Nobel Assembly Got Sued for Awarding ISSCR Stem Cell Con Man

We’d like to carry the story on Voice of Regenerative Medicine about FIRST LAW SUIT FILED AGAINST NOBEL PRIZE ORGANIZATION CITING DEFAMATION AND UNFAIR COMPETITION PRACTICES. Yamanaka of International Society for Stem Cell Research (ISSCR) put 4 oncogenes into the skin cells of lab rats, then claimed that he had made the safe adult cell alternate of pluripotent human embryonic stem cells (hESCs) by calling it as the induced pluriptoent stem cells (iPS cells) without any scientific evidence for the long-term stable self-renewal of stem cells by the definition of stem cells. The iPS cell of Yamanaka is more accurately known as the induced pluripotent somatic cell or the artificially reprogrammed adult cell. Although scientific term is mandated to be as accurate as possible, Yamanaka’s iPS cell term could not be any more confusing and far away from the truth. Anyone (not short of list) who had done what Yamanaka did before all had the scientific integrity to call what they had done as cancer studies. The only difference is what Yamanaka did was published in the prestigious top scientific Journal “Cell” (How?) that had been quickly endorsed and followed by a group of prestigious scientists of ISSCR that include the “father of stem cell” Jamie Thomson and Rudy Jaenisch and George Daley of Harvard, and had a committee of big names to campaign for Nobel prize for him with sugar-coated hidden political interest or agenda. The iPS abnormal cell of Yamanaka of ISSCR is a serious stem cell scam or fraud committed by someone who has no scientific integrity, misleading the stem cell community and general public to waste the public and taxpayers’ money enormously. The iPS abnormal cells of Yamanaka of ISSCR have created unfair competition practices for normal stem cell research and have stalled human embryonic stem cell research. Please see our blogs about it, such as “CIRM Embezzle State Fund and Resources to Waste on Induced Adult Stem Cell Scam (CIRM iPS Cell Initiative) Against Prop 71 – ISSCR Stem Cell Conman’s Thick Skin”, “CIRM’s iPS Cell Initiative — The Cloning Saga of ISSCR”, “Human Embryonic Stem Cells: The Most Positive Stem Cells — The Positivity CIRM Not Get”, “Frenzy over Reprogramming — Nobel Prize Condescended to Cooked Stem Cell Fraud”, “CIRM Lucrative RFAs Make Prop71 Stem Cell Research Impossible to Get Lawful Public Funds whereas Give Unlawful Frauds the Green Light”, “iPS Cells or Man-Made Junk”.

Quote from James Watson: “You could sequence 150,000 people with cancer and it’s not going to cure anyone ---”, “most of the experiments we do are irrelevant (to find a cure) ---”.

MEBO International: We wanted to reach out about the newest developments in Chinese researcher Rongxiang Xu's lawsuit against the Nobel Assembly as well as recent statements by James Watson regarding the ineffectiveness of genetic sequencing. Please take a look to see if this is would interest your readers, as both have relevance for the future of regenerative medicine

Human’s Innate Regenerative Ability

After Nobel’s assertion that his lawsuit is frivolous, Xu is seeking clarification on misstatements made in awarding the 2012 Nobel Prize. The suit was filed against the Nobel Assembly to clarify essential scientific details that Dr. Xu believed were misstated in their October 2012 Nobel prize announcement. Errors made in the statements not only discredit Dr. Xu's science (which has illustrated innate regenerative potential), but also involve the health and safety of people worldwide.

Xu is urging the Assembly to distinguish whether or not the human regenerative potential is innate or must be artificially created.

Background

Rongxiang Xu’s work in applied regenerative restoration science has implications in many medical fields, including helping severe burn victims and potentially assisting in the fight against cancer. With James Watson’s recent comments regarding the ineffectiveness of genetic sequencing, the growing need for stem cell research and regenerative medicine has made this topic even more relevant.

For more background on James Watson’s statements and Dr. Xu’s lawsuit:

UT San Diego - “Watson dings genetics, Irish, fellow Nobelist”: http://bit.ly/Yr5WCB

The Scientist - “Snubbed for a Nobel”: http://bit.ly/X96rjG

Sacramento Bee - “Nobel Assembly Attempts to Downplay Lawsuit with Dr. Rongxiang Xu”: http://bit.ly/10eNuw7

You can also learn more at the MEBO International Website or visit the MEBO International Facebook Page.

Views of Human Embryonic Stem Cell Epigenomic Landscape Open up the Future of Stem Cells to Transparency

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ original research article supported by the National Institutes of Health, titled “Human Stem Cell Derivatives Retain More Open Epigenomic Landscape When Derived from Pluripotent Cells than from Tissues”, in Journal of Regenerative Medicine at http://dx.doi.org/10.4172/2325-9620.1000103 & http://scitechnol.com/jrgmhome.php.

The growing number of identified stem cell derivatives and escalating concerns for safety and efficacy of these cells towards clinical applications have made it increasingly crucial to be able to assess the relative risk-benefit ratio of a given stem cell from a given source for a particular disease. Genomic and proteomic profiling in isolation has not provided such a tool. Gene expression analysis has indicated that stem cell derivatives do not seem to have a common core transcription profile that dictates the undifferentiated self-renewing state, which suggests that gene expression alone is not sufficient to define either intrinsic plasticity or developmental potential of a given stem cell. A search for a common set of transcribed genes that defines the characters of all stem cell derivatives, known as stemness, has been unsuccessful; there is virtually no overlap in the gene expression profiles of various types or derivations of stem cells, in spite of their apparent phenotypic similarity. Even the expression of a lineage-defining gene within stem cells seems to require additional epigenetic cues. It is clear that epigenetic processes are providing additional regulatory dimensions to stem cell behavior.

The eukaryotic genome is packaged into a nucleoprotein complex known as chromatin, in which the DNA helix is wrapped around an octamer of core histone proteins to form a nucleosomal DNA structure. Packaging of eukaryotic genome into chromatin confers higher order structural control over the lineage programming processes. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations might reside in chromatin modifications that shape the respective epigenomes of their derivation routes. Previously, we have generated engraftable human neuronal progenitors direct from pluripotent human embryonic stem cells (hESCs) by small molecule induction (hESC-I hNuPs). Unlike the prototypical neuroepithelial-like nestin-positive human neural stem cells (hNSCs), these in vitro neuroectoderm-derived Nurr1-positive hESC-I hNuPs are a more neuronal lineage-specific and plastic hESC derivative. In this study, the global chromatin landscape changes in pluripotent hESCs and their neuronal lineage-specific derivative hESC-I hNuPs were profiled using genome-wide mapping and compared to CNS tissue-derived hNSCs. This study found that the broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds closely with those of acetylated nucleosomes genome-wide. The epigenomic transition from pluripotency to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Tissue-resident CNS-derived hNSCs have acquired a substantial number of additional histone H3K9 methylation, therefore, more silenced chromatin. These data suggest that the intrinsic plasticity and regenerative potential of human stem cell derivatives can be differentiated by their epigenomic landscape features, and that human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs in vitro than from the CNS tissue in vivo.

Human stem cell transplantation represents a promising therapeutic approach closest to provide a cure to restore the lost nerve tissue and function for a wide range of devastating and untreatable neurological disorders. However, to date, 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 therapy as a treatment option for restoring the damaged or lost CNS structure and circuitry. The traditional sources of engraftable human stem cells with neural potential for transplantation therapies have been multipotent human neural stem cells (hNSCs) isolated directly from the human fetal CNS. Under protocols presently employed in the field, the prototypical neuroepithelial-like nestin-positive hNSCs, either isolated from CNS in vivo or derived from pluripotent cells in vitro via conventional multi-lineage differentiation, appear to exert their therapeutic effects primarily by their non-neuronal progenies through producing trophic and/or neuroprotective molecules to rescue endogenous dying host neurons, but not related to regeneration from the graft or host remyelination. Under conventional multi-lineage differentiation approaches, hESC-derived cellular products consist of a heterogeneous population of mixed cell types, including fully differentiated cells, high levels of various degrees of partially differentiated or uncommitted cells, and low levels of undifferentiated hESCs, posing a constant safety concern when administered to humans. We recently reported that pluripotent hESCs maintained under a defined platform can be uniformly converted into a cardiac or neural lineage by small molecule induction. This technology breakthrough enables well-controlled generation of a large supply of neuronal lineage-specific derivatives across the spectrum of developmental stages direct from the pluripotent state of hESCs with small molecule induction. This novel lineage-specific differentiation approach by small molecule induction of pluripotent hESCs not only provides a model system for investigating human embryogenesis, but also dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. This study by high-resolution genome-wide mapping of chromatin modifications in human stem cell derivatives further supported the view that the tissue-resident CNS-derived hNSCs have acquired more silenced chromatin, therefore, they are likely resides at a more advanced stage of development with more limited developmental potential or plasticity for tissue or organ regeneration. Conversely, the hESC derivatives retain more open epigenomic landscapes, therefore, they might start at an earlier embryonic developmental stage with more plasticity for scale-up regeneration.

CIRM Embezzle State Fund and Resources to Waste on Induced Adult Stem Cell Scam (CIRM iPS Cell Initiative) Against Prop 71 – ISSCR Stem Cell Conman’s Thick Skin

Like a self-testimony to California Institute for Regenerative Medicine (CIRM) alleged favoritism in doling out grants to conflicts of interest (COI), CIRM this week & next week’s ICOC meetings will not consider funding CA Prop 71 stem cell research, but waste CA taxpayers’ money to give CIRM’s acquaintances preferential treatment for hundreds of millions of CA State bond, in simultaneous proceeds with bond sells of the State for the convenience of embezzling State fund to COI. It is called CIRM stem cell con man leadership awards, one corrupted way invented by CIRM COI so they could preferably give their own out-of-state acquaintances excess amount of easy money without having to follow Prop 71 without any competition, because those out of state stem cell con men, including Andrew Mcmahon of USC & Robert Wechsler-Reya of Sanford-Burnham, have never demonstrated any record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine in accordance with Proposition 71 & pursuant to Proposition 71, besides their known relationships with Larry Goldstein, Alan Trounson, or somebody on CIRM board. So, it is no surprise that those stem cell con men of CIRM awards favoritism, after sucking in hundreds of millions of active state fund for 6-7 years, still do not have anything of their “good sciences” to disclose to the public or show in the “best stem cell meeting of Alan Trounson”, besides their thickest faces self-stamped with stem cell con man leaders not any shy of showing in the news. Such enormous waste and embezzlement of State Fund and resources to COI would not happen if the government funding agency, such as CIRM, is held accountable, and if CIRM has high level of transparency and high standards of review in accordance with Proposition 71 & pursuant to Proposition 71 & consistence with Proposition 71.

CIRM next week’s ICOC meetings will not consider funding CA Prop 71 stem cell research, but waste hundreds of millions of CA State bond in doling out grants to induced adult stem cell scam or so-called CIRM iPS cell initiative, favoritism to Larry Goldstein & Craig Venter of UCSD, Kristin Baldwin of Scripps, and other associates of Sanford consortium & Gladstone & Cedar Sinai & ISSCR in CIRM. Larry Goldstein and his favoritism in UC & Sanford Consortium have financially benefited hundreds of millions from CIRM iPS cell initiative, which is just another corrupted way invented by CIRM COI, such as Larry Goldstein & those in Sanford Burnham, to get CIRM preferential treatment for hundreds of millions more of taxpayers’ money to waste without any competition by getting around Prop 71, in simultaneous proceeds with bond sells of the State for the convenience of embezzling State fund to COI.

CA gave CIRM $3 billions in designated fund Prop 71 to research the developmental and therapeutic potential of pluripotent human embryonic stem cells (hESCs). However, CIRM has been withholding public fund from hESC research, so CIRM could embezzle State fund to their own luxury salaries and give their COIs preferential treatment of hundreds of millions of taxpayers’ money in secrecy, such as CIRM leadership awards, faculty awards, basic biology awards, early translational awards, which have never demonstrated any record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, besides their known relationships with Larry Goldstein, Alan Trounson, Jon Tomas, Ellen Feigal, Duane Roth, or somebody on CIRM board. So, what is CIRM iPS cell initiative? It is a high profile stem cell scam of ISSCR (International Society for Stem Cell Research) to mislead the scientific community & the public to waste hundreds of millions of taxpayers’ money on making very dangerous malicious cancer cells from skin or adult cells/tissues by calling it as induced pluripotent stem cells (iPS cells) to endanger public health. There is no scientific evidence for self-renewal of iPS cells by the definition of stem cells. It is junk sciences of waste that has been turned into Larry Goldstein & stem cell con man’s empty words of “good sciences” after they received millions of financial benefit from CIRM alleged favoritism in doling out grants to COI, so they could cheat more taxpayers’ money to waste without competition by getting around Prop 71.

In today’s molecular biology, in today’s genetic engineering, it is nothing new or difficult to put a few genes into cells. Particularly, those genes are notorious oncogenes. Particularly, those cells are the thickest skin cells, which are very easy to manipulate & tolerate to all kinds of abuse or mistreatment by genetic engineering, unlike the very delicate stem cells. However, cell fate is determined by complex molecular and cellular processes, not just a few genes. The real technique challenge or difficult thing to do is to prove that these cells can self-renew for a long-term, to prove those cells can maintain genetic stability and integrity for a long period of time. The real technique challenge or difficult thing to do is to show those cells can generate functional cells, generate a lot of functional cells, and generate a homogeneous population of functional cells useful for therapy. When Jamie Thomson group made their human embryonic stem cells (hESCs), they had done at least eleven months of observation to make sure their hESCs remained genetically stable after eleven months of proliferation before published in Sciences. Yamanaka of ISSCR has not done even 1 day of observation after he made his iPS cells before published in Cell. Without solid proof for self-renewal and long-term genomic stability, any tumor or cancer cells can also be easily mis-identified as stem cells. Without solid proof for self-renewal and long-term genomic stability, Yamanaka and those stem cell con men of ISSCR’s thick skin became invincible, could become whatever scams they want and could be called by whatever scams they named. Without solid proof for self-renewal and long-term genomic stability, those induced adult stem cell scams & frauds, such as iPS cells, direct differentiation/transdifferentiation/reprogram/deprogram of somatic cells, proliferate like weeds in high profile scientific journals in the last few years, such as Rudy Jaenisch’s Cell and Inder Verma’s PNAS. Therefore, it is not too unfair to say Yamanaka of ISSCR has no scientific integrity at all, cheated Nobel prize with his junk sciences, because he did what a cheater usually does to take the easiest way up by simply changing the name of his dangerous malicious cancer cells to iPS cells to confuse the public & the scientific community, even to endanger public health for his own personal and financial gain. Yamanaka of ISSCR made iPS cells from the skin, now he claims he is going to turn iPS cell back into skin cells to treat eye diseases, so he can con the public for more attention and scam for more money. Well, probably even high school kids would know that the pigment epithelial cells in the eyes are not skin cells, and if Yamanaka of ISSCR put his very dazzling skin-to-iPS-back-to-skin cells into the eye, the only outcome probably would make any diseases even worse, besides hundreds of millions of taxpayers’ money (e.g., NIH & CIRM) have been sucked into these greedy high profile stem cell conman’s own pockets & disappeared. CIRM iPS cell initiative is ISSCR super stem cell con man’s joke, and it is just those high profile stem cell con man’s another excuse to embezzle hundreds of millions of taxpayers’ money to their COI and waste, such as Sanford consortium‘s Larry Goldstein, Craig Venter, Evan Snyder, Kristin Baldwin, Jean Loring, UCLA/CedarSinai Clive Svendensen, Gladstone &Yamanaka, Rudy Jaenisch, George Daley, and other ISSCR associates in connection with CIRM top officials, such as Jon Thomas, Alan Trounson, Ellen Feigal, Duane Roth, or somebody on CIRM board. 

San Diego Regenerative Medicine Institute (SDRMI) Open Appeal Letter to ICOC for CIRM Flawed Grant Review Showing That a Demonstrable Financial and Scientific Conflicts of Interest Had a Negative Impact on the Review Process

Dear ICOC,

We would like to appeal CIRM’s review & score for Application number TR4-06762, titled “Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models” according to California Institute for Regenerative Medicine (CIRM) official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, which specifies appeals of scientific review showing that a demonstrable financial or scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review, indifference of the type of applications.

According to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, CIRM Application Review should be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. In accordance with Proposition 71 & pursuant to Proposition 71 (Health and Safety Code section 125290.60), the ICOC has established criteria for the evaluation of Applications by the GWG, including: A demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine. CIRM review comments, including “hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells” (please see more such comments below provided by CIRM review summary), are against Prop 71 and scientific evidences, which have provided evidences for a demonstrable financial and scientific conflicts of interest that had a negative impact on the review process and resulted in a flawed review.

A demonstrable financial conflicts of interest that had a negative impact on the review process and resulted in a flawed review: Only UC & Sanford consortium groups with multiple ICOC members on CIRM board have financial interests in direct differentiation & reprogramming & deprogrammed somatic cells that have no stem cell or stem cell research involved as provided by CIRM review summary, which has financial conflict of interest with California stem cell research & cure bond initiative Prop 71 & hESC research of regenerative medicine startup with no member on CIRM board.

A demonstrable scientific conflicts of interest that had a negative impact on the review process and resulted in a flawed review: Only UC & Sanford consortium groups with multiple ICOC members on CIRM board have scientific interests in direct differentiation & reprogramming & deprogrammed somatic cells that have no stem cell or stem cell research involved, which has scientific conflict of interest with California stem cell research & cure bond initiative Prop 71 & hESC research of regenerative medicine startup with no member on CIRM board.

According to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, CIRM Application Review should be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. Consistent with Proposition 71, only the 15 scientist members of the GWG shall score Applications for scientific merit. However, not consistent with Proposition 71, CIRM officials not in the GWG with 3 biased unidentifiable reviewers selected by themselves scored the application according to their own opinions that show that a demonstrable financial and scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review, as evidenced by CIRM review summary.

We will appreciate your consideration for our appeal for CIRM flawed grant review showing that a demonstrable financial and scientific conflicts of interest had a negative impact on the review process in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71 according to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf. Please see below SDRMI application in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, CIRM score & review NOT in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, & our responses.

SDRMI presents its application in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71.

Preliminary Application for RFA 12-07

Application number TR4-06762

Project Title (300): Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models

Objective (1000): Due to the prevalence of heart disease worldwide and acute shortage of human myocardial grafts, there is intense interest in developing hESC-based therapy. However, realizing the potential of hESCs has been hindered by uncontrollable and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under defined culture can be uniformly converted into a cardiac specific lineage by small molecule induction. To address unmet medical need in regenerating the damaged myocardium, this proposal uses small molecule directing hESC cardiac lineage-specific differentiation into human CM-specific derivatives at scale, purity, and myocardium regenerative potential adequate for clinical translation. The hESC CM cell therapy products will be characterized and their potential in myocardium regeneration and contractile function restoration will be assessed by transparentation into infracted models. Fulfilling the goal will lead to hESC-based therapy to restore heart function.

Rationale, Significance and Responsiveness (2000): To date, lack of a suitable human cardiomyocyte (CM) source with adequate myocardium regenerative potential has been the major setback in regenerating damaged human heart. 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 hESC derivatives has been hindered by generating CMs from pluripotent cells through uncontrollable and inefficient multi-lineage differentiation. Grafts generated by such hESC-derived CMs have been small, insufficient to restore heart function and functional enhancement not related to regeneration from the grafts. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a cardiac specific lineage by small molecule induction. This technology breakthrough enables well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human CM derivatives at scale, purity, and myocardium regenerative potential adequate for restoring heart function. With reproducible and scalable production of clinically-suitable hESC CM precursors and CMs, the goal of this project is to provide all necessary evidences of safety and efficacy in preclinical infracted models for moving into IND-enabling preclinical development for tissue and function restoration in myocardium infraction. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Fulfilling the goal of this project will lead to extending healthy life span for millions of patients suffering from end-stage heart failure and reducing the burden of illness and disability of major health problems.

CIRM presents its score & review NOT in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, demonstrating that CIRM officials & reviewers financial and scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review.

SUMMARY OF REVIEW

Overall Scientific Score: 44.00

Comments provided by reviewers:

The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation

Unmet need: Heart Failure

Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available

SDRMI presents its response to CIRM flawed review & score in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71.

Comments provided by CIRM: The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

Our response: This reviewer’s comment is a factual error. Our approach to MI in this application has not been represented in CIRM portfolio. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. CIRM current portfolio does not have any approach that can efficiently regenerate heart muscle (myocardium). CIRM portfolio Cedars-Sinai’s Eduardo Marban & Capricor have no scientific evidences that their adult heart cells can regenerate heart muscle, may produce some smooth muscle or other supporting cells to slow down the dying patient heart muscle cells. CIRM portfolio Joe Wu/Robbin of Stanford U use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function. Gladstone/UCSF reprogrammed adult cells or trans-differentiated cells are abnormal, have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics. We have addressed previous reviewers’ biased comments and our effective directed CM differentiation approach by small molecule induction has been fully developed for preclinical studies in this application (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications).  

Comments provided by CIRM: hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

Our response: This reviewer’s comment is biased, anti-Prop 71, anti-hESC research, and a factual error. This project translates advances and medical innovations in hESC research, not pluripotent hESC cell type, which itself cannot be used for therapeutic application. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. This project translates hESC cardiomyocyte (CM) derivatives, including CM precursors & CMs, by direct differentiation of hESCs using small molecule induction, which is more likely to be approach of the future. Human embryonic stem cell (hESC) research holds tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. In particular, hESC cardiac derivatives are the only cell source so far that can regenerate the contractile heart muscle (known as cardiomyocytes), vital for cardiovascular repair. In fact, partially or fully deprogrammed or reprogrammed somatic cells are abnormal, & have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics, or partially or fully deprogrammed or reprogrammed somatic cells are clearly not translatable cell type. By the way, Prop 71 is passed by CA voters to fund hESC research, majority of CA voters have said that hESCs are clearly translatable cell type. Did this CIRM reviewer intentionally make comments in CIRM grant review against CA Prop 71 or hESC research, or have any COI with translating hESC research of this CIRM RFA, or telling the public that Prop 71 is not translatable? Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. We all know we are translated from embryos, not any somatic cells or skin cells. Is this review telling the public that he was translated from some somatic cells, against billions of living evidences? It is shocking to hear such anti-hESC research anti-Prop 71 false or biased comments from CIRM grant reviewers so often.

Comments provided by CIRM: DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation, Unmet need: Heart Failure. Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available.

Our response: This reviewer’s comment is biased. Our novel hESC direct differentiation protocols have been published, are now widely available in public domains, which should be strengthen of this project to CIRM. Only those without scientific integrity like this reviewer, who like to take others’ research for their own private use, would think widely available protocols as weakness to them. Our protocol of hESC CM lineage-specific differentiation by small molecule is novel and ground-breaking, has not been represented in CIRM portfolio (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications). This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Conventional protocols to generate CMs from ESC through traditional multi-lineage differentiation are widely available, but have extremely low efficiency (<4%). CIRM current portfolio does not have an approach that can efficiently regenerate heart muscle (myocardium). CIRM Joe Wu/Robbin of Stanford & Geron use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function. 

CIRM Grant Review Not In Accordance with Proposition 71 --- CIRM Made Up Scores & Reviews with Biased Reviewers to Embezzle State Fund & Resources to Stem Cell Con Men Tied to CIRM Officials

According to California Institute for Regenerative Medicine (CIRM) official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, CIRM Application Review should be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. In accordance with Proposition 71, the Scientific and Medical Research Funding Working Group (Grants Working Group or GWG) makes funding recommendations to the ICOC. Pursuant to Proposition 71 (Health and Safety Code section 125290.60), the ICOC has established criteria for the evaluation of Applications by the GWG, including: A demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine ---. Consistent with Proposition 71, only the 15 scientist members of the GWG shall score Applications for scientific merit ---. However, CIRM grants reviews and awards have not been in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71.

Not in accordance with Proposition 71 & pursuant to Proposition 71, > $ 1 billion of CIRM awards have gone to those stem cell con men who have no “demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine” but have financial ties to CIRM president, vice president, chair, directors, reviewers, and ICOC. Not in accordance with Proposition 71 & pursuant to Proposition 71, none of the university physicians in CIRM last round of faculty awards have demonstrated any record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine. Not consistent with Proposition 71, CIRM officials not in the GWG, including CIRM president Alan Trounson & vice president Ellen Feigal & directors with 3 biased & conflict of interest (COI) unidentifiable reviewers selected by themselves, have been setting up grants selection criteria and making up CIRM policy according to their own opinions to score applications & select their own financial interests. Not consistent with Proposition 71, CIRM officials sell snake oil purveyors & make anti-Prop 71 comments in CIRM RFAs (e.g., CIRM RFA 12-02 to 12-06) and grant review statements, such as claiming “direct differentiation is the future approach” against scientific evidences. So CIRM officials can cover up Prop 71 stem cell research & make up scores & reviews themselves to ask the ICOC board in public meetings to give their companies/associates/institutions hundreds of millions, such as direct differentiation/reprogramming/iPS cells & MSC & tissue cells of UCs (no any stem cells involved, not even stem cell research) against CIRM grants policy & Prop 71. Whether their cells and hundreds of million dollar snake oil purveyor projects would work after they get the money would end up be the taxpayers & CA problems.

CIRM official grants policy & Prop 71 do not have anything about pre-application, nor anything about no appeal for pre-application as made up by Allan Trounson, Ellen Feigal & CIRM directors. Even if ICOC changed the law without any official amendment or notifying the State government, should CIRM pre-application also be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71? Human embryonic stem cells (hESCs) are the most potential stem cells for regenerative medicine & the priority of Prop 71. Any hESC research proposals of CIRM applicants should go directly to full application if CIRM grant review, indifference of pre- or full applications, is in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. Anything less only demonstrated CIRM officials & reviewers financial or scientific conflicts of interest that had a negative impact on the review process and resulted in a flawed review according to CIRM official grants policy.

Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. CIRM chair, president, vice president, directors, & ICOC are bound by the law to ensure Prop 71 go to stem cell research with high economic impact, not their own companies & institutions with financial ties. CIRM patient advocates are supposed to advocate stem cell research as the cure for patients, not the diseases. However, CIRM > $1.5 billion awards tell a different story of improper use of state fund & resources. CIRM president, vice president, & directors openly claim that they do not select Prop 71 stem cell research that has economic impact of >$10 billion annually for consideration & funding, but those snake oil purveyors of their own opinions & financial ties, such as direct differentiation & MSC. CIRM even gave a huge amount of Prop 71 to make the diseases to endanger public health, such as 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). > $1.5 billion awards later, CIRM portfolio still lacks any representation to provide solution, treatment, or cure for heart disease or any other major health problems that clinical application of hESC therapy derivatives would. If has, CIRM officials do not have to waste another $300,000 state fund to degrade its economic impact to some job numbers and taxes with trivial impact to state’s economy.  

Why would CIRM president Allan Trounson, vice president Ellen Feigal & Directors, chair & ICOC be so resistant to transparency and accountability in government grant review process, not even up to the standard of transparency in Prop 71, if they have nothing to hide? Any responsible person would think it is CIRM officials’ responsibility to identify problems and loopholes in grant review process that jeopardy Prop 71 & the mission of CIRM, and make the recommendation to ICOC, to do things in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71 according to CIRM official grants policy, rather than make up the rules and policy themselves to cover up their improper use of state fund & resources. However, CIRM top officials such as Ellen Feigal & directors claimed that they do not do their job according to CIRM official grants policy, even though they are paid top dollars from public fund. Instead of showing any support to Prop 71 & ensuring Prop 71 go to stem cell research, CIRM top officials & directors have been intentionally giving Prop 71 stem cell research in CA a difficult time to apply for Prop 71 funding, issuing RFAs and setting eligibility & grant review criteria against Prop 71, withholding state fund and resources from Prop 71 stem cell research against the law, sending applicants back some shocking anti-stem-cell-research & ant-Prop 71 comments & scores only those stem cell con men would say again and again, making Prop 71 stem cell research applicants have to go appeal, even changing the law themselves to use pre-application to counteract transparency & accountability & denying appeal in public; so those associates in UCs/Company tied to Ellen Feigal & CIRM board can easily get hundreds of millions from Prop 71. What would we call something like that in public? Government corruption & improper use of state fund and resources!!! If CIRM top officials & directors can make and have already made the changes of the law whenever they like and whatever they like to fit their own financial interest, why would they need to waste another $700,000 state fund to pay IOM to make the recommendation?

CIRM is publically well known for falsifying grant review statements for snake oil purveyors, such as CIRM review statements for Stem Cell Inc & disease teams tied to Ellen Feigal & CIRM board. CIRM pre-application scores & comments, which are not even close to equitable & informed review comments made by someone who have relevant scientific expertise, could be easily falsified by Ellen Feigal & CIRM directors with reviewers tied to themselves, considering > 1 billion of Prop 71 fund has gone to someone with financial conflicts of interest. It is hard to think 3 different highly-educated persons with different expertise and background would give exactly the same comments & scores, make the same errors & anti-Prop 71 opinions that are completely in common with Ellen Feigal & CIRM directors’ comments & opinions. Prop 71 requires 15 members on working group board to score grants and make recommendation to ICOC, and the 15 reviewers in GWG are publically identifiable according to Prop 71. Why would CIRM president, vice president, & directors change the law to use 3 outside unidentifiable reviewers not even in the GWG to score applications & cover up their outside pre-application reviewers tied to themselves against the law? If they are really expertise, they should have no shame of identifying themselves, so the public can know who are those so-called experts or stem cell con men hidden behind CIRM directors, Ellen Feigal, & Alan Trounson.

I want to ask CIRM top officials what they are going to do to fix flawed grant review against scientific evidences & having COI. Only UC & Sanford consortium groups with members on CIRM board have financial interests in direct differentiation & reprogramming, which has conflict of interest with Prop 71 & hESC research of regenerative medicine startup with no member on CIRM board. If Ellen Feigal is working for CA state stem cell agency not just her few industry & UC ties, her productive response for anyone like a state official should be like “I cannot believe this, what can we do to prevent flawed grant review from happening again.” Instead, she would never call me back, even hanged up on me. Do CIRM officials only serve the financial interests of CIRM board members and their few close connections such as Larry Goldstein/Jean Loring/Deepak Srivastava, not Prop 71?

Last year, CIRM top officials & directors refused my multiple requests to appeal CIRM biased & COI grant reviews for clinical application of hESC therapy derivatives urgent to patients & Prop 71. In urgent need of funding to keep running crucial hESC resources & infrastructure of regenerative medicine start up built with millions of taxpayers’ money, I had to go to ICOC public meeting to bring their attention and plead for CIRM to give Prop 71 funding to keep critical hESC research & medical innovation going vital to Prop 71 & extending healthy life and reducing the burden of illness & disability. I asked CIRM directors for some time and assistance to show some slides of those amazing hESC neuronal & heart cells that may bring hope to patients, CIRM directors said no and would only gave me 5 min. to speak. And I had to sit through a whole day ICOC meeting, probably the most bureaucratic meeting, for ICOC members, Alan Trounson & Ellen Feigal & Craig Venter to talk about giving $6 millions of CA stem cell research & cure fund to an out-of-state fruit fly person in Buck Institute tied to NIH CRM director Mahendra Rao & ISSCR (International Society for Stem Cell Research), another $40 millions to Larry Goldstein/Craig Venter/Jean Loring, and another $100 millions to UCs & their companies, as if it is their money, not even any slightest concern for improper use of state fund & resources, not even any slightest interest in Prop 71 & stem cell research & cures for patients. If we know that Ellen Feigal has close tie to NIH CRM director Mahendra Rao and ISSCR that overly favor their opinions to iPS cells & direct reprogramming & against Prop 71, perhaps we would not be too shocked to see Ellen Feigal have helped CIRM to make up scores & reviews with biased reviewers tied to ISSCR & NIH director Rao to embezzle hundreds of millions of state fund & resources to stem cell con men tied to CIRM officials against Proposition 71 against CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf. Now they have got their money for their own company/institute and connect, got a lot, and want more. I wonder Stem Cell Inc & UC Davis & CIRM directors’ institutions/companies have not made their adult cells & projects work for any patients any diseases for >20 years, how are those CIRM top officials & directors going to make their cells & hundreds of million dollar snake oil purveyor projects to work for patients, or they are just some super con men in government funding agencies?  

Both Self-Renewal and Differentiation – The Simple Way to Tell Stem Cells from Deceptive Terms of CIRM & Reviewer/Professor’s Snake-Oil Purveyors

The scientific definition and proof for stem cells are that they have the ability of both self-renewal and differentiation. Self-renewal means that one cell can become 2 identical cells that can become hundreds of identical cells that can become millions of identical cells. Differentiation means that placenta cells can become cells not found in the placenta, such as cells found in the heart. Although the ~ $50 M investment from California Institute for Regenerative Medicine (CIRM) vice chair Duane Roth’s Roth Capital to Pluristem has boosted Pluristem’s stem cell fraud/scam PLX to investors and made their executives a lot of richer, so far no one has any scientific evidences that any cells from placenta can do what the stem cell do by definition, or no one has any proof that there is any stem cells in placenta.

Pluristem is not alone at this. Since CA passed Prop 71, those against human embryonic stem cell (hESC) research of Prop 71 or stem cell conmen have claimed that they made or discovered a lot of stem cells by lowering the standards for stem cells, such as they call any cells as stem cells by expressing few markers. A lot of cells express similar markers, even they are completely different. The most popular stem cell fraud/scam is the induced pluripotent stem cells (iPS cells) made from skin or adult cells, published in most prestigious scientific journal like Cell and even won the Nobel prize last year. The iPS cells express similar markers as hESCs, however, cancer cells express those markers too. The iPS cells fit the political need of some people, however, no one has come up with any scientific evidences that iPS cell can self-renew, nor there is any proof that iPS cells are stem cells. In fact, iPS cells cannot self renew, mutating and aging quickly by many scientific publications and evidences, like cancer cells do. The iPS cells have been proven neither safe nor the future of stem cells. Now the same group of greedy professors who easily made iPS cells wants to cheat Prop 71 & stem cell research with some of their deceptive terms such as “direct differentiation”, claiming they made heart from skin, REALLY?!!! Perhaps, they should tell the public the truth about their snake oil purveyor that they have been trying to hide in their deceptive terms in top scientific journals, about their extremely low non-viable efficiency & accelerated aging of “direct differentiation” that would make their approach anything but the approach of the future.

The public and investors are easily to be confused or fooled by the word-game of those greedy professors who have no scientific integrity since most people have little scientific knowledge. If we simply ask: “Is anybody born from placenta? Is anybody born from skin? Are you your own grandpa?” I am sure anyone would know the answers. Saying stem cell in placenta is just as absurd as saying anyone is born from placenta. Calling the iPS cell or “direct differentiation” a breakthrough is just as absurd as saying you are your own grandpa or made from someone else.  

Directors’ Conflict of Interest Alliance: CIRM Grant Reviews Reveal Some Shocking Anti-Prop 71 Anti-hESC Research Biased Comments Full of Factual Errors against Scientific Evidences

California Institute for Regenerative Medicine (CIRM) grant reviews reveal some shocking anti-Prop71, anti-hESC research, biased comments full of factual errors against scientific evidences, please see most recent example below. We understand there are some directors’ conflict of interest (COI) alliance who are not only not doing any Prop71 stem cell research, but block those who are doing stem cell research to get funding from government funding agencies (e.g., NIH, CIRM), such as Gladstone’s Deepak Srivastava who talks pediatric heart disease in public, then blocks hESC research for pediatric heart disease using his well-connected alliance. It is serious scientific misconducts for those reviewers without scientific integrity use false statements & biases to predispose grants & papers of their COI. We’d like to bring your attention to such procedural flaw in CIRM grant review. Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. Scientific grant review process is supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. CIRM reviewers’ comments are full of biased or false statements, not even near to any standards of scientific grant review involving the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications. Even we are just scientists or applicants, we strive to voice transparency & fair competition & accountability, not COI & corruption.

Preliminary Application for RFA 12-07

Application number TR4-06762

Project Title (300): Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models

Objective (1000): Due to the prevalence of heart disease worldwide and acute shortage of human myocardial grafts, there is intense interest in developing hESC-based therapy. However, realizing the potential of hESCs has been hindered by uncontrollable and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under defined culture can be uniformly converted into a cardiac specific lineage by small molecule induction. To address unmet medical need in regenerating the damaged myocardium, this proposal uses small molecule directing hESC cardiac lineage-specific differentiation into human CM-specific derivatives at scale, purity, and myocardium regenerative potential adequate for clinical translation. The hESC CM cell therapy products will be characterized and their potential in myocardium regeneration and contractile function restoration will be assessed by transplantation into infracted models. Fulfilling the goal will lead to hESC-based therapy to restore heart function.

Rationale, Significance and Responsiveness (2000): To date, lack of a suitable human cardiomyocyte (CM) source with adequate myocardium regenerative potential has been the major setback in regenerating damaged human heart. 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 hESC derivatives has been hindered by generating CMs from pluripotent cells through uncontrollable and inefficient multi-lineage differentiation. Grafts generated by such hESC-derived CMs have been small, insufficient to restore heart function and functional enhancement not related to regeneration from the grafts. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a cardiac specific lineage by small molecule induction. This technology breakthrough enables well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human CM derivatives at scale, purity, and myocardium regenerative potential adequate for restoring heart function. With reproducible and scalable production of clinically-suitable hESC CM precursors and CMs, the goal of this project is to provide all necessary evidences of safety and efficacy in preclinical infracted models for moving into IND-enabling preclinical development for tissue and function restoration in myocardium infraction. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Fulfilling the goal of this project will lead to extending healthy life span for millions of patients suffering from end-stage heart failure and reducing the burden of illness and disability of major health problems.

Dear CIRM President and Chair,

We would like to appeal CIRM’s pre-application review for above application for evidences that have indicated a flawed review for lack of appropriate expertise, factual errors, bias or predisposition, and conflict of interest (COI) that have compromised the integrity of scientific review for CIRM. Could you please let me know who to contact and how to appeal a flawed grant review of CIRM, and information about CIRM procedure for appealing a flawed grant review or procedural flaw in CIRM grant review. I just received CIRM announcement yesterday that it seems CIRM proposed dramatic changes in response to IOM report. CIRM must have implemented or will implement their recommendations to ensure CIRM grant review process involve the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications to CIRM. Is CIRM grant review process supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. The reviewers’ comments below are not even near to any standards of scientific grant review. We will appreciate your consideration for our appeal. Please see the procedural flaw in CIRM grant review indicated by the reviewers’ comments below and do not hesitate to contact us should you have any questions.

Comments provided by reviewers: The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed.

Our response: This reviewer’s comment is a factual error. Our approach to MI in this application has not been represented in CIRM portfolio. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. CIRM current portfolio does not have any approach that can efficiently regenerate heart muscle (myocardium). CIRM portfolio Cedars-Sinai’s Eduardo Marban & Capricor have no scientific evidences that their adult heart cells can regenerate heart muscle, may produce some smooth muscle or other supporting cells to slow down the dying patient heart muscle cells. CIRM portfolio Joe Wu/Robbin of Stanford U use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function. Gladstone/UCSF reprogrammed adult cells or trans-differentiated cells are abnormal, have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics. We have addressed previous reviewers’ biased comments and our effective directed CM differentiation approach by small molecule induction has been fully developed for preclinical studies in this application (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications).  

Comments provided by reviewers: hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

Our response: This reviewer’s comment is biased, anti-Prop 71, anti-hESC research, and a factual error. This project translates advances and medical innovations in hESC research, not pluripotent hESC cell type, which itself cannot be used for therapeutic application. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. This project translates hESC cardiomyocyte (CM) derivatives, including CM precursors & CMs, by direct differentiation of hESCs using small molecule induction, which is more likely to be approach of the future. Human embryonic stem cell (hESC) research holds tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. In particular, hESC cardiac derivatives are the only cell source so far that can regenerate the contractile heart muscle (known as cardiomyocytes), vital for cardiovascular repair. In fact, partially or fully deprogrammed or reprogrammed somatic cells are abnormal, & have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics, or partially or fully deprogrammed or reprogrammed somatic cells are clearly not translatable cell type. By the way, Prop 71 is passed by CA voters to fund hESC research, majority of CA voters have said that hESCs are clearly translatable cell type. Did this CIRM reviewer intentionally make comments in CIRM grant review against CA Prop 71 or hESC research, or have any COI with translating hESC research of this CIRM RFA, or telling the public that Prop 71 is not translatable? Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. We all know we are translated from embryos, not any somatic cells or skin cells. Is this review telling the public that he was translated from some somatic cells, against billions of living evidences? It is shocking to hear such anti-hESC research anti-Prop 71 false or biased comments from CIRM grant reviewers so often.

Comments provided by reviewers: DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation, Unmet need: Heart Failure. Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available.

Our response: This reviewer’s comment is biased. Our novel hESC direct differentiation protocols have been published, are now widely available in public domains, which should be strengthen of this project to CIRM. Only those without scientific integrity like this reviewer, who like to take others’ research for their own private use, would think widely available protocols as weakness to them. Our protocol of hESC CM lineage-specific differentiation by small molecule is novel and ground-breaking, has not been represented in CIRM portfolio (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications). This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Conventional protocols to generate CMs from ESC through traditional multi-lineage differentiation are widely available, but have extremely low efficiency (<4%). CIRM current portfolio does not have a approach that can efficiently regenerate heart muscle (myocardium). CIRM Joe Wu/Robbin of Stanford & Geron use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function.

From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, January 25, 2013 5:07 PM
To: parsons@sdrmi.org
Subject: CIRM ET4 PreApp Review

Dear Dr. Parsons:

Thank you for submitting your proposal under the CIRM RFA 12-07: Early Translational IV 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 151 PreApps and selected about 40 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. Each application is assigned to 3 independent reviewers and each reviewer assesses approximately 20 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: 415-396-9103gsambrano@cirm.ca.gov

SUMMARY OF REVIEW

Overall Scientific Score: 44.00

Comments provided by reviewers:

The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation

Unmet need: Heart Failure

Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available