The Word Game --- Should Human Embryonic Stem Cell Research Be Considered As Human Subject Research?

Human embryonic stem cell (hESC) research has been categorized as human subject research under exemption category 4 where the proposed research involves the study of existing data, documents, records, human tissue or specimens. Those sources are publicly available and the information is recorded in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects. The author recently noted that NIH has begun to list it as NO human subject research, therefore, sent her inquiry, below is the answer from NIH:

“In terms of human subjects, none of the NIH-approved hESC lines has any identifiers attached, and so research using these lines is not considered human subject research under NIH definitions.”

Which definitions seem fall into the human subject research exemption category 4 too, so the author asked again, below is the answer from NIH:

“Here is the guidance from OER:

·  When does research with human specimens, cells, cell lines, or data involve human subjects?
In order for research with human specimens, cells, cell lines, or data to involve human subjects,

1. The specimens, cells, or data:

• Must be or must have been obtained from individuals who are alive; AND
• Must be or must have been obtained by an investigator conducting research

AND

2. The investigator EITHER:

• Must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals; OR
• Must be obtaining or have obtained individually identifiable private information.

IF providers of coded human specimen, cells, cell lines or data:

• Obtained or will obtain the specimens or data, AND
• Can link the specimens or data to living individuals, AND
• Will also collaborate on other activities related to the conduct of a proposed research project with the investigators who obtain the specimens or data;

THEN both the providers and recipients will be considered to be involved in the conduct of the research and are conducting human subjects research.”

Now it goes back to the controversy surrounding human embryonic stem cell research again --- when does life begin? should an embryo be considered as a living human being? Since those questions remain controversial, it gives NIH the legal definitions to take completely different stand points.

NIH hESC Grant Review Samples

San Diego Regenerative Medicine Institute Releases Samples of NIH Grants Review on Human Embryonic Stem Cell Research Proposals

Scientific grants review score is very arbitrary, nothing scientific about it. In a scale of 1 to 10, the errors are in the range of 1 to 10. In order to be fair to CIRM, we decide to also release some samples of NIH grants review summary statement on human embryonic stem cell research proposals. To think about it, even funding like California stem cell research & cure bond act that is designated for human embryonic stem cell research, protected by a law Prop71, and closely watched under the public eyes, media, oversight committee, and government officials, was still taken mostly by those fruitfly dissecting, abnormal iPS cell, cancer cell, no stem cell, endogenous cell, mesenschymal junk cell individuals. And conflict of interest and non-transparent incidents happen all the time, such as a cluster of 5/6 out of 20, none had the scientific merits of the law, openly and carelessly went to the same institute in the same round. The NIH grant review on human embryonic stem cell research is not protected by any law, therefore, must be very shaky, the program officials often suddenly disappear, nowhere to find. Please note, since we did not write a full response, in the sample#1, human embryonic stem cell research was considered as human subject research by NIH, and in the sample#2, it was not. The score of sample#1 was overridden by the study section to outside of the funding range. For sample#2, the potential of stem/progenitor cells is to use their ability to be molded in vivo, not the conventional approach of using already molded adult cells. The reviewers obviously were not for human embryonic stem cell research, it is very common for reviewers to ignore the scientific data and stick to their own ideology, and human embryonic stem cell research critical to the National Institutes of Health’s mission and improvement of human health is only at the mercy of those reviewers.

See SDRMI wordpress for NIH grant review samples.

Letter to CIRM Grant Pre-Application Review

San Diego Regenerative Medicine Institute Releases Dr. Parsons’ Letter to CIRM Grant Pre-Application Review.

Dear CIRM,

First, we’d like to let CIRM know that SDRMI announced the publication of ground-breaking technique on direct conversion of human embryonic stem cells into neuronal cells. Realizing the developmental and therapeutic potential of human embryonic stem cells has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. The original research, titled “Efficient Derivation of Human Neuronal Progenitors and Neurons from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction” is the first to show that pluripotent human embryonic stem cells can be uniformly converted into a neuronal lineage by simple provision of small molecules. This technology breakthrough not only provides a large supply of clinical-grade human neuronal therapeutic products for neuron regeneration and replacement therapy against a wide range of neurological disorders, but also offers means for small-molecule-mediated direct control and modulation of the pluripotent fate of human embryonic stem cells when deriving an unlimited supply of clinically-relevant lineages for regenerative medicine. The protocol of this novel technology was published in JoVE (http://www.jove.com ), and more information can be found on SDRMI & Xcelthera website.

Second, we are surprised how irresponsible, biased, and non-transparent (sorry have to say so) CIRM’s pre-grant selection process still is that left CA’s promising and critical human embryonic stem cell research unfunded by Prop71. CIRM is supposed to dole out CA stem cell research & cure bond act for using human stem/progenitor cells, prioritizing human pluripotent stem cells, for developing cell therapy and cure. So far, human embryonic stem cells remain the only pluripotent normal stem cells. Whether the proposal is eligible for CA stem cell bond act should be the first and only consideration for pre-selection of grants, considering the abstract style of pre-application, which limits words and space, not allow data, description, and anything more than general statement. In answering of your reviewer to our Pre-App CIRM RFA-11-02 TR3-05505, titled “Heart precursors directed from human embryonic stem cells for myocardium regeneration.”

“CIRM Reviewer: Target product indication is very vague; this especially needs clarification given that proposed mechanism of delivery is injection during open heart surgery.”

Answer: Our target product described in the App: Cardiac precursors induced direct from pluripotent hESCs with small molecule treatment will contain a homogeneous population of cells that express heart precursor markers and generate beating cardiomyocytes with a drastic increase in efficiency in vitro, compared to untreated control. Following transplantation, hESC-derived cardiac precursors will survive, integrate and differentiate into contracting myocardium to remuscularize the injured heart and rescue the contractile function, and the function improvement will depend on the contractile properties of human myocardial grafts. We are the first to develop the novel technology to convert human embryonic stem cells directly and exclusively into cardiac precursors that yield beating heart muscle cells efficiently, potentially useful for developing effective cell therapy for heart muscle repair, so far has no cure. However, there is 600 character limitation/space in the pre-app to allow us to be more clear and specific. By contrast, CIRM awarded endogenous heart cells of cedars-sinai did not have to show any stem/progenitor activity, only improving the pump factor from ~ 30 to ~ 40.

“CIRM Reviewer: Other approaches to accomplishing cardiac repair with hESC are available and well ahead of this one. The real issue is whether the culture system the applicant has developed with nicotinamide induction offers any benefits in efficiency, stability, safety or manufacturing to the other systems. This is not clear from the general statements made in the application.”

Answer: So far, other approaches have been using multi-lineage differentiation of hESCs, efficiencies are low, especially in generating the contracting heart muscle or myocardium. Reprograming/trans-differentiation of adult cells not only efficiency is low, and abnormal, and immnuo-rejection has been a big issue even for transplanting normal adult cells. Our small molecule NAM induction approach offers the benefits in efficiency, stability, safety, and scale-up production over existing conventional approaches. However, the character limitation in the pre-app made us unable to be clear besides general statements.

“CIRM Reviewer: The applicant does not address the issue of immunogenicity.”

Answer: hESCs and their derivatives are less immunogenic than any other cells and tissues, and also can find isotype matches through hES cell lines. It is adult cells, like mesenchymal stem cells, and adult cell derived or trans-differentiated cells that have a big issue of immune-rejection, aging, not graftable. The word and space limited pre-app did not specify us to address the issue of immunogenicity, which has not been one of the major obstacles of hESC therapy. None of CIRM awarded grants, like last round of 5 or 6 mesenchymal stem cell awards, addressed their major well-known issue of immunogenicity either. Turning down a promising hESC grant by CIRM for not addressing an issue not so critical in the hESC field than the adult cell field seems more of an issue of conflicts or opponents of hESC research or anti-the law of Prop71.

“CIRM Reviewer: She has no apparent experience in drug development.”

Answer: Prop71 is for human stem/progenitor cells and cell therapy, not for drug development company. I have extensive experiences in developing the hESC therapeutic product and technology we proposed here for heart repair that give me the skill and knowledge to lead the preclinical study of this early translation project to clinical development. If those experiences may not be enough, CIRM should provide resources and training to help investigators to reach the goals of prop71. Many PIs of CIRM awarded grants have no stem/progenitor experience or cell therapy development experience that the law requires, let the public wonder how they are going to make progress.

Third, Our grant application RFA 10-05 Application number DR2-05339, titled “ Developing human-pluripotent-stem-cell-derived neuron regeneration therapy for spinal cord repair.” was not on you scored or not scored list, what happened to it? Our grant addresses developing new pluriptotent stem cell therapy of Prop71, why it was not even brought up for consideration? Rather, last round of grants, there were cancer stem cells (still cancer cells not stem cells), no stem cell awards, not eligible for Prop71, and a cluster of 5/6 went to the same UC, a obvious sign of conflict or violation of transparence. Mesenchymal stem cells are known to have no stem/progenitor cell activity, extremely toxic, not graftable (> 1000 papers on it). Do you need state legislation to change CIRM’s grants criteria in the stem cell bond ballot? Not talking about these adult mesenchymal stem cell awards, I know my mentor Stuart Lipton’s mef cells are neither dopaminergic nor have any in vivo functional data. How come you did not require them to do all those things you required us to do?

Fourth, CIRM’s funding process, as State’ agency for its stem cell bond act, is supposed to be transparent, is it ok for us to discuss it on the internet?

Best regards,

Public Comments to CIRM ICOC Board

San Diego Regenerative Medicine Institute Releases Dr. Parsons’ Public Comments to CIRM ICOC Board Meeting 01/17/2012/Sheraton/Baytower/Bel Aire Ballroom/1380

I come here try to bring board’s attention to fund human ES cell research and leaders in California. Human ES cells are the most potential stem cells for developing therapy & cure, so far only a very small % CIRM awards are for human ES cells. We have developed ground-breaking techniques to turn human ES cells into neurons and heart muscles for cell therapy development, critical to bring cures to many incurable diseases. We are the leaders in stem cell research, doing exactly what California’s stem cell research and cure bond act intent to do, should be prioritized for CIRM funding, but so far we have received a penny support for our important stem cell research from CIRM. I feel that it is my responsibility to come to ICOC meeting to give our input for the common goal of advancing stem cell research & therapy. Therefore, I have a few questions and suggestions I hope the board will consider. I was told I only got 3 mins, so I will make it very brief,

1. Questions regarding CIRM’s stem cell research leadership awards:
a. Why is that CIRM excludes stem cell scientists in California from the stem cell research leadership awards, only scientists out-of-state are eligible?
b. One of Prop71 awards’ requirement is that the PI needs to have demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine, why is that CIRM gave the stem cell research leadership awards to scientists who have no stem cell research experience? It would be much more helpful for the public to understand if CIRM can list their achievements in stem cell research and leader activities, such as developing ground-breaking stem cell therapy products and research essential to advance the stem cell field that made this person a stem cell research leader.
c. Why there is no human ES cell research leaders awarded?

2. Question regarding the transparency of CIRM pre-application.
We have developed a new cutting-edge technique to turn human ES cells into beating heart muscles efficiently, intent to move forward to develop cell therapy for heart diseases that so far have no cure and no other treatment options through CIRM early translational award. Our research for developing new stem cell therapy for unmet needs exactly met the purpose of CIRM early translational awards, but turned down by pre-application by unfair critiques such as the PI has no drug development experience, not address the issue of immunogenicity. We understand Prop71 is for developing new stem cell therapy, not for drug development company. Human ES cells are considerably less immunogenic than any other cells and tissues, immunogenicity is not a major issues comparing to adult cells and reprogrammed cells. I have demonstrated record of achievement in preclinical developments of pluripotent stem cell therapy products of this award. It is our understanding that it is CIRM’s job to ensure California’s potential stem cell research & therapy development to be funded to develop treatment & cures for those patients CIRM really cares. Those unfair critiques to pre-application have made crucial research & advancements in stem cell therapy development of CA stem cell research & cure act unnoticed, unfunded, could not move forwards. Therefore, we’d like CIRM board to consider more transparent grant review process, such as allow formal appeal or petition for PreApps, to improve CIRM’s transparency and progress.

3. We have developed a ground-breaking technique to convert human ES cells into a large supply of neuronal cells for nerve regeneration for spinal cord repair in clinical trials. Our novel approach will dramatically increase the clinical efficacy for human ES cell-derived cellular products, targeting both acute and chronic patients, a much broader population than Geron’s trial. We submitted our part-I planning grant on time and requested extraordinarily exceptions twice upon request, but for some reason, the proposal was not considered according to the normal grant review procedure. Due to its novelty, its potential for safe and effect treatment, its benefit to those patients CIRM really cares if the cell therapy is developed, and its stem/progenitor activity & advantage/efficiency/safety over Geron’s trial and all other CIRM awarded developments, we’d appreciate it if the board reconsider our extraordinary petition, so critical stem cell therapy development of Prop71 & patients’ hope/need would not be delayed and the progress of California stem cell research and cure act would not be delayed.

Thank you for your patience.