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

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

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

RFA 13-02, RB5-07199:

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

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

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

Dear Dr. Parsons:

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

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

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

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

Sincerely,

Gil Sambrano

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

SUMMARY OF REVIEW

Overall Scientific Score: 33.33

Comments provided by reviewers:

Comments 1:

Strengths:

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

Weaknesses:

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

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

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

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

Weaknesses:

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

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

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

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

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

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

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

novelty of this application not at all clear

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

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

CIRM Comments:

NA

Gilberto R. Sambrano, Ph.D.

Associate Director, Review

California Institute for Regenerative Medicine

210 King Street

San Francisco, CA 94107

(415) 396-9103