Category Archives: California Stem Cells

An interactive stem cell lesson introducing key concepts in stem cell science to young students. The lesson is intended to be flexible and is made up of a set of short modules, mixing group activities with presentation and facilitator-led discussion.

classroom arranged for group work

2 facilitators: scientists, science communicators or teachers

Assumes students know the body is made up of cells, and that blood contains red and white blood cells.

From my point of view the experience was positive because, in addition to the discussion of the issue relating to stem cells, the aspect of cellular differentiation (a topic that is being discussed in higher classes) was also conveyed and, above all, the construction of this knowledge has come about through a process that makes students active subjects in the process of learning.

Teacher, Italy

Discover stem cells is an easy-to-use lesson packed with games and group activities to engage young students with fundamental ideas in stem cell science. A PowerPoint presentation provides the core structure for the session, but the session is broken up into small modules with regular opportunities for students to explore concepts for themselves. This lesson includes the popular card game, Cell Families.

By the end of the session, students will:

Download the PowerPoint slides and the pdf file called 'Lesson plan and print resources'. You then have everything you need for the lesson and its activites. The lesson plan gives a handy overview of the session and includes a checklist of the materials contained in the pdf that you need to print in advance. For detailed step-by-step guidance on delivering all aspects ofDiscover stem cells, see the facilitators notes in the PowerPoint presentation.

You can now order a print pack of Cell Families cards to use either as part of this lesson or as a stand-alone quick activity. Up to four players compete to collect families of cells, made up of one stem cell and three specialised cells it can produce. A great way to introduce tissue and embyronic stem cells, their roles and properties.

Orderyour pack for just 5 or a class set for 20 on the University of Edinburgh website

Lesson Plan and Print Resources1.88 MB Powerpoint Slides with Facilitator Notes5.82 MB Editable Stem Cells Decision Sheet - Students1.21 MB Editable Takeaway Sheet360.5 KB Stem Cell Family Cards3.9 MB

Acknowledgements

Discover stem cells was created and developed by Ian Chambers and Emma Kemp, MRC Centre for Regenerative Medicine, University of Edinburgh. Important contributions, advice and opportunities to pilot the activities were provided by many colleagues, teachers and students and are detailed within the lesson plan. Particular thanks to Shona Reid of the James Young High School, Livingston, Scotland.Image credits are included within the resources where the images appear.

Permissions:This work is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported License. To view a copy of this license, visithttp://creativecommons.org/licenses/by-sa/3.0/or send a letter to Creative Commons, 171 Second Street, Suite 300, San Francisco, California, 94105, USA

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Discover Stem Cells | Eurostemcell

Landscape with the Fall of Icarus, attributed to Pieter Brueghel the Elder

What happened to the disgraced Italian surgeon who dazzled the world with artificial tracheas built up with stem cells, Paolo Macchiarini? Despite all the hype, several of his patients eventually died; others are still seriously ill. The ensuing debacle dragged Swedens Karolinska Institute into the mire and Swedish police are investigating whether he should be charged with involuntary manslaughter.

At the moment Macchiarini is the head of a research team in bioengineering and regenerative medicine at the University of Kazan, in Tatarstan, about 800 kilometers east of Moscow. But Russian authorities do not allow him to do clinical work. Instead he is confined to doing research on baboons.

Unfortunately, the story of the Italian Icarus is the story of many research projects with stem cells noisily rising and rising and rising and then silently falling out of sight. Very few stem cell therapies have reached stage IV of clinical trials.

As journalist Michael Brooks points out in the BMJ, stem cell research is a field plagued by unrealistic expectations. One study showed that 70% of newspaper articles about stem cell research have stated that clinical applications are just around the corner, in the near future, or within 5 to 10 years or sooner.

This is not simply a problem of media hype, writes Brooks. In a surprisingly large number of cases, the source of these unrealistic expectations can be traced back to the scientists themselves.

Another source of false hope is the very success of some treatments. In clinics all over the world, doctors are using unproven techniques to treat patients and sometime they appear to work. But despite grandiose claims, these successes are not documented properly and could even be spontaneous remissions. There need to be rigorous clinical trials.

A major figure in the growth of the stem cell field, Alan Trounson of the Hudson Institute in Victoria, Australia, who used to head the California Institute for Regenerative Medicine, told Brooks that Fame and fortune is seductive and stem cells is one of those areas which can provide this. Close supervision is needed to keep researchers on the straight and narrow.

Finally, one cause of the stem cell hype is simply pride. The Karolinska succumbed to this temptation. According to its internal investigation, protecting its reputation led to a risk of inadequacies and shortcomings not coming to light.

Perhaps, says Brooks, The Macchiarini affair might have a silver lining for stem cell research as a whole. He quotes a man who should know, Alan Trounson: I believe the field will move on with a little more carewe certainly need to.

See the article here:
Stem cell Icarus - BioEdge

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [2]

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) [3] of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease.[4]

iPSCs are typically derived by introducing products of specific set of pluripotency-associated genes, or reprogramming factors, into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, cMyc, and Klf4. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.

iPSC derivation is typically a slow and inefficient process, taking 12 weeks for mouse cells and 34 weeks for human cells, with efficiencies around 0.01%0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan, in 2006.[1] They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

Similar to ESCs, these iPSCs had unlimited self-renewal and were pluripotent, contributing to lineages from all three germ layers in the context of embryoid bodies, teratomas, and fetal chimeras. However, the molecular makeup of these cells, including gene expression and epigenetic marks, was somewhere between that of a fibroblast and an ESC, and the cells failed to produce viable chimeras when injected into developing embryos.

In June 2007, three separate research groups, including that of Yamanaka's, a Harvard/University of California, Los Angeles collaboration, and a group at MIT, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells.

These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs.[5][6][7][8]

Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, OCT4, SOX2, KLF4, and C-MYC, using a retroviral system,[9] while Thomson and colleagues used a different set of factors, OCT4, SOX2, NANOG, and LIN28, using a lentiviral system.[10]

Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible.[11][12] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck.[13][14] In 2010, iPSCs were derived from peripheral blood cells,[15][16] and in 2012, iPSCs were made from renal epithelial cells in the urine.[17]

Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[11][12] time it takes to expand the population of starting cells,[11] and the ability to differentiate into a given cell type.[18]

[citation needed]

The generation of iPS cells is crucially dependent on the transcription factors used for the induction.

Oct-3/4 and certain products of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table at right summarizes the key strategies and techniques used to develop iPS cells over the past half-decade. Rows of similar colors represents studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small compounds that can mimic the effects of transcription factors. These molecule compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanakas traditional transcription factor method).[32] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[33] Deng et al. of Beijing University reported on July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[34][35]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the MET (mesenchymal-epithelial transition) process in which fibroblasts are pushed to a stem-cell like state, Dings group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, Thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks. [36][37]

In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[38] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

Another key strategy for avoiding problems such as tumor genesis and low throughput has been to use alternate forms of vectors: adenovirus, plasmids, and naked DNA and/or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[39] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[40] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[41] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the PiggyBac Transposon System. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis. [42]

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[43]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[44] On 4 June 2014, the lead author, Obokata agreed to retract both the papers [45] after she was found to have committed research misconduct as concluded in an investigation by RIKEN on 1 April 2014.[46]

MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential.[47] Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed.[47] ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc.[48]microRNAs can also block expression of repressors of Yamanakas four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.[47]

Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.[49]

Gene expression and genome-wide H3K4me3 and H3K27me3 were found to be extremely similar between ES and iPS cells.[50][citation needed] The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in the following respects, thus confirming the identity, authenticity, and pluripotency of iPSCs to naturally isolated pluripotent stem cells:

Recent achievements and future tasks for safe iPSC-based cell therapy are collected in the review of Okano et al.[62]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells.[63] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound[64]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[65][66] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease.[67] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of disease. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[68] Furthermore, combining hiPSC technology and genetically-encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening.[69]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human liver buds (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the liver quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[70][71] Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.[72]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[73][74]

Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.[75]

Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.[76]

The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 in Kobe. However the trial was suspended after Japan's new regenerative medicine laws came into effect last November.[77] iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration were to be reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into the affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring would last one to three years.[78][79] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and it eliminates the need to use embryonic stem cells.[79]

More here:
Induced pluripotent stem cell - Wikipedia

ome of the most exciting biomedical research of the 21st century isn't getting done. Research on stem cells from human embryos has become so entangled in politics and public misunderstanding that researchers are worried about serious delays in understanding life-threatening diseases.

Particularly in the United States, research involving human embryonic stem cells has slowed because of philosophical qualms, political opposition and confusion about the science. What's more, the field now seems treacherous for scientists, largely due to legislative uncertainties and restrictions on research from the White House.

"There are a lot of experiments that are obvious and would be extremely valuable for scientists to do," says Keith Yamamoto, vice dean for research at the University of California, San Francisco School of Medicine. "But it's too much work to put together a research proposal only to find out it's going to be made illegalor that there will be a four-year moratorium proposed."

President Bush declared in 2001 that scientists who receive federal research fundsby far the majoritycould work only with a handful of stem cell lines (those that were in existence before August 9, 2001). The White House said that more than 60 usable embryonic stem cell lines were available. But in reality the number is closer to nine.

To compound the problem, Congress has threatened to make it illegal to use cloning to create new stem cell lines for biomedical research. The possibility that Congress will outlaw the use of cloning technology to derive new cell lines is scaring researchers away, according to Yamamoto and other scientists.

Prospects seem dim that the controversiesand the uncertaintieswill be resolved anytime soon. However, one "research friendly" bill has been introduced in the Senate and has attracted support from an odd but important coalition of influential people. One of them is Nancy Reagan, whose husband, the former President, is in a late stage of Alzheimer's disease.

"I am determined to do what I can to save other families from this pain," she said in a letter, arguing in favor of stem-cell research with appropriate safeguards.

The opening days of the new Congress saw a virtual rerun of last year's fights. Over just the past few weeks:

-President Bush in his State of the Union address urged Congress to prohibit "all" human cloning "because no human life should be started or ended as the object of an experiment."

-Legislation was introduced in both House and Senate to ban the use of "somatic cell nuclear transfer"the cloning technique by which Dolly the sheep was producedto create a living human organism "at any stage of development." Within a few days of its introduction, the House bill had attracted more than 100 co-sponsors.

-A competing bill that would prohibit human reproductive cloning but would permit nuclear transfer to create embryonic stem cell lines for research was introduced in the Senate.

This latter, pro-research measure is cosponsored by an ideologically broad coalition, ranging from Diane Feinstein (D-CA) and Ted Kennedy (D-MA) to Zell Miller (D-GA) and Orrin Hatch (R-UT), whose right-to-life credentials are unassailable.

Essentially the same alignment of forces in the previous Congress produced a stalemate. The House passed a broad anti-cloning bill by a 265-162 vote in July 2001, but neither the broad prohibition nor a pro-research version came to a vote in the Senate because neither side could muster the 60 votes needed to shut down a Senate filibuster.

The most likely outcome now seems to be a continuing standoff unless members of Congress can learn the difference between using stem cells for research and using them for human reproduction.

Even if the Senate passed a pro-research bill, the House would be unlikely to agree. And even if such a bill made it through Congress, President Bush would likely veto it. The question of using somatic cell nuclear transfer to derive human embryonic stem cells involves an uncomfortable mix of science (including cell cloning), ethics and theology. It has not yet resulted in any useful compromise.

One of the stumbling blocks is a broad, deep lack of understanding of what the word "cloning" means. The word is widely used in our society and has been given a number of meanings, most of them wrong.

To scientists, cloning means making a copy of somethinganything, a stretch of DNA, a virus, a cell. To most laypeople, including many members of Congress, cloning means creating a carbon-copy organism, like Dolly the sheep or the army of clones in a recent "Star Wars" movie. It means making an exact copy of a living adult and the imagination often focuses on evil ones at that.

"We have to do a better job of educating the public that the word 'clone' is not synonymous with movies such as 'The Boys from Brazil' or 'The March of the Clones' or whatever else Hollywood has manufactured," says Nobel Laureate Paul Berg of Stanford University in California.

Opponents, such as President Bush and Leon Kass, chairman of the President's Council on Bioethics, believe that any use of somatic cell transfer could result in a human embryo, and thus a human life. "We find it disquieting, even somewhat ignoble, to treat what are in fact the seeds of the next generation as mere raw material for satisfying the needs of our own," a majority of Kass's council reported last July.

But proponents of this somatic cell technology deny that the technique produces the seeds of any generation. "I'm in favor of cloning nuclei in the form of stem cells," says Berg. "The product of that is not a human being." Some scientists and ethicists go so far as to argue that it is actually unethical not to do research that shows unusual promise for treating or preventing devastating disease.

Senator Hatch, whose influence as a conservative leader makes him an important player in the debate, argues that human life begins in the womb, not in a petri dish.

"Even those who believe that life begins at conception, even if the unison of sperm and egg takes place in the lab, need to consider carefully whether the joinder of an enucleated egg with a somatic cell nucleus, accompanied by chemical or electrical stimulation, should fairly be thought of as the same process as conception," Hatch told a Senate hearing in January.

Last July, Kass's bioethics council recommended a four-year moratorium on all research with somatic cell transfer if the intent is to produce human embryonic stem cells. Seven of the scientists on the Kass council voted against a moratorium; all of the ethicists voted in favor, as did one physician-scientist. Meanwhile, two separate committees of the National Academy of Sciences endorsed the research on grounds of its value to medicine.

Several states with ambitions to attract the biotechnology industry, including California and New Jersey, have tried to pass legislation of their own that would prohibit the use of cloning to make babies but would allow somatic cell nuclear transfer for scientific research.

In addition, some major research institutions, including Stanford and UCSF, have established satellite research centers that receive no federal funds to pursue such research. An outright federal prohibition would override these efforts.

A federal prohibition of all research to use this technology to create human embryonic stem cells also could erode one of the major potential benefits of stem cell science: the growth of replacement tissue such as cardiac muscle to repair heart damage, insulin-producing beta cells to cure type 1 diabetes, or dopamine-producing neurons to treat Parkinson's disease.

Theoretically, if a patient is his or her own donor of the somatic cell from which the embryonic stem cells would be grown, implanting the replacement tissue would raise no immunologic problems. This, clearly, has nothing to do with human reproduction.

The congressional standoff leaves would-be stem cell researchers with limited options. They can try to develop procedures with private industry or state fundingalthough that may eventually be prohibited. Or they can work with human embryonic stem cell lines derived from embryos originally created for in vitro fertilization (IVF) procedures.

This is where the president's moratorium of 2001 becomes an issue. A repertoire of nine cell lines with which to work is far different than 60 available cell lines. And because data suggest that none of those lines may be the best for use in medical experimentation, the need to develop new lines is imperative.

This amounts to a double whammy against stem cell research.

"At the present time, I don't think we have enough documented, usable cell lines to entice people into this field," says Berg.

James Battey, director of the National Institute on Deafness and Other Communication Disorders, who heads the National Institutes of Health's Stem Cell Task Force, contends that the restraints leave plenty of room for researchers.

"There's an enormous amount of basic research that can be done and needs to be done before anybody anticipates any clinical trials," Battey says.

Among the basic-research questions: How do you drive human embryonic stem cells to differentiate in a particular wayto be heart muscle or to produce dopamine in the brain, for instance? How do you then generate a pure population of the desired target cells? How do you assure that the cells will be long-lived? How do you prove, in animal models of disease, that they are effective therapies?

"All of these studies can be done right now, with human embryonic stem cell lines that you can order today on the NIH registry," Battey says.

Battey also challenges the contention that researchers are being scared away. At a meeting in London in January, however, he and research-funding officials from seven other nations agreed that a shortage of scientists trained to work with stem cells is a major problem. "That is probably the rate-limiting factor right now in moving the research agenda forwards," Battey says.

And political uncertainty is one of the reasons for the shortage. "These are careers," says Kevin Wilson, director of public policy for the American Society for Cell Biology, and vice president for legislative affairs of the Coalition for the Advancement of Medical Research. "Is a scientist going to get involved in a career field that could become against the law?"

As Wilson notes: "It's not a warm and fuzzy environment."

Read more:
The Politics of Stem Cells - Genome News Network

Proposition 71 of 2004 (or the California Stem Cell Research and Cures Act) is a law enacted by California voters to support stem cell research in the state. It was proposed by means of the initiative process and approved in the 2004 state elections on November 2. The Act amended both the Constitution of California and the Health and Safety Code.

The Act makes conducting stem cell research a state constitutional right. It authorizes the sale of general obligation bonds to allocate three billion dollars over a period of ten years to stem cell research and research facilities. Although the funds could be used to finance all kinds of stem cell research, it gives priority to human embryonic stem cell research.

Proposition 71 created the California Institute for Regenerative Medicine (CIRM), which is in charge of making "grants and loans for stem cell research, for research facilities, and for other vital research opportunities to realize therapies" as well as establishing "the appropriate regulatory standards of oversight bodies for research and facilities development".[1] The Act also establishes a governing body called the Independent Citizens Oversight Committee (ICOC) to oversee CIRM.

Proposition 71 is unique in at least three ways. Firstly, it uses general obligation bonds, which are usually used to finance brick-and-mortar projects such as bridges or hospitals, to fund scientific research. Secondly, by funding scientific research on such a large scale, California is taking on a role that is typically fulfilled by the U.S. federal government. Thirdly, Proposition 71 establishes the state constitutional right to conduct stem cell research. The initiative also represents a unique instance where the public directly decided to fund scientific research.

Proposition 71 states that "This measure shall be known as the California Stem Cell Research and Cures Act. That is therefore the official citation. However the measure is also headed as the California Stem Cell Research and Cures Initiative.[2] The Act is long and complex. It amends the state constitution by adding "Article 35 Medical Research". This article establishes the CIRM and guarantees a right to conduct stem cell research. Proposition 71 also amends the Health and Safety Code, by introducing a provision in Part 5 of Division 106 called "Chapter 3 California Stem Cell Research and Cures Bond Act". This chapter, among other provisions, establishes the ICOC.

CIRM may have up to 50 employees, who are exempt from civil service. CIRM is divided in three working groups.

Human embryonic stem cell research became a public issue in 1998 when two teams of scientists developed "methods for culturing cell lines derived, respectively, from: (1) cells taken from the inner cell mass of early embryos, and (2) the gonadal ridges of aborted fetuses".[3] Since then, this type of research has sparked intense controversy in the United States.

Ever since 1996, Congress has attached to the Health and Human Services appropriations bill (which regulates the funding for the National Institutes of Health) a provision known as the "Dickey Amendment". This amendment, named after the former representative Jay Dickey, Republican from Arkansas, prohibits the use of federal monies to fund "research that destroys or seriously endangers human embryos, or creates them for research purposes".[4]

In 1999, however, the General Counsel of the Department of Health and Human Services issued a legal opinion arguing, "that the wording of the law might permit an interpretation under which human embryonic stem cell research could be funded".[5] This interpretation stipulated that the government could fund this research so long as the embryos used had been destroyed by researchers privately paid. Although the Clinton administration adopted this interpretation and wrote the corresponding guidelines, it did not have the time to enforce them. The issue would pass on to the next administration.

On August 9, 2001, President George W. Bush announced his administration's policy regarding human embryonic stem cell research. The President opted to fund only research on the existing 60 cell lines. The large number of cell lines quoted by the President surprised many scientists. Furthermore, they were concerned about the availability and quality of these lines. Scientists also worried about the impact the presidents policy could have on the American research community. The United States, they argued, lags behind other countries where governments support stem cell research. This, in turn, could cause American scientists to move to these countries.

Proposition 71 represents a response to the federal policy. The idea for this proposition came about after the California legislature blocked a billion-dollar measure to fund stem cell research. Robert N. Klein II, a real-estate developer from Palo Alto, whose son suffers from diabetes and whose mother has Alzheimer's, became the leader of the campaign effort to pass Proposition 71, and spent three million dollars of his own money in the campaign.

The Coalition for Stem Cell Research and Cures comprised a broad group of people and organizations that included: 22 Nobel laureates; celebrities such as Christopher Reeve, Sharyn Rossi, Monica Siegenthaler, Brad Pitt, Saba Motakef, and Michael J. Fox; a number of elected officials such as State Treasurer Phil Angelides, and State Controller Steve Westly, and State Senator Deborah Ortiz; more than fifty patient and disease advocacy groups (e.g., Juvenile Diabetes Research Foundation, Alzheimer's Association California Council, Sickle Cell Disease Foundation of California), medical groups and hospitals (e.g., California Medical Association, Children's Hospital-Los Angeles), groups representing Latinos and African Americans (e.g. National Coalition of Hispanic Organization, California NAACP), women's advocacy groups (e.g., Planned Parenthood, California NOW) and religious organizations (e.g. Catholics for a Free Choice).

The Republican Party opposed this initiative, but two key Republican figures endorsed it. They were George P. Shultz, the U.S. Secretary of State in the Reagan Administration and California Governor Arnold Schwarzenegger. Although Schwarzenegger did not endorse it until October 18, 2004, his support may have helped to solidify the proposition's lead in the polls.

This campaign raised approximately $25 million. The contributors included such prominent figures as Bill Gates, who donated $400,000; Pierre M. and Pamela Omidyar, the founders of eBay who together gave $1 million; Gordon Gund, the owner of the Cleveland Cavaliers basketball team, who contributed $1 million; Herbert M. Sandler, chairman of the board of World Savings Bank, who gave $500,000; John Doerr, a Silicon Valley venture capitalist, who donated $2 million; and William Bowes Jr., a founder of Amgen (a biotech company), who gave $600,000.

Those who opposed Proposition 71 included the Roman Catholic Church, Orange County Republicans, and the California Pro-Life Council, an affiliate of the National Right to Life Committee. Among the politicians in this group were State Senator Tom McClintock (R-Thousand Oaks) and Orange County Treasurer-Tax Collector John Moorlach. The Hollywood actor Mel Gibson also joined the efforts to defeat this initiative. Conservative groups, however, were not the only ones opposing Prop. 71; organizations such as the California Nurses Association (CNA), the Green Party, the Center for Genetics and Society, Our Bodies Ourselves, among others, were also against the initiative.

Two prominent groups campaigning to defeat the initiative were the Pro-Choice Alliance Against Proposition 71 and Doctors, Patients, and Taxpayers for Fiscal Responsibility. These two groups lacked the wide range of endorsements that the proponents had (however, the Pro-Choice Alliance Against Proposition 71 was endorsed by seven organizations and a number of university professors). On the Doctors, Patients, and Taxpayers for Fiscal Responsibility website (which no longer exists) there were only fourteen members listed. Among these members were Dr. Vincent Fortanasce, a physician; Diane Beeson, a medical sociologists; Carol Hogan, a spokesperson for the California Catholic Bishops; and Dr. H Rex Greene, an oncologist and hospital administrator.

The four organizations campaigning against the initiative raised almost $400,000. The main contributors were the United States Conference of Catholic Bishops, which donated $50,000 and Howard Ahmanson Jr., founder and president of Fieldstead & Company, who gave $95,000.

Sociologist Ruha Benjamin offers the first in-depth analysis of Proposition 71 in People's Science: Bodies and Rights on the Stem Cell Frontier (Stanford University Press 2013). Too frequently the debate over stem cell research devolves in to simple judgmentsgood or bad, life-saving medicine or bioethical nightmare, symbol of human ingenuity or our fall from graceignoring the people affected. Benjamin moves the terms of debate to focus on the shifting relationship between science and society, on the people who benefitor don'tfrom Proposition 71 and what this says about democratic commitments to an equitable society. Benjamin discusses issues of race, disability, gender, and socio-economic class that serve to define certain groups as more or less deserving in their political aims and biomedical hopes.

Link:
California Proposition 71 (2004) - Wikipedia, the free ...

Welcome

Welcome to USC Stem Cell, a university-wide initiative connecting researchers and highlighting the latest news in regenerative medicine across USC.

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September 8, 2016

By Cristy Lytal

Without collaboration between universities and pharmaceutical companies, scientists might never have developed essential medicines ranging from the antibiotic streptomycin in the 1950s to HIV medications in the 1990s. In recognition of the ever increasing importance of these academia-industry partnerships, USC and Amgen are jointly offering two new opportunities: a 10-week biotechnology lecture series for students and postdoctoral researchers, and a monthly seminar series open to all.

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September 7, 2016

By Meg Alrich

Keck Medical Center of USC today announced that a team of doctors became the first in California to inject an experimental treatment made from stem cells, AST-OPC1, into the damaged cervical spine of a recently paralyzed 21-year-old man as part of a multi-center clinical trial.

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September 1, 2016

Francesca Mariani: In a recent study in the journal Cell, Kyle Loh and colleagues in Irving Weissmans group established a rapid protocol for converting human pluripotent stem cells into mesodermthe progenitors for heart, skeleton, muscles and a variety of other critical tissue types in our bodies. Read more

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USC Stem Cell | USC

Health 2 Zika proteins responsible for microcephaly identified

Its the first study to examine Zika infection in human neural stem cells from second-trimester fetuses, USC researchers say.

Andy McMahon and his colleagues investigate ways to help the millions who suffer from the chronic ailment.

The condition is more widespread in the animal kingdom than scientists suspected, USC study finds.

NIH Pathway to Independence Award will help Lindsey Barske transition to the faculty stage as she hopes to learn more about human birth defects.

Researchers examine the stimulation of the inner ears sensory cells, which could ultimately help the deaf.

USC researchers hope to usher in new treatments for patients with muscular dystrophy.

The scientists receive the first Broad Innovation Awards for their critical analysis of Lou Gehrigs disease and immune systems.

Findings could impact development of clinical strategies to treat cancers of the lung, breast and prostate.

The objective of one current research proposal is to push the frontiers of stem cell and tissue engineering technologies.

Altering transplantation dose could improve outcomes for patients and ultimately save lives.

USC Stem Cell researchers show that cisplatin causes more acute hearing loss in mice with the equivalent of Cockayne syndrome.

Scientists hope that lessons learned from zebrafish jawbone regeneration might hold promise for healing severe human bone fractures.

Researchers discover that two types of molecular signals work to control where and when stem cells turn into facial cartilage.

Colleagues explain how a shared gene directs the development of bone-forming cells.

Influenced by the Jesuits, a USC researcher believes in service, which involves an expansion of knowledge through research and education.

Tracy Grikscheit awarded $7.1 million grant by the California Institute of Regenerative Medicine.

A human has nearly 100 times more nephrons, the functional units of the kidneys, than a mouse.

Next-generation scientists at USC Stem Cell mini-symposium discuss research of anemia and cancer.

Gabriel Linares seeks therapies for patients with Lou Gehrigs disease.

USC-affiliated faculty members aim to cure diseases using stem cells as tools.

Doctoral student in USC Stem Cell lab helps to identify roles for a family of genes.

Prkci influences whether stem cells self-renew or differentiate into more specialized cell types.

The new one-stop shop allows scientists to take stem cell research to the next level and eventually develop translational therapies.

Albert Kim applies his expertise to the challenge of kidney regeneration.

View original post here:
Stem Cells | USC News

Lessons learned from babies with heart failure could now help adults

Inspiration can sometimes come from the most unexpected of places. For English researcher Stephen Westaby it came from seeing babies who had heart attacks bounce back and recover. It led Westaby to a new line of research that could offer hope to people who have had a heart attack.

Westaby, a researcher at the John Radcliffe hospital in Oxford, England, found that implanting a novel kind of stem cell in the hearts of people undergoing surgery following a heart attack had a surprisingly significant impact on their recovery.

Westaby got his inspiration from studies showing babies who had a heart attack and experienced scarring on their heart, were able to bounce back and, by the time they reached adolescence, had no scarring. He wondered if it was because the babies own heart stem cells were able to repair the damage.

Scarring is a common side effect of a heart attack and affects the ability of the heart to be able to pump blood efficiently around the body. As a result of that diminished pumping ability people have less energy, and are at increased risk of further heart problems. For years it was believed this scarring was irreversible. This study, published in the Journal of Cardiovascular Translational Research, suggests it may not be.

Westaby and his team implanted what they describe as a novel mesenchymal precursor (iMP) type of stem cell in the hearts of patients who were undergoing heart bypass surgery following a heart attack. The cells were placed in parts of the heart that showed sizeable scarring and poor blood flow.

Two years later the patients showed a 30 percent improvement in heart function, a 40 percent reduction in scar size, and a 70 percent improvement in quality of life.

In an interview with the UK Guardian newspaper, Westaby admitted he was not expecting such a clear cut benefit:

Quite frankly it was a big surprise to find the area of scar in the damaged heart got smaller,

Of course it has to be noted that the trial was small, only involving 11 patients. Nonetheless the findings are important and impressive. Westaby and his team now hope to do a much larger study.

CIRM is funding a clinical trial with Capricor that is taking a similar approach, using stem cells to rejuvenate the hearts of patients who have had heart attacks.

Fred Lesikar, one of the patients in the first phase of that trial, experienced a similar benefit to those in the English trial and told us about it in our Stories of Hope.

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A healthy T cell

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Directing the creation of T cells. To paraphrase the GOP Presidential nominee, any sane person LOVES, LOVES LOVES their T cells, in a HUGE way, so HUGE. They scamper around the body getting rid of viruses and the tiny cancers we all have in us all the time. A CIRM-funded team at CalTech has worked out the steps our genetic machinery must take to make more of them, a first step in letting physicians turn up the action of our immune systems.

We have known for some time the identity of the genetic switch that is the last, critical step in turning blood stem cells into T cells, but nothing in our body is as simple as a single on-off event. The Caltech team isolated four genetic factors in the path leading to that main switch and, somewhat unsuspected, they found out those four steps had to be activated sequentially, not all at the same time. They discovered the path by engineering mouse cells so that the main T cell switch, Bcl11b, glows under a microscope when it is turned on.

We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on, said Ellen Rothenberg, the senior author in a university press release picked up by Innovations Report. Its interestingthe gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order.

Video primer on stem cells in the brain. In conjunction with an article in its August issue, Scientific American posted a video from the Brain Forum in Switzerland of Elena Cattaneo of the University of Milan explaining the basics of adult versus pluripotent stem cells, and in particular how we are thinking about using them to repair diseases in the brain.

The 20-minute talk gives a brief review of pioneers who stood alone in unmarked territory. She asks how can stem cells be so powerful; and answers by saying they have lots of secrets and those secrets are what stem cell scientist like her are working to unravel. She notes stem cells have never seen a brain, but if you show them a few factors they can become specialized nerves. After discussing collaborations in Europe to grow replacement dopamine neurons for Parkinsons disease, she went on to describe her own effort to do the same thing in Huntingtons disease, but in this case create the striatal nerves lost in that disease.

The video closes with a discussion of how basic stem cell research can answer evolutionary questions, in particular how genetic changes allowed higher organisms to develop more complex nervous systems.

CIRM Science Officers Kelly Shepard and Kent Fitzgerald

A stem cell review that hits close to home. IEEE Pulse, a publication for scientists who mix engineering and medicine and biology, had one of their reporters interview two of our colleagues on CIRMs science team. They asked senior science officers Kelly Shepard and Kent Fitzgerald to reflect on how the stem cell field has progressed based on their experience working to attract top researchers to apply for our grants and watching our panel of outside reviewers select the top 20 to 30 percent of each set of applicants.

One of the biggest changes has been a move from animal stem cell models to work with human stem cells, and because of CIRMs dedicated and sustained funding through the voter initiative Proposition 71, California scientists have led the way in this change. Kelly described examples of how mouse and human systems are different and having data on human cells has been critical to moving toward therapies.

Kelly and Kent address several technology trends. They note how quickly stem cell scientists have wrapped their arms around the new trendy gene editing technology CRISPR and discuss ways it is being used in the field. They also discuss the important role of our recently developed ability to perform single cell analysis and other technologies like using vessels called exosomes that carry some of the same factors as stem cells without having to go through all the issues around transplanting whole cells.

Were really looking to move things from discovery to the clinic. CIRM has laid the foundation by establishing a good understanding of mechanistic biology and how stem cells work and is now taking the knowledge and applying it for the benefit of patients, Kent said toward the end of the interview.

Jake Javier and his family

Jakes story: one young mans journey to and through a stem cell transplant; As a former TV writer and producer I tend to be quite critical about the way TV news typically covers medical stories. But a recent story on KTVU, the Fox News affiliate here in the San Francisco Bay Area, showed how these stories can be done in a way that balances hope, and accuracy.

Reporter Julie Haener followed the story of Jake Javier we have blogged about Jake before a young man who broke his spine and was then given a stem cell transplant as part of the Asterias Biotherapeutics clinical trial that CIRM is funding.

Its a touching story that highlights the difficulty treating these injuries, but also the hope that stem cell therapies holds out for people like Jake, and of course for his family too.

If you want to see how a TV story can be done well, this is a great example.

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A recent study estimated there may be more than 500 million people worldwide who have diabetes. Thats an astounding figure and makes diabetes one of the largest chronic disease epidemics in human history.

One of the most serious consequences of untreated or uncontrolled diabetes is kidney damage. That can lead to fatigue, weakness, confusion, kidney failure and even death. So two decisions taken by the CIRM Board today were good news for anyone already suffering from either diabetes or kidney disease. Or both.

The Board awarded almost $10 million to Humacyte to run a Phase 3 clinical trial of an artificial vein needed by people undergoing hemodialysis thats the most common form of dialysis for people with kidney damage. Hemodialysis helps clean out impurities and toxins from the blood. Without it waste will build up in the kidneys with devastating consequences.

The artificial vein is a kind of bioengineered blood vessel. It is implanted in the individuals arm and, during dialysis, is connected to a machine to move the blood out of the body, through a filter, and then back into the body. The current synthetic version of the vein is effective but is prone to clotting and infections, and has to be removed regularly. All this puts the patient at risk.

Humacytes version called a human acellular vessel or HAV uses human cells from donated aortas that are then seeded onto a biodegradable scaffold and grown in the lab to form the artificial vein. When fully developed the structure is then washed to remove all the cellular tissue, leaving just a collagen tube. That is then implanted in the patient, and their own stem cells grow onto it, essentially turning it into their own tissue.

In earlier studies Humacytes HAV was shown to be safer and last longer than current versions. As our President and CEO, Randy Mills, said in a news release, thats clearly good news for patients:

This approach has the potential to dramatically improve our ability to care for people with kidney disease. Being able to reduce infections and clotting, and increase the quality of care the hemodialysis patients get could have a significant impact on not just the quality of their life but also the length of it.

There are currently almost half a million Americans with kidney disease who are on dialysis. Having something that makes life easier, and hopefully safer, for them is a big plus.

The Humacyte trial is looking to enroll around 350 patients at three sites in California; Sacramento, Long Beach and Irvine.

While not all people with diabetes are on dialysis, they all need help maintaining healthy blood sugar levels, particularly people with type 1 diabetes. Thats where the $3.9 million awarded to ViaCyte comes in.

Were already funding a clinical trial with ViaCyte using an implantable delivery system containing stem cell-derived cells that is designed to measure blood flow, detect when blood sugar is low, then secrete insulin to restore it to a healthy level.

This new program uses a similar device, called a PEC-Direct. Unlike the current clinical trial version, the PEC-Direct allows the patients blood vessels to directly connect, or vasularize, with the cells inside it. ViaCyte believes this will allow for a more robust engraftment of the stem cell-derived cells inside it and that those cells will be better able to produce the insulin the body needs.

Because it allows direct vascularization it means that people who get the delivery system will also need to get chronic immune suppression to stop their bodys immune system attacking it. For that reason it will be used to treat patients with type 1 diabetes that are at high risk for acute complications such as severe hypoglycemic (low blood sugar) events associated with hypoglycemia unawareness syndrome.

In a news release Paul Laikind, Ph.D., President and CEO of ViaCyte, said this approach could help patients most at risk.

This high-risk patient population is the same population that would be eligible for cadaver islet transplants, a procedure that can be highly effective but suffers from a severe lack of donor material. We believe PEC-Direct could overcome the limitations of islet transplant by providing an unlimited supply of cells, manufactured under cGMP conditions, and a safer, more optimal route of administration.

The Board also approved more than $13.6 million in awards under our Discovery program. You can see the winners here.

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Now that Asterias Biotherapeutics CIRM-funded, stem cell-based clinical trial for spinal cord injury (SCI) has safely treated its first group of patients and begun recruiting the second, should other SCI researchers close up shop? Of course not. Since its a first-in-human trial, there certainly will be room for improvement even if the therapy proves successful. And it may not work for every SCI victim. So the development of other therapeutic approaches is critical to ensure effective treatments for all patients with this unmet medical need.

Enter the lab of Michael Fehlings at the University of Toronto. Their recent Stem Cells Translational Medicine study describes a potential, minimally invasive therapeutic strategy which involvesa type of brain cell not previously studied in the context of SCI.

In the case of the Asterias trial, embryonic stem cell-derived cells called oligodendrocytes are being transplanted directly into the injured spinal cord to help restore the disrupted nerve signals that cause a whole range of debilitating symptoms, including painful tingling and loss of movement in arms and legs, loss of bladder control and difficulty breathing.

Instead of trying to directly repair the disconnected nerve signals, Fehlings team looked at reducing the damaging effects of inflammation that occur at the site of injury in the days and weeks following the spinal cord trauma. This sounds like a perfect job for mesenchymal stem cells (MSCs) whose anti-inflammatory effects are well established. But previous animal studies using MSCs for spinal cord injury have had mixed results. Different sources of MSCs are known to have different anti-inflammatory actions so perhaps this is the culprit behind the variability. On top of that, the exact mechanism of action isnt well understood which presents a barrier to getting FDA approval for clinical trials.

So the current study performed a careful comparative analysis of the healing effects of human cord blood MSCs and human brain vascular pericytes (HBVPs) MSC-like cells found near blood vessels in the brain in a rat model of spinal cord injury. Shortly after the SCI injury, the cells were delivered into the rats through the blood. The blood levels of various cytokines proteins that modulate the inflammation response were measured for several days. The only cytokine that increased in the days after the cell delivery of either cell type was IL-10 which is known for its anti-inflammatory effects.

Examining the spinal cord one to seven days after injury, the researchers found that both MSCs and HBVPs were better than controls at reducing hemorrhaging, with the HBVPs showing better improvement. In terms of long-term effects on functional behaviors, the researchers showed that after three weeks, grip strength, body coordination, and hind limb movement were most improved in the HBVPs.

In a university press release, Fehlings described these promising results:

Michael Fehlings

Our study demonstrates that these cells not only display a MSC phenotype in a dish, but also have similar immunomodulatory effects in animals after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of interest for therapeutic use in acute spinal cord injury.

A lot more work will be needed to translate these findings into clinical trials but for the sake of those suffering from spinal cord injury its encouraging that alternative approaches to treating this devastating, life-changing condition are in development.

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Where will stem cell research be in 10 years?

What would you say to patients who wanted stem cell therapies now?

What are the most promising applications for stem cell research?

Why is it important for the government to fund regenerative medicine?

These challenging and thought-provoking questions were posed to a vibrant group of undergraduate and masters-level students at this years CIRM Bridges to Stem Cell Research and Therapy conference.

Educating the next generation of stem cell scientists

The Bridges program is one of CIRMs educational programs that offers students the opportunity to take coursework at California state schools and community colleges and conduct stem cell research at top universities and industry labs. Its goal is to train the next generation of stem cell scientists by giving them access to the training and skills necessary to succeed in this career path.

The Bridges conference is the highlight of the program and the culmination of the students achievements. Its a chance for students to showcase the research projects theyve been working on for the past year, and also for them to network with other students and scientists.

Bridges students participated in a networking pitch event about stem cell research.

CIRM kicked off the conference with a quick and dirty Stem Cell Pitch networking event. Students were divided into groups, given one of the four questions above and tasked with developing a thirty second pitch that answered their question. They were only given ten minutes to introduce themselves, discuss the question, and pick a spokesperson, yet when each teams speaker took the stage, it seemed like they were practiced veterans. Every team had a unique, thoughtful answer that was inspiring to both the students and to the other scientists in the crowd.

Getting to the clinic and into patients

The bulk of the Bridges conference featured student poster presentations and scientific talks by leading academic and industry scientists. The theme of the talks was getting stem cell research into the clinic and into patients with unmet medical needs.

Here are a few highlights and photos from the talks:

On the clinical track for Huntingtons disease

Leslie Thompson, Professor at UC Irvine, spoke about her latest research in Huntingtons disease (HD). She described her work as a race against time. HD is a progressive neurodegenerative disorder thats associated with multiple social and physical problems and currently has no cure. Leslie described how her lab is heading towards the clinic with human embryonic stem cell-derived neural (brain) stem cells that they are transplanting into mouse models of HD. So far, theyve observed positive effects in HD mice that received human neural stem cell transplants including an improvement in the behavioral and motor defects and a reduction in the accumulation of toxic mutant Huntington protein in their nerve cells.

Leslie Thompson

Leslie noted that because thetransplanted stem cells are GMP-grade (meaning their quality is suitable for use in humans), they have a clear path forward to testing their potential disease modifying activity in human clinical trials. But before her team gets to humans, they must take the proper regulatory steps with the US Food and Drug Administration and conduct further experiments to test the safety and proper dosage of their stem cells in other mouse models as well as test other potential GMP-grade stem cell lines.

Gene therapy for SCID babies

Morton Cowan, a pediatric immunologist from UC San Francisco, followed Leslie with a talk about his efforts to get gene therapy for SCID (severe combined immunodeficiency disease) off the bench into the clinic. SCID is also known as bubble-baby disease and put simply, is caused by a lack of a functioning immune system. SCID babies dont have normal T and B immune cell function and as a result, they generally die of infection or other conditions within their first year of life.

Morton Cowan, UCSF

Morton described how the gold standard treatment for SCID, which is hematopoietic or blood stem cell transplantation, is only safe and effective when the patient has an HLA matched sibling donor. Unfortunately, many patients dont have this option and face life-threatening challenges of transplant rejection (graft-versus host disease). To combat this issue, Morton and his team are using gene therapy to genetically correct the blood stem cells of SCID patients and transplant those cells back into these patients so that they can generate healthy immune cells.

They are currently developing a gene therapy for a particularly hard-to-treat form of SCID that involves deficiency in a protein called Artemis, which is essential for the development of the immune system and for repairing DNA damage in cells. Currently his group is conducting the necessary preclinical work to start a gene therapy clinical trial for children with Artemis-SCID.

Treating spinal cord injury in the clinic

Casey Case, Asterias Biotherapeutics

Casey Case,Senior VP of Research and Nonclinical Development at Asterias Biotherapeutics, gave an update on the CIRM-funded clinical trial for cervical (neck) spinal cord injury (SCI). They are currently testing the safety of transplanting different doses of their oligodendrocyte progenitor cells (AST-OPC1) in a group of SCI patients. The endpoint for this trial is an improvement in movement greater than two motor levels, which would offer a significant improvement in a patients ability to do some things on their own and reduce the cost of their healthcare. You can read more about these results and the ongoing study in our recent blogs (here, here).

Opinion: Scientists should be patient advocates

David Higgins gave the most moving speech of the day. He is a Parkinsons patient and the Patient Advocate on the CIRM board and he spoke about what patient advocates are and how to become one. David explained how, these days, drug development and patient advocacy is more patient oriented and patients are involved at the center of every decision whether it be questions related to how a drug is developed, what side effects should be tolerated, or what risks are worth taking. He also encouraged the Bridges students to become patient advocates and understand what their needs are by asking them.

David Higgins

As a scientist or clinician, you need to be an ambassador. You have a job of translating science, which is a foreign language to most people, and you can all effectively communicate to a lay audience without being condescending. Its important to understand what patients needs are, and youll only know that if you ask them. Patients have amazing insights into what needs to be done to develop new treatments.

Bridging the gap between research and patients

The Bridges conference is still ongoing with more poster presentations, a career panel, and scientific talks on discovery and translational stem cell research and commercializing stem cell therapies to all patients in need. It truly is a once in a lifetime opportunity for the Bridges students, many of whom are considering careers in science and regenerative medicine and are taking advantage of the opportunity to talk and network with prominent scientists.

If youre interested in hearing more about the Bridges conference, follow us on twitter (@CIRMnews, @DrKarenRing, #CIRMBridges2016) and on Instagram (@CIRM_Stemcells).

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The Stem Cellar | The Official Blog of CIRM, California's ...

Statement of Benefit to California:

According to the Center for Health Statistics, California Department of Health Services, 13,427 people died of lung cancer in the state of California in 2005. This is more than the deaths attributed to breast, prostate and colon cancers combined. The devastating effects of this disease on the citizens of California and the health care costs involved are enormous. Most cases of lung cancer occur in smokers, but non smokers, people exposed to second hand smoke and ex-smokers are also at risk. In addition, of special concern to California residents, is that exposure to air pollution is associated with an increased risk of lung cancer. Current therapeutic strategies for lung cancer are in general only able to prolong survival by a few months, especially for late stage disease. One reason for this may be that the cancer initiating stem cell is resistant to these therapies. Understanding the stem cell populations involved in repair of the lung and how these cells may give rise to lung cancer is important for potentially generating new therapeutic targets for lung cancer. We propose to study the stem cell populations of the lung that are crucial for normal airway repair and characterize the putative cancer initiating stem cell in the lung. We have also found stem cells in the blood that are critical for normal airway repair and we plan to test their role in the prevention of premalignant lung cancer lesions. We also plan to test whether levels of these stem cells in the blood may be used as a biomarker of lung cancer. Ultimately, the ability to perform a screening test to detect lung cancer at an early stage, and the development of new therapies for lung cancer will be of major benefit to the citizens of California.

Link:

Stem Cells in Lung Cancer | California's Stem Cell Agency

En Espaol

With funding from CIRM, California has become a world-leader in stem cell research. Learn more about how CIRM changes the landscape of research in California and about laws in other states.

How will CIRM accelerate stem cell therapies? What are the economic implications of stem cell research? How does CIRM save the state money? What were the federal restrictions on human embryonic stem cell research under President Bush? How did federal regulations of human embryonic stem cell research change under President Obama? What is happening with stem cell research in other states?

As the largest source of funding for stem cell research outside the National Institutes of Health, CIRM supports innovative research programs focused on accelerating treatments to patients in need.

In addition, CIRM has also supported the construction of state-of-the-art facilities that were needed in order to build the infrastructure and perform research without the restrictions that came with federal funding under President George W. Bush.

CIRM Major Facilities Speed Stem Cell Science and Create Jobs [4:20]

CIRM has specifically targeted areas that will help push stem cell research toward the clinic. Our SEED grants pulled more scientists into stem cell research than ever before, and the Comprehensive awards supported leading stem cell scientists already in California. CIRM encouraged young faculty to commit their labs to stem cell science through two rounds of New Faculty awards. Finally, training grants and Bridges awards ensure a next generation of stem cell scientists and laboratory personnel to fill the needs of a growing stem cell research sector in California.

This NPR story discusses the value of stem cell funding in California:

Stem cell research has the potential to treat diseases that are currently burdened with high health care costsespecially chronic conditions such as heart disease, Alzheimers disease or diabetes, the costs of which threaten to cripple the healthcare system. Even if a stem cell-based therapy doesnt entirely cure a disease, reducing its impact would be an enormous economic benefit.

In addition to reduced health care costs, new therapies would allow those people to go back to work, or allow their caregivers to work again. This increased productivity funnels tax dollars right back into the state.

Stem cell research is expected to be a boon to the biotech industry, bringing new companies to the state and creating high-paying jobs. The new CIRM-funded facilities also provide construction jobs throughout the state.

CIRM funding creates jobs, saves health care costs and creates tax revenue. So far, CIRM's 12 major facilities construction projects are generating 13,000 job-years of employment, bringing in over $100 million in new tax revenue. In addition, CIRMs research grants create tens of thousands of additional job-years.

As of January 2015, CIRM has not cost the state's general fund any money. The bonds used to fund CIRM's activities were forward capitalized, so that the agency paid all its own interest costs for the first five years. Once the state begins paying interest, tax revenue generated by CIRM research grants should exceed interest costs for at least the next three to five years.

New therapies developed from CIRMfunding will be available to the state at a reduced cost, further lowering state spending on health care. Some new therapies will save money compared to current therapies. Over time, these savings should far exceed CIRMs costs to the general fund. Furthermore, intellectual property developed through CIRM funding will generate income to the state.

Individual states have passed legislation that either allow some forms of human embryonic stem cell research or specifically ban certain forms of research. A handful of states have passed laws to either fund stem cell research or at least encourage the research. Other states have laws that make the research extremely difficult and in some cases illegal.

Federal institutions could only fund research with human embryonic stem cell lines that had been created before Aug. 9, 2001when president Bush made his announcement regarding funding for stem cell research. At the time of the announcement there were only 22 lines available for federal funding, and many of those are showing signs of degradation from so many years of growing in a lab.

Because of these restrictions, the National Institutes of Health (NIH) mainly funded adult stem cell research. Federal funds could not be used to create new human embryonic stem cell lines, a strategy that is critical in order to fulfill the promise of new therapies based on embryonic stem cell research.

In addition to not funding basic research, scientists could not use any equipment or lab space that had been paid for by federal funds to do work with non-federally approved human embryonic stem cell lines. This is why CIRM invested more than $271 million in grants that have funded the construction of new stem cell research facilities where work on all types of stem cells takes place.

On March 9, 2009, President Barack Obama lifted the restrictions on federal funding for human embryonic stem cell lines created after August 9, 2001. New regulations to guide this funding were finalized by the NIH in July 2009. The first stem cell lines to be reviewed and approved under the new guidelines were announced five months later.

This decision put an end to the restrictions on working with new cell lines with federal equipment. Institutions that had previously maintained dual laboratory space and equipment for working with federal and non-federal stem cell lines could immediately start using federal equipment in research with all cell lines.

Find out More:

California Researchers Look Forward to Obama's Stem Cell Research Policies (4:22)

CIRM Statement: Obama's Policies will up the Value of California's Investment inStem Cells

This NIHpage contains information about the federal stem cell policy

Updated 1/15

Excerpt from:
California: The Leader in Stem Cell Research | California ...