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