Legal Assaults on Human Embryonic Stem Cell Research: A Sanford-Burnham Lab Technician’s Blackmail

Everyone knows that those opponents of human embryonic stem cell (hESC) research love to go to court for ridiculous reasons, such as contestable job threats to the superior legal status of a couple of adult stem cell researchers. So much so even a lab technician in Sanford-Burnham knew how to abuse the law. As we announced publication of Regenerative Medicine Startup’s important hESC research advances and breakthroughs as the only available cures/treatments urgent for patients suffering from heart attack and heart disease [see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419496/ released by NIH public access and Press Release: Mending the Borken Heart — Towards Clinical Application of Human Embryonic Stem Cell Therapy Derivatives], those opponents of hESC research know their legal status to steal public fund from stem cell research is numbered, even reckon on making baseless false complaints and legal threats to blackmail editors as their last resort to prevent the release of our important hESC research to the scientific community. We are shocked to learn that Andrew Crain, Evan Snyder’s lab technician at Sanford Burnham, made repeat unauthorized offenders behind our back to retract Regenerative Medicine Startup’s original hESC research that he has no knowledge no contribution by false complaints, as if it is being stolen from him; as if Sanford Consortium for Regenerative Medicine, built with California public funds for stem cell research (Prop 71) and required by the law to open to all stem cell researchers in San Diego scientific community, only belongs to Andrew’s boss Evan Snyder; as if Andrew Crain, Evan Snyder, Vincent Chen, Jean Loring generated any stem cell research data. In Andrew Crain’s exact reckless bully words --- “--- if not retracted immediately ---, legal action will be strongly pursued by our insitute and the NIH will be notified ---”. To see if Andrew Crain’s complaint has any truth in it or it has violated every canon of scientific conduct, maybe we should ask Andrew Crain, or any other plagiarizers Andrew Crain would like to name, if he can provide a single piece of data in this paper to show it was done by him, or write a interpretation for our data showed in this paper, where the data was from, what was for, how the experiment was designed, what was the question we want to answer, and how did we answer it. Why Andrew Crain or Evan Snyder, or any other repeat offenders Andrew Crain would like to name, dared not to send their complaints to me? May be he is totally aware that he is making false complaints and that making false claims or lying in front of judge is serious scientific misconduct or felony if he goes to court. Andrew Crain, Evan Snyder, Vincent Chen, and Jean Loring and their institutes care nothing about stem cell research, maybe their financial conflicts of interest are the real reason that Andrew Crain made the repeat false complaints to prevent publication and release of important hESC research of Regenerative Medicine Startup. If simply see how Evan Snyder/Vincent Chen/Yang Xu plagiarized Dr. Parsons’ original research data for California Institute for Regenerative Medicine (CIRM) grants without any collaboration agreement or permission of Dr. Parsons, violated every canon of scientific conduct, but they never retract public stem cell research fund they have stolen immediately, WHY? If simply see how Evan Snyder, an adult stem cell researcher claimed himself to be the west coast correspondent of NIH and founder of Southern California Stem Cell Consortium, and Sanford Burnham executives lobbied CIRM to steal hundreds of millions of Prop 71 from hESC research through closely-connected Southern California consortium club members that include Larry Goldstein, Yang Xu, Inder Verma, Jean Loring, Vincent Chen, Catriona Jamieson, Leanne Jones, Kristin Baldwin, Bing Ren, and Clive Svendsen (more can be found listed on Stem Cell Meetings on the Mesa), violated every canon of scientific conduct, but they never retract public stem cell research fund they have stolen immediately, WHY? If simply see how Evan Snyder’s Duke, Florida, Harvard connections would give Robert Wechsler-Reya of Sanford-Burnham and those who have never done any stem cell research $ Ms of CIRM funding as ring leader awards, violated every canon of scientific conduct, but they never retract public stem cell research fund they have stolen immediately, WHY? If simply see how Evan Snyder and Sanford-Burnham executives and their consortium members lobbied CIRM to set up many exclusionary unlawful eligibility criteria and issue conflicts of interest RFAs to make sure public stem cell research to come their way without having to generate any scientific data, violated every canon of scientific conduct and Prop 71, but they never retract public stem cell research fund they have stolen immediately, WHY? If simply see why CIRM would set up many exclusionary unlawful eligibility criteria for their RFAs, such as leadership awards have to be out of state, cell line derivation awards have to be iPS adult cells, faculty awards have to be MD, etc., and who have been the biggest financial beneficiary of such conflicts, violated very canon of Prop 71 and Federal and State Laws. If simply see why Sanford-Burnham/UC connect and their associated Crops (e.g., Viacyte, International Stem Cell Corp, Capricor, ACT, Cedars Sinai, Pfizer, Millipore, Johnson & Johnson) would have seminars, meetings, public propaganda events closely corresponding to CIRM RFAs and awards. If simply see why CIRM would give Vincent Chen $Ms for iPS cell conflict of no Prop 71 scientific merit, while block hESC research of Prop 71 scientific merits, and who would be the financial beneficiary of such conflicts, violated every canon of scientific conduct and Prop 71, but Vincent Chen never retract public stem cell research fund he has stolen immediately, WHY? Voice of Regenerative Medicine (VORM) condemn such reckless bullies who have no knowledge no contribution of scientific research data but scientific misconduct and financial conflicts to falsify statements to prevent publication of hESC research breakthroughs and advances release to the scientific community.

Greed & Debt --- CIRM Fraud Manufacturing Machine

Maybe we do not know California Institute for Regenerative Medicine (CIRM) board conflict of interest connections, maybe we do not know CIRM scientific review board conflict of interest connects, maybe we do not know Irv Weissman/Alan Trounson/ISSCR university corruption network connections, maybe we do not know Duane Roth/Connect Washington lobby connections, maybe we do not those glorious cheaters FDA/NIH/Corp alliance connections, but we do know for sure those CIRM awards bearing CA $ 1 billion in debt by greed & debt STEM & Capricor & UC are not stem cell research of Prop 71 not hope for patients CA voted. No scientific evidence $STEM/Weissman adult neural stem cells can work on chronic patients & Alzheimer, no scientific evidence Capricor tissue adult cells can become heart cells regenerate heart muscle as falsified by CIRM grant review statements. CIRM block CA prop71 stem cell research urgent for patients from lawful consideration, but give their board member $STEM/Capricor/UC frauds & scams special treatment against the law. CIRM not only has falsified the $STEM/Capricor/UC grant review statements against scientific evidences, but has not followed 2/3 quorum of Prop71 required for all non pluripotent stem/progenitor cell research. $STEM has cheated investors for > 10 years, now corrupt CA state agency cheat CA Prop71 public stem cell research fund bankrupt CA. STEM/Irv Weissman/SU have 7 conflict-of-interest CIRM bureaucrat connections do not mean STEM openly corrupt CA state agency is ok, CIRM board anti-law anti-ethics anti-moral is ok. Dumb wall street investors throw your money into stock frauds we care none, but STEM/Weissman/Capricor/UC corrupt CA state agency corrupt moral/ethics to cheat CA Prop 71 stem cell research fund we care VORM care patients care law care. Stop greed & debt STEM & Corp corrupt CA state agency cheat Prop 71.

Letter to Editor: Lineage-Specific Differentiation of Pluripotent Human Embryonic Stem Cells Opens the Door to Investigate Molecular Embryogenesis in Human Development

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ original research, titled “MicroRNA Profiling Reveals Distinct Mechanisms Governing Cardiac and Neural Lineage-Specification of Pluripotent Human Embryonic Stem Cells”, released in The International Open Access Journal of Stem Cell Research & Therapy.


Understanding the much more complex human embryonic development has been hindered by the restriction on human embryonic and fetal materials as well as the limited availability of human cell types and tissues for study. In particular, there is a fundamental gap in our knowledge regarding the molecular networks and pathways underlying human embryonic development. The enormous diversity of human somatic cell types and the highest order of complexity of human genomes, cells, tissues, and organs among all the eukaryotes pose a big challenge for characterizing, identifying, and validating functional elements in human embryonic development in a comprehensive manner. Many of the biological pathways and mechanisms of lower-organism or animal model systems do not reflect the complexity of humans and have little implications for the prevention and cure of human diseases in the clinical setting. As a result of lacking a readily available human embryonic model system, the mainstream of biomedical sciences is becoming increasingly detached from its ultimate goal of improving human health.


Pluripotent human embryonic stem cells (hESCs) have the unconstrained capacity for long-term stable undifferentiated growth in culture and the intrinsic potential for differentiation into all somatic cell types in the human body, holding tremendous potential for restoring tissue and organ function. Derivation of hESCs, essentially the in vitro representation of the pluripotent inner cell mass (ICM) or epiblast of the blastocyst, provides not only a powerful in vitro model system for understanding the human embryonic development, but also a pluripotent reservoir for derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. However, realizing the developmental and therapeutic potential of hESCs has been hindered by the current state of the art for generating functional cells through multi-lineage differentiation of pluripotent cells in a 2-dimentional (2D) culture, which is uncontrollable, inefficient, highly variable, difficult to reproduce and scale-up, and often causes phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity following transplantation. Development of novel strategies for well-controlled efficient differentiation of hESCs into functional lineages is crucial not only for unveiling the molecular and cellular cues that direct human embryogenesis, but also to harnessing the power of hESC biology for cell-based therapies.


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, which enables lineage-specific differentiation direct from the pluripotent state of hESCs and opens the door to investigate human embryonic development using in vitro cellular model systems. MicroRNA (miRNA) expression profiling using microarrays is a powerful high-throughput tool capable of monitoring the regulatory networks of the entire genome and identifying functional elements in development and disorders. Recently advances in human miRNA expression microarrays have provided powerful genome-wide, high-throughput, and high resolution approaches that will lead to great advances in our understanding of the global phenomena of developmental processes. To identify mechanisms of small molecule induced lineage-specification of pluripotent hESCs, in this study, we compared the expression and intracellular distribution patterns of a set of cardinal chromatin modifiers in pluripotent hESCs, nicotinamide (NAM)-induced cardiomesodermal cells, and retinoic acid (RA)-induced neuroectodermal cells. Further, genome-scale profiling of miRNA differential expression patterns was used to monitor the regulatory networks of the entire genome and identify the development-initiating miRNAs in hESC cardiac and neural lineage-specification. We found that NAM induced nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing, while RA induced silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family to high levels. Genome-scale miRNA profiling indentified that a unique set of pluripotence-associated miRNAs was down-regulated, while novel sets of distinct cardiac- and neural-driving miRNAs were up-regulated upon the induction of lineage-specification direct from the pluripotent state of hESCs. These findings suggest that a predominant epigenetic mechanism via SIRT1-mediated global chromatin silencing governs NAM-induced hESC cardiac fate determination, while a predominant genetic mechanism via silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family governs RA-induced hESC neural fate determination. This study provides critical insight into the earliest events in human embryogenesis as well as offers means for small molecule-mediated direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. This original research article of Dr. Parsons supported by the National Institutes of Health was published in The International Open Access Journal of Stem Cell Research & Therapy.

Pluripotent Human Embryonic Stem Cells as Model Systems of Human Development for Mechanism and Disease Studies

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ original research, titled “MicroRNA Profiling Reveals Distinct Mechanisms Governing Cardiac and Neural Lineage-Specification of Pluripotent Human Embryonic Stem Cells”. 


Understanding the much more complex human embryonic development has been hindered by the restriction on human embryonic and fetal materials as well as the limited availability of human cell types and tissues for study. In particular, there is a fundamental gap in our knowledge regarding the molecular networks and pathways underlying human embryonic development. The enormous diversity of human somatic cell types and the highest order of complexity of human genomes, cells, tissues, and organs among all the eukaryotes pose a big challenge for characterizing, identifying, and validating functional elements in human embryonic development in a comprehensive manner. Many of the biological pathways and mechanisms of lower-organism or animal model systems do not reflect the complexity of humans and have little implications for the prevention and cure of human diseases in the clinical setting. As a result of lacking a readily available human embryonic model system, the mainstream of biomedical sciences is becoming increasingly detached from its ultimate goal of improving human health.


Pluripotent human embryonic stem cells (hESCs) have the unconstrained capacity for long-term stable undifferentiated growth in culture and the intrinsic potential for differentiation into all somatic cell types in the human body, holding tremendous potential for restoring tissue and organ function. Derivation of hESCs, essentially the in vitro representation of the pluripotent inner cell mass (ICM) or epiblast of the blastocyst, provides not only a powerful in vitro model system for understanding the human embryonic development, but also a pluripotent reservoir for derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. However, realizing the developmental and therapeutic potential of hESCs has been hindered by the current state of the art for generating functional cells through multi-lineage differentiation of pluripotent cells in a 2-dimentional (2D) culture, which is uncontrollable, inefficient, highly variable, difficult to reproduce and scale-up, and often causes phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity following transplantation. Development of novel strategies for well-controlled efficient differentiation of hESCs into functional lineages is crucial not only for unveiling the molecular and cellular cues that direct human embryogenesis, but also to harnessing the power of hESC biology for cell-based therapies.

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, which enables lineage-specific differentiation direct from the pluripotent state of hESCs and opens the door to investigate human embryonic development using in vitro cellular model systems. MicroRNA (miRNA) expression profiling using microarrays is a powerful high-throughput tool capable of monitoring the regulatory networks of the entire genome and identifying functional elements in development and disorders. Recently advances in human miRNA expression microarrays have provided powerful genome-wide, high-throughput, and high resolution approaches that will lead to great advances in our understanding of the global phenomena of developmental processes. To identify mechanisms of small molecule induced lineage-specification of pluripotent hESCs, in this study, we compared the expression and intracellular distribution patterns of a set of cardinal chromatin modifiers in pluripotent hESCs, nicotinamide (NAM)-induced cardiomesodermal cells, and retinoic acid (RA)-induced neuroectodermal cells. Further, genome-scale profiling of miRNA differential expression patterns was used to monitor the regulatory networks of the entire genome and identify the development-initiating miRNAs in hESC cardiac and neural lineage-specification. We found that NAM induced nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing, while RA induced silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family to high levels. Genome-scale miRNA profiling indentified that a unique set of pluripotence-associated miRNAs was down-regulated, while novel sets of distinct cardiac- and neural-driving miRNAs were up-regulated upon the induction of lineage-specification direct from the pluripotent state of hESCs. These findings suggest that a predominant epigenetic mechanism via SIRT1-mediated global chromatin silencing governs NAM-induced hESC cardiac fate determination, while a predominant genetic mechanism via silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family governs RA-induced hESC neural fate determination. This study provides critical insight into the earliest events in human embryogenesis as well as offers means for small molecule-mediated direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. This original research article of Dr. Parsons supported by the National Institutes of Health was published in The International Open Access Journal of Stem Cell Research & Therapy.

Stem Cell Mafia --- The Professor’s Ethics

It was interesting to see Alan Trounson, Gerald Schatten, and David Baltimore all showed up in Qatar, because before there was Gerald Schatten’s international cloning scandal, there was “David Baltimore Case”.


Ithaca Cornell was a blessing I could only appreciate after I became the Ithaca James missed. Unlike all his brothers who went to Ithaca College in London, James missed the deadline, so had to go to Regents College in London. Even today, I could not find any scientific explanation for why I caught up with some trivial things, missed the bus, caught up with some other trivial things again, missed the bus again, just to catch the wrong bus so I could lose in the right moment for James to pick up his Ithaca on the streets he grew up, and for me to meet the Irish I had pretended to be in Ithaca Cornell.


Where I was from, the moral was demolished. If there was any preserved by the ideologist bubble delicately built by loving parents, it was crushed by June 4^th’s gunshots. Cornell was a perfect escape from a generation of anger of betrayal by your own government, a perfect hideaway to restore the normality of society and to rebuild the trust and faith once lost. I was more shocked to see Cornell’s honor system than to see anyone cheating. Cornell was the academic excellence and achievement of everyone’s dream. Cornell was the highest standard of ethics that everyone in Cornell was in. So one semester, when we all suddenly received an email to ask everyone to take a mandated ethics class, no one had any idea what was ethics. For experiments boggled minds, the ethics sounded extremely boring. I prepared to sleep through that 2 hour class just not to get in trouble. However, the class turned out to be more interesting and memorable than I thought. The ethics class was about the forbidden cheating. It was to tell everyone the dark side of sciences by case after case of scientific misconducts that we would have never heard of by any other chances. We heard many untold Cornell’s shocking tales. There was this anonymous Cornellee who faked all his experimental data because no technology was available at his time to examine his theory. But, ironically, he turned out to be a genius later on when the technique was developed to prove his theory all correct. Amazed, we wondered, unsympathetic to his fate of being kicked out of Cornell, “how did he do that?”

Besides school, I was drawn into Cornell’s co-op, bible study, upstate New York’s endless waterfalls and finger-lakes, and lost my identity in the exotic Celtic drum beats and the massive medieval war Pennsic (see photos below), I barely knew who had won the Noble Prize. So we heard “David Baltimore Case” before we were mind-blown to figure out he was the Noble Prize winner and the real reason that we all had to take this class and got to hear those unspeakable tales. If I knew I would have something to do with David Baltimore later in my life, I probably would have paid more attention to the class. The instructor was trying to end the class by asking the question “Are you going to be a whistle-blower?” No one had known enough about the consequence of being a whistle-blower to give the answer she wanted. After realizing that the university’s effort to try to protect those innocent and brilliant young minds was wasted, the instructor desperately spent the last few minutes of her class to import the idea of “DO NOT BE A Whistle-Blower” into our clueless heads. The ethics was soon to be forgotten. Only history was left to remember to prove she was right. David Baltimore resigned from New York Rockefeller University, only to reappear in the west coast a few years later as the President of California Institute of Technology (CalTech). His whistle-blower had disappeared in history, no one could remember her name. David Baltimore was the head of AIDS vaccine research panel at the National Institute of Health (NIH). He was appointed to the oversight committee of California Institute for Regenerative Medicine (CIRM) later and resigned again in connection with a $ 20 million HIV CIRM grant to UCLA AIDS institute and his out-of-state AIDs vaccine company. David Baltimore has more CIRM grants connections that have not been so visible, such as ~ $ 10 M to his own clan Yang Xu at UCSD.


Coming out of Cornell’s honor system, it was devastatingly demoralizing to see CIRM cheating Prop 71, cheating by professors, cheating organized through departments and institutes, cheating by prestigious universities and research institutes, cheating by the system I had rebuilt my trust and faith on. David Baltimore was known as a strong supporter of the highly controversial issue of stem-cell research. His famous argues include "Embryonic stem cells hold remarkable promise for reversing the devastation of human disease" and "To refuse to allow [the country] to participate in this exciting research would be an affront [an offense] to the American people, especially those who suffer from diseases that could one day be reversed by these miraculous cells" [The Wall Street Journal, 2002]. Despite that, David Baltimore, like all others in CIRM independent citizen oversight committee (ICOC) board, has not been able to perform the simplest duty of ICOC board required by the law, to ensure Prop 71 funds to go to human pluripotent stem/progenitor cell, known as human embryonic stem cells (hESCs), research and therapy, not to ensure Prop 71 funds to go to their own institutions and clans. They, who are deans and presidents of institutions holding the highest standards of ethics, all did just the latter, so one by one was got caught and resigned, and the new ones appointed by the State government officials would only turn out to be the same.


After Cornell, ethics had not become a constraint in my life until I received a hESC research award from NIH that ethics training was one of requirements of the award. Soon after California passed Prop 71, prestigious professors, most of them had zero stem cell research experience, suddenly became eligible for stem cell center directors overnight at California campus. Those directors also became eligible to teach ethics of stem cell research to others. In San Diego, there are Evan Snyder of Burnham and Larry Goldstein of UCSD. However, those directors who teach ethics have turned out to be rogue professors with so little ethics. They are more like stem cell mafia, not directing nor serving any stem cell research for the scientific community. The affiliation with stem cell center supported by public funds has become their bargain chip to be on papers and grants without having to do anything, turning the real stem cell research workforce into something like Jean Loring’s “professional collaborators” with no name, no title, no position, no recognition, so your hard work would be easily the director’s, if not, you may soon find yourself under legal action. These stem cell directors are extremely hard to reach. If you have any inquiries or need any help regarding shared research resource, stem cell research collaboration, communication, coordination, or anything you thought would be the directors’ job, you would never get any responses from those directors. But they have never been shy of receiving director’ glory for things they’ve never done in any public events, like interviews and speakers.


My former mentor Evan Snyder has also been on the editorial boards of many stem cell journals, including Cell Stem Cell, Regenerative Medicine, Stem Cell, Exp. Neurol., J. Stem Cell Research & Therapy, which have been his bargain chips to be on many other people’s papers of not his work. His editorial positions have allowed him to reject or stuck many of his competitors’ papers without even sending out for review, including mine, which has been the sad reason that I could not get my stem cell research, despite breakthroughs, published in any of those stem cell journals. I have never seen anyone with such a big appetite for data, which maybe the only reason he would suddenly become very friendly. He would tell you he could help you to get your data published, send him your data, not just regular ones, high defi ones, and he would come back for more and more. Then you would not hear anything about submissions for months or years from him, until you might accidently bump into his talks about your data, which most times would be twisted to fit into his purpose, without you in one of those meetings he loves to go, or it would come back with his collaborators on it with nothing else increased and become his hostage for you have to do more and more to give to him. After you finally realized that he has not done, and probably would never do, anything he promised again and again, it probably would be too late for you to try to publish these data you consider as your life and career. Your data have become his. He would use his director and editor position to retract those submissions and publications what he called repeat offenders and claimed his superior position for affiliation with Sanford Consortium for Regenerative Medicine and not anyone else eligible for affiliation with public stem cell research facility, so your research can only be published through his mafia hands. If not, he would or would have his lab technician to make false allegations, complaints, and threats to authors, editors, and journals, and even resolute to pursuing legal action by Sanford Burnham institute and notifying NIH for those normal scientific activities of publishing scientific data to the scientific community. And you would end up thinking --- “what a hell, my only crime is I did the research, not him.”


If you would like to know how those center grants were done, here is an example. In 2005, Burnham received an Exploratory Center Grants for Human Embryonic Stem Cell Research from NIH to establish one of ~ 6 national stem cell centers. I wrote/co-wrote 2 core projects (out of 3-4) and 3 pilot projects (out of 3-4), took my entire NIH K award data as the only human embryonic stem cell research data to put into the center grant, and replaced Mark Mercola’s cardiac project (not on hESCs) with my hESC cardiac project with Evan Snyder’s promise to be the Co-Investigator and Project Leader on the center grant. Right before the grant was sent out, I finally got some time to check the personnel assembled by Jean Loring. I was blown away because I could not find my name on it, neither my biosketch. Jean Loring has put ~ 20 people on the center grant application, most of them had never done anything, but excluded me on the team. The hESC center grant was awarded by NIH, citing outstanding hESC research. Evan Snyder became the PI and director, and Jean Loring became the co-PI and co-director responsible for hESC training classes. After Jean Loring took over, she excluded me from Burnham NIH funded stem cell center, claiming legal action if I would gain access. I protested with Burnham officials, but did not succeed. Later on, I was ready to apply for CIRM grant with all my hESC research data I have done, but Burnham grants officials denied to sign my hESC grant as the PI (principal investigator), instead, organized those professors who have never done any stem cell research to apply, and my hESC research and grants would end up to become Jean Loring’s again. I had a very tough time under Jean Loring’s regime, so finally I gave Evan Snyder the permission to put David Smotrich as the PI.

Mending the Broken Heart --- Towards Clinical Application of Human Embryonic Stem Cell Therapy Derivatives

San Diego Regenerative Medicine Institute, Xcelthera, La Jolla IVF, and Sanford Consortium for Regenerative Medicine announce the publication of collaborative original research, titled “Defining Conditions for Sustaining Epiblast Pluripotence Enables Direct Induction of Clinically-Suitable Human Myocardial Grafts from Biologics-Free Human Embryonic Stem Cells”. To date, lacking of a clinically-suitable human cardiac cell source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent human embryonic stem cells (hESCs) proffer unique revenue to generate a large supply of cardiac lineage-committed cells as human myocardial grafts for cell-based therapy. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. However, realizing the therapeutic potential of hESCs has been hindered by the inefficiency and instability of generating cardiac cells from pluripotent cells through uncontrollable multi-lineage differentiation. In addition, the need for foreign biologics for derivation, maintenance, and differentiation of hESCs may make direct use of such cells and their derivatives in patients problematic. Understanding the requirements for sustaining pluripotentce and self-renewal of hESCs will provide the foundation for de novo derivation and long-term maintenance of biologics-free hESCs under optimal yet well-defined culture conditions from which they can be efficiently directed towards clinically-relevant lineages for cell therapies. We previously reported the resolving of the elements of a defined culture system, serving as a platform for effectively directing pluripotent hESCs uniformly towards a cardiac lineage-specific fate by small molecule induction. In this study, we found that, under the defined culture conditions, primitive endoderm-like (PEL) cells constitutively emerged and acted through the activin-A-SMAD pathway in a paracrine fashion to sustain the epiblast pluripotence of hESCs. Such defined conditions enable the spontaneous unfolding of inherent early embryogenesis processes that, in turn, aid efficient clonal propagation and de novo derivation of stable biologics-free hESCs from blastocysts that can be directly differentiated into a large supply of clinically-suitable human myocardial grafts across the spectrum of developmental stages using small molecule induction for cardiovascular repair. This original research article of Parsons et al was published in Journal of Clinic. Exp. Cardiology Special Issue on Heart Transplantation.

Cardiovascular disease (CVD) is a major health problem and the leading cause of death in the Western World. In the United States, around 5 millions survive heart failure but live with insufficient cardiac function, and about 550,000 new cases are diagnosed annually. Heart attacks, known as myocardial infarction (MI), are the main cause of death in patients with CVD. Around 1/3 of the patients suffering from heart attacks each year die suddenly before reaching the hospital. In the remaining patients who survive their initial acute event, the damage sustained by the heart may eventually develop into heart failure, with an estimated median survival of 1.7 years in men and 3.2 years in women. To date, lacking of a suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart, either by endogenous cells or by cell-based transplantation or cardiac tissue engineering. In the adult heart, the mature contracting cardiac muscle cells, known as cardiomyocytes, are terminally differentiated and unable to regenerate. Damaged or diseased cardiomyocytes are removed largely by macrophages and replaced by scar tissue. Although cell populations expressing stem/progenitor cell markers have been identified in the adult hearts, the minuscule quantities and growing evidences indicating that they are not genuine heart cells have caused skepticism if they can potentially be harnessed for cardiac repair. There is no evidence that stem cells derived from patients’ heart tissues, such as Cedars-Sinai’s Eduardo Marban’s autologous heart tissue cells (who said the last thing he would do was hESC research, maybe the last thing he should cheat was taking Prop 71 fund for hESC research from California Institute for Regenerative Medicien [CIRM] if he has any professor’s ethics), are able to give rise to the contractile heart muscle cells following transplantation into the heart. There is no evidence that stem cells derived from other sources, such as bone marrow or umbilical cord or cord blood, are able to give rise to the contractile heart muscle cells following transplantation into the heart. Therefore, the need to regenerate or repair the damaged heart muscle (myocardium) has not been met in today's healthcare industry. Heart transplantation with the donor organ has been the only definitive treatment for end-stage heart failure. For millions living with the damaged heart, there is no alternative definitive treatment available at present time. For patients who need the heart transplantation, there is an acute shortage of donor organs. Many patients die while waiting on the shortlist.

Pluripotent human embryonic stem cells (hESCs), derived from the inner cell mass (ICM) or epiblast of the human blastocyst, proffer unique revenue to generate a large supply of cardiac lineage-committed cells as adequate human myocardial grafts for cell-based therapy. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. The hESCs and their derivatives are considerably less immunogenic than adult tissues. It is also possible to bank large numbers of human leukocyte antigen isotyped hESC lines so as to improve the likelihood of a close match to a particular patient in order to improve the engraftment and survival efficiency, and minimize the potential risk and side-effect of immune rejection following transplantation. However, there are 2 major obstacles to bring hESC therapy to clinics. One major obstacle to translate hESC biology is that most currently-available hESC lines were derived and maintained on animal cells and proteins, therefore, those hESCs have been contaminated with animal biologics and cannot be used for patients in clinical trials. The other major obstacle to develop hESC therapy is very difficult to channel the wide differentiation potential of hESCs in order to generate a large supply of uniform functional cells as the cell therapy product targeting for a particular disease. Our breakthroughs have overcome both obstacles, enabling both de novo derivation of clinical-grade cGMP (Current Good Manufacturing Practices) compatible hESCs from blastocysts (Xcel-hESCs) that have never been contaminated by animal cells and proteins, and a large supply of clinical-grade functional cardiac precursors and cardiomyocytes to be translated to patients in clinical trials for mending the heart. The heart is the first organ formed from the cells of the ICM/epiblast of the blastocyst in early embryogenesis. The hESC-derived embryonic heart cells resemble the heart cells in human development, therefore, they have the powerful potential to form human contractile heart muscle as well as the cardiovascular structure with intact 3D geometry and vasculature of the whole heart. The availability of a large supply of clinically-grade human myocardial grafts in high purity and large quantity with adequate potential to mend the heart makes heart disease possible to be the first major health problem to be cured by clinical translation of human embryonic stem cell research.

Decision Point: Political Stem Cells --- Obama Failed Stem Cell Policy

Among President Obama promised changes, his policy on stem cell research probably is the biggest disappointment. In part, the President’s scientific advisories surrounding him may be responsible, if simply check who he invited to white house and who are among those he gave medals to. Democrats have been known as the supporters of human embryonic stem cell (hESC) research, which is crucial to driving the advance of medicine to provide treatment options for many major world-wide incurable diseases, such as Alzheimer disease, Parkinson’s disease, ALS, diabetes, heart disease, to relieve health care burden and budget deficit. For supporters of hESC research, we all were very excited to see a Democrat President come to office in 2009. President Obama acted very quickly to relax the National Institutes of Health (NIH) policy on hESC research in March, 2009, and set up 6 month deadline for NIH to meet that we would expect NIH to come up with a new guideline and to increase funding on hESC research. However, 3 years later, the bureaucratic NIH has made little progress, still has not met the President’s deadline to come up with a new guideline, even cut the NIH funding for hESC research to a level worse than previous administration reigned by a Republican President. During Obama administration led by a Democrat President, crucial hESC research and advances cannot proceed, and existing national hESC research labs and resources that had been open for research progress even in Bush administration have been shut down due to lack of funding. It has become a major concern when we come to this year’s big decision point if he will be the President who can keep his promises or the President incapable of getting anything done.