“The Valley of Death” — Behind The Gianormous Fruitfly on ICOC Board

For those who are working in biomedical research, “the valley of death” is nothing unfamiliar. It refers to the difficulty of crossing the gulf between finding a promising new agent and demonstrating its safety and efficacy in humans. For those who do not know what “the valley of death” is, those on ICOC board, those journal editors and reviewers, those grant reviewers, it can be found in the cover story in Newsweek by journalist Sharon Begley titled “Desperately Seeking Cures: How the road from promising scientific breakthrough to real-world remedy has become all but a dead end.” It refers to the status quo of mainstream biomedical research being stuck in the non-human simple model organisms, such as bacteria, drosophila, zebrafish, and mouse, with vast investment to only generate a vast amount of knowledge completely useless for the prevention and treatment of human diseases. It refers to the vast waste land of biomedical research. It refers to all drug development leads but only very few lucky ones have fallen out of clinical trials. It refers to among those few lucky ones, there were not any cures, or even meaningfully effective treatments, for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives. It is hard for anyone to imagine that it would come up with a cure for cancers, Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease, diabetes, or heart disease by dissecting a fly to molecular levels. However, it has been the status quo of all major universities and institutes. It is still where the vast amount of funding of National Institutes of Health goes, to maintain the status quo of these universities and institutes, despite no return on investment to the American taxpayer for the slightest improvement to human health, despite no return on investment to the American taxpayer judging by the only criterion that matters to patients and taxpayer — not how many interesting discoveries have been made, but how many treatments for diseases the money has bought. The consequence is pounding. To date, after all the biomedical research investment, there is no cure or even meaningfully effective treatment developed for those major health problems that are deadly and affect millions. The extremely toxic chemotherapy, which is based on a simple fact that cancer cells as well as all the normal dividing cells known as stem cells are more sensitive to toxics and radiations, is still the only treatment option for the deadly disease after close to trillion of investment to cancer research, after all those years.

When Prop71 was passed in CA, human embryonic stem cell (hESC) research was a new forefront in human subject research, a unique opportunity to bridge the valley of death, a promising opportunity to turn investment of the California taxpayer into meaningfully effective treatments or cures to relieve the huge burden of those deadly diseases to the CA health care and society we live in. There has been a law for it in CA, a law to ensure hESC research to be funded in CA, a law to ensure stem cell therapy and cures can be developed, a law to ensure return on investment to the California taxpayer. Why could it be that most of the funding has still gone to the valley of death? Why it has been so difficult to fund hESC research?

When Prop71 was passed in CA, as a controversial human subject research that can still be sued, hESC research virtually did not exist in all the universities and institutes in CA. Unlike every other scientific field where the director has demonstrated record of achievement in the field they direct, in order to get a piece of the stem cell pie, all the universities have appointed professors, mostly very prestigious in their own research field but no hESC research experience at all, as stem cell center directors overnight. However, research is not community charity or communism. It has research data ownership, research facility ownership, authorship, and intellectual properties. It has competition, recognition, prize, and award to outstanding individuals for the achievement. Those directors, created solely for the money purpose, have no demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine that the law requires to deliver the real goods, but have strong connections in the scientific community, such as on, affiliated, or connected to many advisory boards of companys and foundations, many editorial boards, review boards, committee boards, meeting committee boards. In order for multi-millions of stem cell bond to come their ways, they have used their muscles to compart the research community, to block their competitors, in the name of collaboration. Some of those directors are also on CIRM advisory board, with majority of the board members are from the same universities and institutes, it would not be too difficult for them to sneak in multi-millions initiatives that can bypass the law, multi-millions initiatives that have nothing to do with Prop71 but bore the criteria of their resume so that only qualify themselves and disqualify their competitors. To make things even easier for them, there were hand-shakings and undocumented internal meetings with CIRM behind the public eyes. Finding one stem cell professor in UC was difficult, where did the 100 stem cell professors, publicly known as stem cell experts, come from? Finding one stem cell professor in UC was difficult, but finding 100 fly-dissecting professors in UC was no problem. Larry Goldstein sent a mass email to 100 fly-dissecting professors in UC to promise everyone a guaranteed spot on Sanford Consortium for Regenerative Medicine and easily got $40M come his way, so did every other appointed stem cell center directors. Craig Venture and Ellen Feigal only needed 50 of them to sneak through another round $40M of genomic initiative for Catriona Jamieson despite that there already are many companys that can provide the same or even better genomic services. You could not believe your ear to hear some stem cell director or professor, who really is a virus professor or a fly-dissecting molecular biologist without slightest care for or knowledge of hESC research, saying things like “I just got $5M from CIRM, I do not even know what I am going to do with it”, while those stem cell research facilities do have the demonstrated record of achievement that the law requires, such as ACT, had to close their facility because they could not get that $5M to keep their facility open and some meaningful stem cell research going. With 100 of those fly-dissecting professors awarded $M by CIRM without any record of achievement that the law requires and without having to do anything to advance stem cell research, those really qualified applicants would only feel shocked their stem cell therapy development grants blocked by CIRM’s pre-application with critiques saying things like that the PI did not have drug development experience or did not address immunogenicity issue. When did California stem cell research and cure bond act become drug development for big Pharms? Do we all know Ellen Feigal from drug development company, has drug development experience, was there any connection, was that why most of CIRM disease teams went for drug development? You would wonder why there was the immunogenicity initiative while hESCs are already less immunogenic than anything else, why the stem cell research leadership initiative excludes anyone in CA, why there is only iPS cell bank, not hESC bank initiative. Why would Catriona Jamieson need another $40M from CIRM while she already got $20M CIRM disease team award not for a stem cell therapy but a conventional drug development in her drug development company, is it because her connection with Stanford, with those Harvard reviewers on CIRM board, or her drug development company’s close connection with CIRM board member and UC Connect Duane Roth, you go figure.

To ensure fairness, in a democratic capitalism country, all the federal and state contracts usually need to have at least 2 bidders. However CIRM has no competition, therefore, can do whatever they want, their job is to dole out the money, to dole out someone else’s money not single one of those on CIRM board and staff would really care, and whoever receives the money and what happens to someone else’s investment would not really matter to any of them. To believe the fairness of CIRM is just like to believe the idea of communism. Do you think it is a bit of odd that 8 years after passing Prop71, there is still only stem cell center, but no stem cell faculty for stem cell research in all the universities and institutes? Do you think it is a bit of odd that CIRM’s stem cell research leadership awards have never listed those leaders’ achievement in stem cell research and leadership activity as any leader should have. If take a look at ICOC board, there was not any one advocate for hESC research considering it is a stem cell agency, Bob Klein probably was the only one who is a strong supporter for hESC research. Whoever wrote Prop71, whoever voted for it, must feel ill to see a gianomous fruitfly on ICOC board qualified for a piece of stem cell pie, while the same group behind the gianomous fruitfly on stem cell pie was also plotting to sue the remaining of the hESC research labs that have struggled hard to open to develop crucial stem cell therapy to the patients that CIRM really cares about, to force them to close, to shut them down for good. What makes those big universities and institutes so ruthless? NIH’s new iPS cell center director Mahendra Rao was mentioned at the ICOC board to implicate that NIH might be part of the conspiracy too. We all know Mahendra Rao was from Buck, has close connection with Sanford Burnham and my mentors. Subconsciously, the gianomous fruitfly might be little bit too odd to the picture of the CIRM ICOC board, so one of the board member asked CIRM staff about the grants criteria in the law to make sure, and the CIRM staff could not give a full account either. The ICOC board meeting definitely was an eye opening experience. Without total transparency, without competition for the job that CIRM is doing, whoever thinks their grant will get a fair review by CIRM, judging by the demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine, judging by the scientific merits written into the law, judging by the return on investment to the California taxpayer, is just as naïve as I was.

The result of CIRM’s strategy to fund the valley of death is the valley of death. The consequence is pounding. To date, after having doled out $1.3B investment of the California taxpayer on stem cell research by CIRM, there is no return no stem cell therapy no cure developed for those major health problems that remain a huge burden to the CA health care and the society we live in.

The Enormous Waste of CA Prop71 by CIRM on Those Entitlements Not Called Stem Cell Research

The public assumes that California Institute for Regenerative Medicine (CIRM) understands that the law Prop71 was passed for utilizing human embryonic stem cell (hESC) potential to develop therapies and cures for those major health problems that so far have no other options, like heart diseases, diabetes, Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease, and spinal cord injury. Since the large cap of the healthcare market, in return, it would benefit the State’s economy, not waste their investment. The public assumes that CIRM understands that they did not pass a public bond measure for anything less than human cells. The public assumes that CIRM has the basic public knowledge that only human cells can be used for medicine, therapy and cure. However, CA’s human embryonic stem cell research and therapy awards, urgent to those patients CIRM really cares in their public statement, have not been able to make to CIRM ICOC board meetings $100M after $100M, years after years, months after months. By contrast, how did a fruit-fly individual not in CA prioritized by CIRM to their ICOC board meeting for stem cell research leadership award in less than 2 months? Did really Sanford-Burnham’s President Kristina Vuori have no public knowledge at all to cast her outstanding Yes vote for $6M CA stem cell bond to waste on fruit-fly? Who are those really behind it? Who are those who really want to turn CIRM into snake oil purveyor #1 in the world, considering that even those stem cell con men out there or on 60 minutes still have the least moral concern to use human cells?

People were asking me that what the hell we need $100M on Sanford Consortium for Regenerative Medicine in historic La Jolla in this economy that cannot even be used for stem cell research? People were asking me that how come our human embryonic stem cell research and therapy development, leading the California and the whole world, could not even pass CIRM’s pre-applications to receive a penny support from Prop71 in 8 years? People were asking me that, with $3B CA stem cell research and cure act to prioritize human embryonic stem cell research, how come human embryonic stem cell research labs were shut down by those officials who have already entitled $1.3B of it? People were asking me how come the mesenchymal stem cell (MSC) has more stem cell activity than the human embryonic stem cell against any scientific merits to pass ICOC board eligible for wasting other $200M state stem cell bond? People were asking me …?

In the next few blogs, we will take you to inside the ICOC board meeting, to cases of CIRM human embryonic stem cell research and therapy pre-applications and applications in the hope that you will find those answers we all search for.

Stem Cell Research A Year in Review — Give Dog A Bone

Besides all the dramas, 2011 was very grey for stem cell research, following the never-ending lawsuits to federal funding for human embryonic stem cell (hESC) research. NIH (National Institutes of Health), 2 years after a Democrat President came to office and relaxed the Federal policy on hESC research, has made no progress but surrendered to politics to reduce federal funding for hESC research to a level worse than the previous era reigned by a Republican President. Unable to defeat hESC research in the scientific ground where every living person in this planet is an undeniable scientific evidence of its potential, adult stem cell research, more likely driven by their financial interests rather than their concerns for ethics and public health, turned to legal and religion to renew their spotlights, fleshing on God’s money after $92M of NeoStem investor’s money had gone into smoke. Adult stem cell research prevailed, but could not reach beyond the law of naked science to ring the bells, casting a dense fog over the future of stem cell research. CIRM (California Institute for Regenerative Medicine), with each round of awards that revealed no hESC research that the law shall but their invited speakers that the law shall not, are following Neostem’s suit on the way to burn what is left of CA $3B stem cell bond on nothing better than Larry Goldstein’s snake oil purveyor. CIRM’s strategy to deprive CA’s hESC research of funding to a dire situation has left the State’s dire economy with no therapy no cure but mounting prospect of $B in debt. When it had come to everyone’s mind that how long Geron was going to go on their safety trial, they surprised the whole world by performing a disappearing act. With Geron’s sudden exit, idolized leaders by CIRM awards could not step into the shoes of their overnight fame, only surfacing to reveal the emptiness of leadership that no title and money can buy. CIRM’s rush to award centers and leaders of no stem cell research finally brought CA’s $3B ambitious stem cell project to welcome its 8th year with no promised glory of stem cell research but the oddest scene of harsh reality. CA’s most advanced hESC research labs, deprived of receiving a penny support from Prop71 by CIRM over 8 years of $1B funding strategy, face the shutdowns, while CIRM’s pristine core facilities scattering along academia campus waste the public money for stem cell research on nothing more than a general store house. CIRM’s leadership awards have gone to the extreme to blur the line between leaders and stem cell con men, barring CA’s hESC research leaders from receiving a penny of its own bond measure. With CIRM’s center directors’ strong resistance to stem cell faculty for the convenience of their own entitlement, CIRM’s impressive architectures that cost CA a fortune of borrowed money to build only magnify the vacancy of stem cell research in the strangest scene, looking nothing like public stem cell research infrastructures but private housing advertisements.

CIRM continued to defy the law, having its nose dragged by the interests of big institutes and universities as above the law of Prop71 that created CIRM, leaving only a few dog-bones for hESC research to chew. With the representatives of big institutions taking their liberty to rewrite the law to maximize their own return, CIRM’s RFAs and initiatives showed no sign of prioritizing hESC research to maximize the State’s return that the law shall, but the non-transparent measures that the law shall not. No money for hESC research from California’s $3B ambitious stem cell project was highlighted by their large disease team awards. The 2nd round of disease team awards revealed, not any better than the previous round of > $200M, no new hESC therapy but a cluster of mesenchymal stem cells (MSCs) triumphing over the much more potential hESCs against any laws, turning blind to > 20 years of MSC studies that have already produced negative results in clinical trials. Their last award of 2011 to an out-of-state molecular biologist idolized no leader but stem cell con man no exception to academia, proving once again how wrong it has been to put the public’s trust for a law on executives and outrageous salaries.

The statute of that CIRM can do whatever they want was established in California Governor Arnold Schwarzenegger’s effort in vain to persuade CIRM to fund hESC research, discouraging anyone to think that CIRM would take any comments or arguments of authority, government officials, congressmen, public, media, or stem cell scientists into accounts. In a cyperfly age, CIRM gives no opportunity for any feedbacks or suggestions. CIRM incapability of delivering the law has been re-enforced by their long list of awards welcomed not by the grants criteria written into California stem cell research and cure bond act or Proposition 71 [1], but the tangled financial interests of academia and big Institutes that could not even hide behind their non-transparent measures and symbolic barring of directors, making each round of awards like a slam on the reason of their own existence. With each round of awards that revealed no welcome to hESC research, CIRM has lost its colorful vibrancy of hope that drove the pass of Prop71, abandoned by all major media to the dark side of science infested with conflicts of interests and broken scientific integrity to threaten the sacred knowledge passing through the academic ground.

A far cry from CIRM’s no concern for a state law, uncontested complains to tiny-bit things such as job threats from a couple of adult stem cell researchers have caused national stirring for the concern for a federal law, the Dickey-Wicker Amendment [2]. However, Dickey-Wicker Amendment was written in no way for demanding their common interests of justice for injustice. Dickey-Wicker Amendment is added so that the federal funding cannot be used to destroy embryos only for the benefit of mankind but it surrenders to the greater benefit of public health, such as the uses for incurable diseases. Without asking if their decision would jeopardize the hard work of those men and women who sacrifice their careers to pursue hESC research in order to unlock the Dickey-Wicker Amendment, the supreme court’s decision almost choked the entire NIH’s hESC research that just started to breath the precious air of freedom, threw the whole hESC research field into turmoil, triggered hESC research lab shutdowns, and caused a much bigger job threat spreading all over the country.

Not long after the Korean scandal in science, shocked by those science traitors, I came back from a keystone chromatin meeting to tell my admiration to Rudy Jaenisch for his scientific integrity to Evan Snyder, but confounded by Evan’s sneer expression that he knew those Harvards were actually the real persons behind that science paper, had absolutely no scientific integrity. A few years later a few weeks before Christmas in 2009, at ASCB (American Society for Cell Biology) meeting in San Diego, I attended Rudy Jaenisch keynote address to a very large audience again. NIH’s new Director Francis Collins flew to the meeting that morning to give an unscheduled speech right after Rudy Jaenisch. I could not believe my ear to hear that then ASCB president Duke University professor Brigid Hogan announced that no question was allowed. As a prestigious professor in DNA methylation and chromatin, Rudy Jaenisch was totally aware, more than anyone else, of the altered DNA methylation and genomic integrity in iPS cells, cloned cells, and trans-differentiated cells that made reprogrammed adult cells nothing close to stem cells or normal tissues, too dangerous and too greater of a risk to public health to be used as alternatives for embryonic stem cells. Failure to mention it to the big picture of general audience, as one of the most influential persons in sciences, he opted to select the facts in favor of his theory that has misled both the scientific field and the general public. His republican favored theory would soon prevail in the unfolding of a turmoil of events: democrats’ loss of Ted Kennedy’s seat to republicans right before that Christmas, lawsuit to federal funding on hESC research the following year, hESC research lab shutdowns over the country, the downfall of democrats in Congress before the next Christmas, the aftermath of government budget battles over a bipartisan Congress, and narrowly escaped government shutdowns right before this past Christmas.

At one UC connect event, a business-tier looked well-educated lawyer was asking me that “I heard that the potential of human embryonic stem cells is decreasing, there are stem cells in placenta, …”. I stopped gulfing down the refreshments to effort polite while wondered if this handsome block was from his mother’s placenta so got no brain of his own. Obviously, all those public education campaigns launched by CIRM have failed. Picking a spokesman for hESC research from CIRM’s long-list of awardees is like finding a tiny fish in the ocean, therefore, it is quite expectable that their public education might just have the opposite effect. I would not be too surprised to see a herd of placenta-born men burgeoning in front of me after all those brain-washing lectures and spotlights by their spokesmen.

Science is naked, accepting nothing less than a truth, and freedom is the soul. Without it, science cannot hold its integrity as a whole. Depriving of freedom has imprisoned stem cell research, ripping the integrity apart. In 2011, the status of human embryonic stem cell research was no better than the prisoner of war, the stem cell war. With the pending lawsuit on federal funding for hESC research crouching closely behind the political agenda of the election year, the future the stem cell research has never become so uncertain. However, no matter pro or con, the potential of human embryonic stem cells lies in the survival of human race and will never decrease. Only the advances of human embryonic stem cell research hold the key to unlock the Dickey-Wicker Amendment, the last legal obstacle to restrict the federal funding on human embryo research.

References: The Laws:
1. Proposition 71:
(c) Recommendations for Awards
Award recommendations shall be based upon a competitive evaluation as follows:
(1) Only the 15 scientist members of the Scientific and Medical Research Funding Working Group shall score grant and loan award applications for scientific merit. Such scoring shall be based on scientific merit in three separate classifications—research, therapy development, and clinical trials, on criteria including the following:
(A) A demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine, unless the research is determined to be a vital research opportunity.
(B) The quality of the research proposal, the potential for achieving significant research, or clinical results, the timetable for realizing such significant results, the importance of the research objectives, and the innovativeness of the proposed research.
(C) In order to ensure that institute funding does not duplicate or supplant existing funding, a high priority shall be placed on funding pluripotent stem cell and progenitor cell research that cannot, or is unlikely to, receive timely or sufficient federal funding, unencumbered by limitations that would impede the research. In this regard, other research categories funded by the National Institutes of Health shall not be funded by the institute.
(D) Notwithstanding subparagraph (C), other scientific and medical research and technologies and/or any stem cellresearch proposal not actually funded by the institute under subparagraph (C) may be funded by the institute if at least two-thirds of a quorum of the members of the Scientific and Medical Research Funding Working Group recommend to the ICOC that such a research proposal is a vital research opportunity.

2. Dickey-Wicker Amendment
SEC. 509. (a) None of the funds made available in this Act may be used for–
(1) the creation of a human embryo or embryos for research purposes; or
(2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under 45 CFR 46.204(b) and section 498(b) of the Public Health Service Act (42 U.S.C. 289g(b)).
(b) For purposes of this section, the term `human embryo or embryos’ includes any organism, not protected as a human subject under 45 CFR 46 as of the date of the enactment of this Act, that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells.

Stem Cell Meeting on the Mesa — The Hijacked Stem Cell Research

In 2008, a few months after Beijing Olympics, I was at Singapore for a keystone stem cell meeting. One speaker at the meeting jokingly opened his talk by saying that he was the only speaker invited to the meeting who was not an organizer, greeted by a loud laugh from the audience for the utter truth about today’s meetings. I was not completely out of guilt because my real motivation coming to the meeting was en route to mount city Chongqing to pay my over-due visit to my folks. Chongqing sits on the top of Yangzi River guarding the heavenly roads to China’s far west and the flourishing veins stretching through the rich plateau to Northeast. Yang Song, my brother-in-law I was hoping to see, was not at the Chongqing airport to pick me up, my very old folks were. Inside the taxi, my mom broke the grave news to me that Yong Song was found to have later stage brain tumor and about to have brain surgery, which made me immediately think about Ted Kennedy, who had brain tumor, and Evan Snyder, who was just granted a stem cell patent for brain tumor, before I realized the seriousness of the situation. My mom, an old-fashioned math professor who would not even accept computer science as a science, begun to recite to me some stem cell wonders she read from newspapers and wanted to know if the American scientists could do the magic. Yang Song had been my shuttle from the beginning. In the early days, he came to pick me up in his tiny three-wheel bug, rattled through the treacherous dirt road along Jiaoling river, almost rocked my stomach out and every time I swore I would never come back again. The last time I saw him, he was in a real four-wheel car, his own, drove me through the newly-paved wide freeway like we owned it. If it was not for those alien high-rise buildings up the cliff that looked scarily dangerous and the misty Jiaoling river deep-down the cliff that looked so familiarly lovingly, in a brief moment in my mind, I would have been able to overcome the distance between the two homes.

In the old days, scientific meeting is open for communications, questions, and discussions of most recent, important, and exciting advances of scientific research. Sadly, such purpose and openness are lost in today’s meetings. With the presence of editors from top scientific journals and representatives of funding agencies, invitation to speak at a meeting is like a golden ticket to front page publication and multi-million grants. Such privileges usually are reserved for the meeting organizers and a small group of their kin. Stem cell meeting on the mesa has been such close door privilege meetings in extreme. At one mesa meeting, not one stem cell was shown by any of the speakers, but $6M CIRM grant to the out-of-state speaker and a cluster of Nature publications soon afterwards made regular scientists hardly believe there was no connection. Although I wrote to Sanford consortium president to express our interest in collaboration & partnership, we did not receive any announcement about the meeting or invitation to their partners held by CIRM. I knew our abstract about human embryonic stem cell research would have a difficult time to get in since Jennifer Braswell, the sidekick of Larry Goldstein at UCSD, was in charge, but still surprised how quickly they responded to me that they were full, but not full for themselves of any posters. Did we hear such familiar responses too often? CIRM also used pre-application to turn down State’s human embryonic stem cell research & therapy for the patients they cared about by saying that they had too many not stem cell applications.

My family is very supportive, has been saving all the local newspaper clippings about stem cells so I would not miss any. I reluctantly took a look of the golden photo of Sanford consortium, noticed that there were a few impostor’s faces next to it. Larry Goldstein is famous for sending emails all over UCSD to blowup others’ faculty job, I could hardly believe he is OK of impostors of his kin now. Meeting was heavily about adult cell reprogramming and cloning, iPS cell keynote in the morning and cloning keynote in the afternoon, with speakers of meeting organizers and CIRM disease teams between. With 2 former mentors sitting in front of me and the table-banging mentor behind, I tried to ask the dumbest questions to keep myself safe this time. Geron would be the significant presence of human embryonic stem cell therapy partner at the meeting, but because of its surprising exit right before the meeting, the partner meeting held by CIRM vice president Ellen Feigal was heavily on adult cell, reprogramming, and gene therapy, and was purposely only for disease teams that already had a slot for CIRM funding. The swift impact of the meeting could soon be shown in the next ICOC meeting, where everyone, including NIH, had turned into Japanese, the iPS cells.
Although it remains questionable whether colaboratory will be collaborative and Sanford will be as its intent to house open stem cell research, Sanford consortium for regenerative medicine is sitting on the premier property of La Jolla, overlooking the magnificent sunset of Pacific Ocean and giving the unearthly impact of “Life is a Miracle.”

This piece is written in memory of Yang Song.

Human Embryonic Stem Cells for Heart Regeneration — The Vital Source for Cardiovascular Repair

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of ground-breaking technique on direct conversion of human embryonic stem cells into cardiac cells. Due to prevalence of heart disease worldwide and acute shortage of donor organs or human myocardial grafts, there is intense interest in developing human embryonic stem cell (hESC)-based therapy. However, 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 Cardiac Precursors and Cardiomyocytes from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction” funded by the National Institutes of Health, is the first to show that pluripotent human embryonic stem cells can be uniformly converted into a cardiac lineage by simple provision of small molecules. This technology breakthrough not only provides a large supply of clinical-grade human cardiac therapeutic products for myocardium regeneration and replacement therapy against heart disease and failure, 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 developed from human embryonic stem cell research was published in JoVE (http://www.jove.com ), the World’s first peer-reviewed scientific video Journal through open access link.

To date, lacking of a suitable human cardiac cell source has been the major setback in regenerating the damaged human myocardium, either by endogenous cells or by cell-based transplantation or cardiac tissue engineering. The heart is the first organ developed in early embryogenesis. In the adult heart, the mature contracting cardiac muscle cells (cardiomyocytes) are terminally differentiated and unable to regenerate. Damaged cardiomyocytes are replaced by non-functional cells or scar tissues that eventually lead to heart failure or heart attack. Endogenous stem cells or stem cells derived from other sources, such as mesenchymal stem cells, umbilical cord stem cells, and cord blood cells, cannot give rise to the beating heart muscle cells. Although cell populations expressing stem cell markers have been identified in the adult heart, 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. Recently, reprogrammed or trans-differentiated adult cells, which can be traced back to 80th, have been rekindled as alternatives. However, adult cell-reprogrammed or transdifferentiated cells have not only the same problems of adult cells, like accelerated aging, immune rejection, not graftable, but extremely low efficiencies (< 0.5%) and abnormality as well to be useful.

Pluripotent human embryonic stem cells proffer unique revenue to generate a large supply of cardiac cells as adequate human myocardial grafts for cell-based therapy. Human embryonic stem cells and their derivatives are considerably less immunogenic than adult cells & tissues. It is also possible to bank large numbers of human leukocyte antigen isotyped cell lines so as to improve the likelihood of a close match. However, conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, which is inefficient and uncontrollable. Only a very small fraction of pluripotent cells (< 2%) spontaneously generate cardiomyocytes. Our novel approach using small molecule direct induction of pluripotent cells offers the benefits in efficiency, stability, safety, and scale-up production over existing conventional approaches. Our ground breaking technique allows producing a large supply of human cardiac cells across the spectrum of developmental stages direct from human embryonic stem cells for cardiovascular repair. The availability of human cardiac cells in high purity and large quantity with adequate potential for myocardium regeneration will accelerate the development of effective cell-based therapy for heart disease and failure that affect millions of survivors and so far have no cure.

The Players of Regenerative Medicine — Neuron, the Star Quarterback

San Diego Regenerative Medicine Institute and Xcelthera announce 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” funded by the National Institutes of Health, 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 developed from human embryonic stem cell research was published in JoVE (http://www.jove.com ), the World’s first peer-reviewed scientific video Journal through open access link.

To date, lacking of a clinically-suitable neuronal cell source, of course, has to be from human, has been the major setback in developing cell-based therapies for restoring the damaged or lost nerve in a wide range of neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease, and spinal cord injury. Like our star quarterback, neurons are the key player of the central nervous system and hard to find the replacement. Despite of initial excitement of early 90th to discover that cells in our brain are still growing, we quickly learned that they could not grow into the damaged or lost neurons we need. Against ethics, restriction, immune-rejection, and all odds on using human fetal tissues, transplantation using tissue-derived human neural stem/progenitor cells became unavoidable if a cure was desired. After almost 20 years of battle, the controversy on using human fetal tissue for cell therapy has faded away. However, 20 years of studies have also outdated a field once fought so hard. It has become known that those tissue-derived cells can only regenerate a supporting team to slow down the disease, but not the neurons to provide a cure.
The derivation of human embryonic stem cells proffers cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types for repair. Therefore, they have been regarded as an ideal source to provide an unlimited supply of human neuronal cells for repair. However, conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, which is inefficient and uncontrollable. So far, the cell products generated from conventional multi-lineage differentiation of pluripotent cells remain supportive, but cannot regenerate the key functional player, neurons. It is understatement that our ground breaking study allows human embryonic stem cells fulfill the large need for a clinically-suitable human neuronal cell source for restoring the damaged or lost nerve tissue and function in today’s healthcare industry. The availability of human neuronal cells in high purity and large quantity with adequate neurogenic potential will accelerate the development of effective cell-based therapy against a wide range of neurological disorders, one step closer to a cure.

The Faces of Regenerative Medicine — The Shadow of Past Dynasties

World stem cell summit coming to Pasadena was both exciting and close to home. More importantly, it was close to home. The beautiful European or Greek style city hall of Pasadena gave everyone inside a compelling sense of being locked into the history undissolvable by any politics and financial crisis. Although it was hard to miss CIRM president Alan Trounson’s keyword “focus”, his keynote address was hitting everywhere but California stem cell research and cure act, or human embryonic stem cell research. Only later on, you would understand that those hits were very proportional to the distribution of his stem cell pie among California power houses that set the meeting agenda. It was no surprise that Ann Tsukamoto of StemCells, Inc would be the first to give ISSCR (International Society for Stem Cell Research) perspectives. Even her soft perfect English and the surrounding mystics of ancient history would not convince the audience that the reopen of a 14 year old Stem Cell clinical trial was because of a not so impressive long-term study, as she wished. Her quote, in 2 different languages, that “in wine, there was truth.” in the end was quickly followed by the shadow of human cloning that would soon return after the meeting. You would feel Arnold Kriegstein’s tense to come to spread the word of iPS cells (induced pluripotent stem cells) that signaled the relentless of human cloning coalition until he got to his own area of research. Larry Goldstein’s strong standing for human embryonic stem cell research on the stage would soon give away to the mixed faces of regenerative medicine coalition of no visible sign of human embryonic stem cell research printed in the program guide.

Sciences were negligible. Although the registration fee was high, abstracts were not printed, only speakers’ faces and staged interviews were. Obviously, my mentor Prue Talbot did not have the trouble I had for my posters since I put my other powerful mentor Evan Snyder as non-consenting mentor to describe our professional relationship in short (or out of laziness). I soon realized that I should spend more time on Evan Snyder because those 2 posters were declined that made Evan furious. Prue had 4 or 5 posters on display which I recognized some were hanging around her office for years, making me suspect that she probably was among those paid by CIRM. Astoundingly, speakers were allowed to make all kinds of claims without any scientific data basis. I remember when iPS cells were made, they were assumed to avoid immune-rejection since made from the same patient, but nobody bothered to do a test. Finally, my other mentor Yang Xu did a test with CIRM money and found out the assumption was not true. In the meeting, such assumptions were wide-spread. Xianmin Zeng from Buck Institute claimed she made DA neurons efficiently for patient trial, although no quantitative data, nor her images looked any way close to efficient. California Stem Cell showed 2 or 3 images and claimed that they had done all the preclinical study ready to go to trial. My questions of where were their data for their claims obviously annoyed Arlene Chiu of Beckman. Of course, there was no way to find out CIRM’s key clinical trial updates from the speakers.

Military speakers’ presence was encouraging and a relief that at least the honor system was still working in some part of the world. MG JK Gilman’s words “it’s not about stem cells, it’s about regeneration” hit to the hearts. Andy Grove’s speech was inspiring. Roman Reed and those patients in wheel chairs made me feel hopeless for the promise we could not keep. For years, I have been wondering how CIRM’s funding decision was made, why > 70% funding did not go to human embryonic stem cell research as promised? Don Reed was frank and most revealing. He said that they wanted to give money to UC Davis, but UC Davis did not have human embryonic stem cell research, so they gave the money to mesenchymal stem cells. Gil Van Bokkelen’s speech of coalition for regenerative medicine did not mention the only human cells that can regenerate, nor had any interest in alliance with the new face of regenerative medicine held by the promise of human embryonic stem cell research. His coalition is not about stem cell, nor regeneration, is about the California’s 3 billions stem cell pie, representing the shadow of past dynasties that could be found in the next stem cell pie meeting at www.stemcellmeetingonthemesa.com or UC connect.

Last night, the brightest shooting star was falling, the loss of a giant Steve Jobs reminds us the opportunity we are given to make the promise become reality. That opportunity was lost in years of anti-trust and anti-competition practices of CIRM, along lost, is the promise we could keep. 

Censored or Unchecked, Stem Cell Celebrity or Stem Cell Con-Man

As a research scientist from Ivy League, I have been regularly going to scientific meetings since I was a graduate student, some as part of my training and continuing education. But I have never felt so unwelcomed by stem cell meetings since I was drawn into the human embryonic stem cell filed. Research is the sanctuary I trusted with high standards and integrity I was taught. The Korean scandal in Science was a shocker, but I thought it was just some isolated incident at that time. So I was shocked when my poster of human embryonic stem cell research from my hard work at the lab was declined by ISSCR program chair last year when it was perfectly OK to be presented in other non-stem cell meetings. At 2010 ISSCR meeting in San Francisco, stem cell celebrity Larry Goldstein was chasing after Taxes stem cell con man in 60 minutes, ironically, the biggest international stem cell con man was giving a keynote speech in the same meeting. Scientists, we did not sign up for this.  

The Non-Consenting Scientific Community

Reprogramming adult cells in recent years was considered as “hot”, a word being used to describe fashion, not science. However, not consenting to its top Journal popularity, little was mentioned in the news is the < 0.01% low efficiency of reprogramming. The ESC field has been struggling for years with single digit efficiency, how did the 100 times worse efficiency become a big breakthrough of stem cell research?

There is CIRM in CA, seem plenty of funding for CA hESC researchers to go on, > 200 millions went to stem cell center construction in CA campus. What happens if the director of stem cell center is an opponent of hESC research, not consent to hESC research (just look at their CIRM grants actually on reprogramming/trans-differentiation/HIV/astrocyte, anything eligible, except hESC research eligible)? What happens if your mentor is an adult stem cell researcher, not consent to your research or publication in press? Every time passing the Salk glider port, the barely broken ground Sanford Consortium for Regenerative Medicine only reminds us that the consent we gave to Prop 71 to fund hESC research in CA 8 years ago is not consenting to the $ 40 millions of CIRM funding not available for stem cell research and termination of hESC research out of conflicts. For scientists, the embryonic and adult stem cell war has become more of a reality than we could consent.

Human Embryonic Stem Cell Research

Last month, U.S. District Judge Royce Lamberth finally came to his conscience to dismiss the lawsuit brought by 2 U.S. adult stem cell researchers against federal Funding for human embryonic stem cell research, ending a year of hiatus. However, a ruthless war is still waged against human embryonic stem cell research by opponents of human embryonic stem cell research through legal, political, media, social, moral, and scientific grounds of all forms. 50 years after civil rights movement, those so-called stem cell stars started to talk about ethnicity of our skin in Salk Auditorium without thinnest shame, while shut the door to human embryonic stem cell research. 7 years after California voters passed Prop71 to fund human embryonic stem cell research in California, 2 years after President Obama relaxed Federal policy on human embryonic stem cell research, the world largest international society for stem cell research (ISSCR) still takes their non-consenting position by coding “human embryonic stem cell research” as “all forms of stem cell research”, erasing the human identity from embryonic stem cell research, making human embryonic stem cell research invisible, and giving their stem cell awards and spotlights to induced pluripotent adult cells. Opponents of human embryonic stem cell research turn main medial channels and top scientific journals into their political puppet dogs to try to make the public believe their baseless claims, such as that stem cells can come out of our skin with chemicals, so much so to the extent that a person can come out of our skin with chemicals, in the name of science. They overlook > 50 years of cancer studies that are for fighting the cancers, not for losing the war by making additional ones, then selling them as stem cells. Such identity thefts are even sold to the class rooms of universities and podiums of major scientific conferences. Opponents of human embryonic stem cell research are afraid that our human race would not become extinct fast enough, not only degraded the human identity to the lowest creature, but made the most dangerous type of abnormal cells – induced pluripotent stem cells to sell to the public as stem cells. It is at the crossroad that the real star must have a voice of its own, a spotlight of its own form.

Stem cell research is not an excuse for universities to get more money to build more faculty clubs just for show, not golden accessory or tenure pass of college professors just for the star power of stem cells. Stem cell is a functional term that no other cells can possess, no other cells can perform, no names can give, and no names can take away. It is time let the star, the human embryonic stem cell, say to the community world — If you are my opponent, say my name, and label yourself, either as induced pluripotent stem cell, adult stem cell, umbilical cord stem cell, transdifferentiated cell, cancer stem cell, artificially reprogrammed cell, cancer cell, fly stem cell, mouse stem cell, or any stem cell names you can think of; and If you are my supporter, say my name, say it loud, and say “have I ever met my equal, my match yet?”

Today, we open the forum on human embryonic stem cell research, a topic so critical, so urgent, so public, so personal, and so controversial that has to have the government and the elite of our society oversee. This forum is to give a voice of free speech, to provide a balanced view, to increase the visibility of human embryonic stem cell research, to weed out false information, to identify caveat, to avoid hiatus, and to facilitate progress. So if our future hangs on stem cell research, this is the place you speak for your future.

Hyper-Gee — the Fusion

Energy fusion is considered as the future. Biological energy fusion makes hyper-gee move like a spin-wheel at an unbelievable speed usually not seen in their own species. Watch the videos at YouTube http://www.youtube.com/watch?v=sgg_yu8Rmuc and http://www.youtube.com/watch?v=B70kf9cCAJc .

Patentability of Human Embryonic Stem Cell Research

Patents on Technologies of Human Tissue and Organ Regeneration from Embryo Sources: the Intervened Sciences on a Public Ground.

The successful derivation of human embryonic stem cell (hESC) lines from the in vitro fertilization (IVF) leftover embryos little over a decade ago is considered as one of the major breakthroughs of the 20th century life sciences. The hESCs, derived from the inner cell mass (ICM) or epiblast of human blastocyst, are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of human disease-targeted human somatic cells that are restricted to the lineage in need of repair. Therefore, they have been regarded as an ideal source to provide an unlimited supply of large-scale well-characterized human specialized cell types for cell-based therapies to resolve some worldwide major health problems, such as neurodegenerative diseases, paralysis, diabetes, and heart diseases. Most recently, the IVF pioneer Robert Edwards was awarded last year’s Nobel Prize in physiology or medicine. The Noble prize recognition to the IVF techniques comes to light that a small portion of the millions of excess embryos currently stored in the IVF clinics worldwide, which are otherwise destined for destruction, could potentially be an unlimited source to deliver in the future a whole range of therapeutic treatments for tissue and function restoration in patients with life-threatening diseases and injuries.

US patents directed to human stem cell technologies have generated intense interest as well as controversy. Many patents relating to stem cell technology have faced reexamination, litigation, or both. The US Patent and Trademark Office (USPTO) recently upheld three Wisconsin Alumni Research Foundation (WARF) stem cell patents on the breadth, anticipation, and obviousness of the claims after reexamination requested by a third-party challenger in 2006. These WARF patents involve claims on hESCs as well as certain processes used to make such cells as divisional applications originated from primate embryonic stem cell patents. These WARF patents with extremely broad claims have casted a shadow over the commercialization of these cells as therapeutics in the US’ biotechnology market so far. While the controversies related to hESC patents in the US center on scientific and economic issues, in Europe, the patentability of hESCs has been met with fierce moral opposition. The European Patent Office (EPO) has refused to grant hESC patents based on its interpretation of the “European Directive on the Legal Protection of Biotechnological Inventions”, which holds unpatentable inventions concerning products of human stem cell cultures that can only be obtained by the use, involving their destruction, of human embryos. The EPO regards patents on hESCs as illegal because they are patents on a human body or human body part, offend human dignity, or involve commercial or industrial uses of embryos. However, in spite of controversy surrounding the ownership of hESCs, the number of patent applications related to hESCs is growing rapidly in the last 5 years. It will be of importance to fulfilling the therapeutic promise of hESCs that the hESC patents are placed in the context of the biotechnology and health industry and granted on inventions downstream in the value chain of regenerative medicine. To date, the USPTO has granted 92 hESC-related patents on the process for isolating, culturing, purifying, manipulating, or differentiating hESCs.

The hESC, derived from the inner cell mass or epiblast of the blastocyst, offers both a model system for human development and a potentially unlimited source of graft material for cell-based therapies. The pluripotence of hESCs implies such cells’ tremendous potential for tissue and function restoration, whereas it has vacated a practical approach to generate a large supply of uniform replacement cells from hESCs for treating diseases. How to channel the wide differentiation potential of human pluripotent cells efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation of their therapeutic potential. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ-layer differentiation, which yields mixed populations of cell types that may reside in three embryonic germ layers and often makes desired differentiation not only inefficient, but uncontrollable and unreliable as well. Following transplantation, these hESC-derived grafts tend to display not only a low efficiency in generating the desired cell types necessary for reconstruction of the damaged structure, but also phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. In view of growing interest in the use of human pluripotent cells, teratoma formation and the emergence of inappropriate cell types have become a constant concern following transplantation. Developing more practical approaches that permit to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype is vital to harnessing the power of hESC biology for safe and effective clinical translation.

Standard stem cell differentiation protocols involve cultivation in 2-dimensional (2D) settings, whereas in vivo organogenesis requires a 3D setting to provide the spatial and temporal controls of cell differentiation necessary for the formation of functional tissues. The traditional methods of 2D culture presently employed in the field often result in unpredictable stem cell function and behavior in vivo following transplantation. Developing strategies of complex 3D models of human embryogenesis and organogenesis will provide a powerful tool that enables more rigorous experimentation under conditions that are tightly regulated and authentically representing the in vivo spatial and temporal patterns. It will go beyond “flat biology” to increase the biological complexity of human-based in vitro models and assays to mimic the in vivo human organ systems and functions. Although ethical debate about the patentability of hESCs and policy makers on Funding issues are still lagging behind the scientific developments, in the case of many life-threatening diseases, supporting such research is crucial to driving the advance of medicine to provide optimal regeneration and reconstruction treatment options for the damaged or lost functional tissues and organs that have been lacking. For more information about this topic, please visit Dr. Parsons’ most recent review article “Patents on Technologies of Human Tissue and Organ Regeneration from Pluripotent Human Embryonic Stem Cells” via the open access link at http://www.benthamscience.com/rpgm/openaccessplus.htm.

iPC Cells or Man-Made Junk

Are induced pluripotent adult cells (iPS cells) real stem cells or man-made junk/abnormal cells? iPS cells express embryonic tumor markers and form teratomas, published in Cell, Nature, Science, or Cell Stem Cell would not make iPS cells any more stem cell like, only seems make the editors of those top Journals not stem cell-like or no brain.

In 2007, a paper by a molecular biologist, Shinya Yamanaka, in Japan appeared in Cell claimed that they had made embryonic stem cells from adult cells by simply putting 4 genes in skin cells, which they called induced pluripotent stem cells (iPS cells). If Shinya Yamanaka had been to College, he should know that the appearance of embryonic factors, genes, or phenotypes in adult cells is text book definition of abnormity or phenotype for cancers. If anyone has the time to read the paper for some details of Yamanaka’s claim, you would find Yamanaka did just that, he put 4 proliferative embryonic genes into adult cells using molecular biology methods that have been established for decades and simply showed his cell products expressed embryonic tumor/cancer markers and formed teratomas, phenotypes for tumors or cancers. His entire paper in Cell has no data or characterization showing his cell product has any stem cell phenotype, except the iPS name has something to do with stem cells.

Since Cell is recognized as peer-reviewed top Journal, the iPS cells went unchecked all over the world, hailed as the biggest breakthrough of stem cell research, won numerous awards and brought millions of Funding (taken away from embryonic stem cell research) for Yamanaka, and even worse, used by the opponents of human embryonic stem cell (hESC) research. Yamanaka quickly rose to become the vice president of International Society for Stem Cell Research (ISSCR), and even had a committee to campaign for Nobel Prize for him. In 2010, the ISSCR meeting in San Francisco hailed iPS cells as the future of stem cells, and ensured Yamanaka’s glory by censoring scientific presentations of hESCs. Afterwards, ISSCR quickly downgraded “supporting human embryonic stem cell research” to “supporting all forms of stem cell research”, even deleted the title of human from embryonic stem cell research. Imagine all the ISSCR committee members cover their eyes and say “we are not humans”. However, my friends, I am sure any human can tell the difference between a human and an ISSCR committee member, unless they elect a rat for president.