urgent hESC research & therapy while give COI preferential treatment is telling those patients in need of Prop 71 hESC therapy and treatment to wait because CIRM are embezzling CA stem cell research fund to waste on CIRM board members’ luxury salaries and conflicts of interest and fake science without competition. We said that 3 years ago, said it again 2 years ago, said in ICOC meeting, and said it again in this RFA. It is CIRM board COI members like you have been trying to delay Prop 71 mission.

By the way, my former mentors Dr. Evan Snyder of Sanford Burnham & Dr. Jean Loring of Scripps & others (5) have close connection with Dr. Larry Goldstein & others of UCSD and CIRM president Alan Trounson & his human cloning company ISCO in Carlsbad and majority of CIRM board members such as CIRM vice chair/UC connect CEO Duane Roth & Roth Capital & Biomed Realty (BMR), & have severe conflicts of interest with San Diego Regenerative Medicine Startup. My former mentors and Larry Goldstein are all stem cell center directors and prestigious professors, they have been giving us a hard time in terms of stem cell faculty & resource sharing of Sanford Consortium, using their basic mentor & director duty such as providing reference letter, collaboration, resource coordination, stem cell meeting organization as their bargaining chips for preferential treatment of CIRM funding and public stem cell resources to themselves & their associates. Although we are welcome resource sharing and collaboration of Sanford consortium, my mentors and their institutions had voluntarily withdrawn their supports, therefore, withdrawn their rights to my stem cell research. I am sure they are prestigious professors & directors like the majority of those on CIRM board, should have their integrity not to take the advantage of Regenerative Medicine startup and get preferential treatment for hundreds of millions of CIRM funding & resources using their stem cell center director position and connection with CIRM board members.

---

From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, March 29, 2013 4:51 PM
To: parsons@SDRMI.org
Subject: CIRM Disease Team LOI

Dear Dr. Parsons:

We have reviewed the LOI submitted in response to RFA 13-01, Disease Team Therapy Development Awards. Unfortunately, your proposal does not meet the eligibility requirements described for this RFA and therefore we cannot accept the LOI. The project was found to not yet be at an eligible and competitive stage of readiness for this RFA. For example, a PreIND meeting has not yet been conducted the outcomes of which are critically important in developing a competitive proposal. The information you provided was carefully reviewed by our clinical development and early translation teams and presented to the CIRM president to ensure a careful consideration of the LOI.

We encourage you to continue the development of this candidate and consider applying to the next Disease Team round.

If you have any questions please feel free to contact me.

Gil

-- 

Gilberto R. Sambrano, Ph.D.

Associate Director, Review

California Institute for Regenerative Medicine

210 King Street

San Francisco, CA 94107

(415) 396-9103

CIRM Embezzle $32 million CA Stem Cell Research Fund to Bank Fake Science in UC and Out of State

CIRM (California Institute for Regenerative Medicine) withhold Prop 71 from CA human embryonic stem cell (hESC) research and facility, such as our grant applications targeting for heart and neurological diseases in accordance with Prop 71 pursuant to Prop 71 and consistent with Prop 71 (e.g., TR4-06762; DR2-05339; TR3-05505; RB4-06272). San Diego Regenerative Medicine Institute (SDRMI) hESC neuronal & cardiomyocyte therapy derivatives are the only human cell sources with adequate capacity to regenerate neurons & contractile heart muscles, vital for CNS and heart repair in the clinical setting. Recent advances and breakthroughs in SDRMI hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications. SDRMI & Xcelthera have established human stem cell technology platforms for defined culture systems for derivation and maintenance of clinical-grade pluripotent hESCs (PluriXcel-DCS) and lineage-specific differentiation of pluripotent hESCs by small molecule induction for direct conversion of pluripotent hESCs into neuronal cells or heart muscle cells for developing safe and effective stem cell therapies (PluriXcel-SMI). Such milestone advances and medical innovations in SDRMI & Xcelthera hESC research enable generation of a large supply of high purity clinical-grade hESC neuronal (Xcel-hNuP & Xcel-hNu) & heart (Xcel-hCardP & Xcel-hCM) cell therapy products for treating neurological & heart diseases & injuries. Please go to our websites at http://www.sdrmi.org & http://www.xcelthera.com to see SDRMI & Xcelthera stem cell research breakthrough publications, human stem cell therapy products and technology platforms, and watch videos of hESC heart beats (hESC-derived heart muscle cells) & slideshow of evolution of CNS neuron cells from hESCs by SDRMI & Xcelthera exclusive human stem cell technique PluriXcel-SMI.

On the other hand, CIRM embezzle CA stem cell research fund to conflict of interest in UC and out of state to waste on banking stem cell frauds and scams. Abnormal iPS cells are made from adult skin cells and disease tissues have nothing to do with stem cell research of Prop 71. Anyone in his/her right state of mind would believe such ridiculous fake science that disease tissues would make any stem cells as CIRM press release claimed, which would make CIRM communication officer Kevin McCormack of no moral integrity sound very much like a stem cell con man. Why would CIRM waste ~$32 million taxpayers’ money to have those UC and out of state researchers to collect disease tissues and bank disease cells? CIRM gave $10 M CA bond to Coriell Institute for Medical Research & $16 M more CA bond to Cellular Dynamics International of Jamie Thomson, both company are outside of California. Is it obvious that the only reason they got the multi-millions of awards from California stem cell agency is their connection with somebody on CIRM board, such as CIRM chair Jon Thomas & top officials with these out state company Florida WSCS meeting & NIH director personalized medicine & iPS center director Dr. Rao for banking into CIRM Buck Institute resources. While other CIRM resources so far have been withholding California stem cell research resources & infrastructure built with > $300 millions of state fund, such as Sanford Consortium for Regenerative Medicine & UC Stem Cell Centers, from stem cell research, turning those expensive state stem cell center buildings into few UC professors’ penthouses, visibly vacant of any stem cell research, no recruiting or collaborating or sharing activities with any stem cell research expertise who have demonstrated achievement in the area of pluripotent stem cell & progenitor cell biology & medicine according to Prop 71, wasting state fund and resources enormously.