Advance Understanding of Spinal Muscular Atrophy with Stem Cells

Cedars-Sinai's Regenerative Medicine Institute research sheds new light on cell death in a common, lethal genetic disease in children, suggesting paths for potential treatment
Thursday, 21 June 2012 

Cedars-Sinai's Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

The study, published in the June 19 online issue of PLoS ONE, extends the institute's work to employ pluripotent stem cells to find a pharmaceutical treatment for spinal muscular atrophy or SMA, a genetic neuromuscular disease characterized by muscle atrophy and weakness.

"With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process," said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute.

Svendsen and his team have investigated this disease for some time now. In 2009, Nature published a study by Svendsen and his colleagues detailing how skin cells taken from a patient with the disorder were used to generate neurons of the same genetic makeup and characteristics of those affected in the disorder; this created a "disease-in-a-dish" that could serve as a model for discovering new drugs.

As the disease is unique to humans, previous methods to employ this approach had been unreliable in predicting how it occurs in humans. In the research published in PLoS ONE, to the team reproduced this model with skin cells from multiple patients, taking them back in time to a pluripotent stem cell state (iPS cells), and then driving them forward to study the diseased patient-specific motor neurons.

Children born with this disorder have a genetic mutation that doesn't allow their motor neurons to manufacture a critical protein necessary for them to survive. The study found these cells die through apoptosis – the same form of cell death that occurs when the body eliminates old, unnecessary as well as unhealthy cells. As motor neuron cell death progresses, children with the disease experience increasing paralysis and eventually death. There is no effective treatment now for this disease. An estimated one in 35 to one in 60 people are carriers and about in 100,000 new-borns have the condition.

"Now we are taking these motor neurons (from multiple children with the disease and in their pluripotent state) and screening compounds that can rescue these cells and create the protein necessary for them to survive," said Dhruv Sareen, director of Cedars-Sinai's Induced Pluripotent Stem Cell Core Facility and a primary author on the study.

"This study is an important stepping stone to guide us toward the right kinds of compounds that we hope will be effective in the model – and then be reproduced in clinical trials."

Source: Cedars-Sinai Medical Center 

Contact: Nicole White

Reference:

Inhibition of Apoptosis Blocks Human Motor Neuron Cell Death in a Stem Cell Model of Spinal Muscular Atrophy

Dhruv Sareen, Allison D. Ebert, Brittany M. Heins, Jered V. McGivern, Loren Ornelas, Clive N. Svendsen

PLoS ONE, 19 Jun, 2012, 201210.1371/journal.pone

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Human Embryonic Stem Cells Purified in New, Rapid Technique

Human Embryonic Stem Cells Purified in New, Rapid Technique
Friday, 06 August 2010

UCSF researchers are reporting the first success in very rapidly purifying one type of embryonic stem cell from a mix of many different types of embryonic stem cells in the culture dish. The technique, which avoids the need to genetically alter the cells to distinguish them, is a key advance, the researchers say, for obtaining the appropriate cells for repairing specific damaged tissues.

The new strategy links two existing technologies for the first time: the ability to identify specific embryonic stem cell types in a culture of different embryonic stem cells, and a way to efficiently sort them at a very high rate, a procedure known as “high throughput” processing.

“Before stem cell therapy can become routine, clinicians will need a plentiful and certain supply of pure stem cells that is capable of forming the particular tissue to be repaired, and is free of contamination by other cell types. But the goal of rapidly and safely harvesting vast numbers of a single stem cell type without altering the cell’s genome has been challenging,” says Harold Bernstein, MD PhD, UCSF professor of paediatrics, a member of the UCSF Cardiovascular Research Institute and senior author of the paper.

“Here we were able to purify one specific cell type without resorting to genetically engineering the stem cells themselves, a process that can introduce unwanted traits into the cells.”

The research finding is currently published online in the journal “Stem Cells and Development,” and will appear later this year in a print edition of the journal. Embryonic stem cells, which replicate indefinitely in the culture dish, are capable of forming almost any tissue in the body. Over time, they begin to specialize as specific cell types, such as cardiomyocytes of the heart or neurons of the brain. One goal for stem cell therapy is to be able to identify cells that have begun to specialize in a particular way so that they could serve as a source of cells to repair specific damaged tissues.

While embryonic stem cell cultures are made up primarily of cells that have begun to differentiate, they also include cells that remain unspecialized, and thus have the capacity to form tumours, called teratomas. Scientists have attempted to purify stem cells — whether to eliminate those with the potential to form teratomas or to isolate specific embryonic stem cell types — by using viruses to insert DNA into the stem cells’ genes. This technique allows researchers to distinguish one type of cell from another, but this genetic engineering approach carries the risk of altering the natural makeup of the stem cells.

The UCSF scientists used a different strategy. They identified cells that can form teratomas by searching for a telltale snippet of DNA in the tumour cells’ genes. They chemically tagged these cells without altering them, and the cells were then removed on the basis of this temporary molecular tag. They reported separating out the desired stem cells from the teratoma-forming cells at a rate of about 25,000 cells per second.

The researchers say they expect the same approach could be used to separate and purify different types of cells as they advance from the stem cell state into neurons, heart cells or any other type of tissue needed for future stem cell therapy.

“Stem cell therapy requires us to select the cells we need, to eliminate teratoma-forming cells from the desired stem cells, and to accomplish this in a high-throughput manner so that we can obtain enough cells,” says Bernstein.

“We show how all three goals can be accomplished at once.”

“We envision this as a tool that ultimately could rapidly identify and purify many different kinds of differentiating cells on their way to becoming heart muscle or pancreas or skin cells. This approach could quickly build up a large reservoir of desired cells,” he said.

The research was supported in part by the state-funded California Institute for Regenerative Medicine, or CIRM. The technique has been disclosed to the UCSF Office of Technology Management for potential licensing, as well as to CIRM.

In the technique reported, the scientists introduced into a stem cell culture a pair of DNA snippets containing part of a gene, called Oct4, which is essential to all embryonic stem cells. The gene also allows cells to form teratomas, but it is not active once a stem cell starts down the road to becoming a specialized cell type.

At one end of each snippet, the researchers attached a fluorescent protein, and, at the other end, they engineered the DNA so that it could “quench” the fluorescent light. When introduced into the cell culture, the two DNA fragments naturally sought to bind, or anneal, to similar genetic sequences in the messenger RNA, or mRNA, made by the cell’s Oct4 gene. However, they could do so only if the gene was turned on, as it is in teratoma-forming cells — not in stem cells already destined to become specialized tissue.

When the two DNA snippets annealed to an Oct4 mRNA, their fluorescent proteins lit up, and a cell-sorting machine then fished out these the fluorescently tagged cells — but no others.

“The key to the process is that the two fluorescently tipped fragments light up only when they are close to each other, and they are only close to each other when they both anneal to a target cell’s Oct4 genetic sequence,” says Bernstein. If Oct4 is not active in a cell, then the two introduced DNA strands do not light up. Cells that lack a fluorescent tag can then be automatically sorted separately from the fluorescently tagged target cells.

This approach enabled the researchers to isolate the teratoma-forming cells from stem cells that were already on their way to becoming more specialized cells and thus no longer expressed the telltale Oct4 gene product. The scientists expect that other tags can be developed to separate different kinds of developing cells.

The targeted gene in the process is one that codes for the Oct4 transcription factor, which allows embryonic stem cells to remain pluripotent. The DNA snippets are called “molecular beacons,” and the tagging part of the two-step strategy in which the two snippets interact is known as fluorescence-resonance energy transfer, or FRET. Molecular beacons were first described in 1998 for use in DNA sequence analysis, and cell sorters have been used for decades, but linking them represents a new technology for identifying and purifying special types of stem cells. The use of the cell sorter also allows for high throughput, or the processing and purifying a large number of special cells in a short period of time.

Source: Jennifer O’Brien, UCSF
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See CIRMTV's Channel on YouTube

California's stem cell research funding agency is using YouTube to tell its story. Friday, 11 September 2009 The California Institute for Regenerative Medicine's CIRMTV tells the story of stem cell research through short videos about the work of researchers and doctors and — most compellingly — patients. The 22 videos on the site range from Stanford University stem cell research director Irv Weissman talking about the differences between adult and embryonic stem cells to, most recently, an update about the progress and promise in Parkinson's disease treatments. See CIRMTV's Channel: YouTube - CIRMTV's Channel ......... ZenMaster

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Photo’s of Human Embryonic Stem Cells

CIRM Announces Winners of the 2008 Image Contest Monday, 23 February 2009 The twelve winning images from the first California Institute for Regenerative Medicine stem cell photo contest range from a whirling galaxy of developing nerve cells to a moonscape of retinal pigment epithelial cells, both derived from human embryonic stem cells. Other images show a lightning bolt of a motor neuron axon shooting through a sky of blue and green nerve cells, a sunburst ball of neural progenitor cells and paisley colonies of human embryonic stem cells. Together, this collection of images from CIRM-funded researchers shows the diversity and the beauty of stem cell research. “When scientists read about a research project that has taken a creative route to arrive at an enlightening finding, it is not unusual for them to exalt it as ‘a beautiful piece of science,’” said Alan Trouson, CIRM president. “With these images we show clearly that such exaltations can have two meanings.” Winners of the contest received $100 and a professional enlargement of their entry. The contest winners join a growing collection of stem cell images on the CIRM Flickr site. Images on the site include embryonic stem cell lines created by CIRM grantees and tissues derived from those cells. These more mature cell types, such as cells of the nervous system, eye, liver or heart, are being used to study the origin of diseases and learn how to reverse the effects of those disorders. Don Gibbons, chief communications officer, said the collection of images is part of an ongoing effort to keep Californians informed about the agency’s work. The effort includes a stem cell basics primer about stem cell research, summaries of CIRM-funded research findings and videos about the basics of stem cell research and CIRM news at the agency’s YouTube site. “Together, these materials make it easier for Californians to stay abreast of stem cell developments in the state,” Gibbons said. The image contest winners include: - Juan Carlos Izpisua Belmonte, PhD, Salk Institute for Biological Studies - Bruce Conklin, MD, the Gladstone Institute of Cardiovascular Disease - Brian Cummings, PhD, University of California, Irvine - Guoping Fan, PhD, University of California, Los Angeles - Susan Fisher, PhD, University of California, San Francisco (two images) - Fred H. Gage, PhD, Salk Institute for Biological Studies - Anirvan Ghosh, PhD, University of California, San Diego - David Hinton, MD, University of Southern California - Paul Knoepfler, PhD, University of California, Davis - Martin Pera, PhD, University of Southern California - Prue Talbot, PhD, University of California, Riverside

All pictures by the courtesy of CIRM.

About CIRM: The California Institute for Regenerative Medicine (CIRM) was established in 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The state-wide ballot measure, which provided $3 billion in funding for stem cell research at California universities and research institutions, was overwhelmingly approved by voters, and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research opportunities. To date, the CIRM governing board has approved 279 research and facility grants totalling more than $693 million, making CIRM the largest source of funding for human stem cell research in the world. For more information, please visit www.cirm.ca.gov. ......... ZenMaster

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Human Embryonic Stem Cells Induce Immune Response in Mice

Suggests that human therapy may face challenge, Stanford study shows Monday, 18 August 2008 Human embryonic stem cells trigger an immune response in mice, researchers from the Stanford University School of Medicine report. The finding suggests that the effectiveness of human therapies derived from the cells could be limited unless ways are found to dampen the rejection response. The researchers found the immune response in mice could be mitigated by the use of common anti-rejection medications. Overall, the work indicated that, contrary to previous suggestions, the immune system is not blind to the presence of foreign embryonic stem cells. “It’s getting harder and harder to believe that these cells are immunoprivileged,” said Joseph Wu, MD, PhD, assistant professor of cardiovascular medicine and of radiology. “In fact, the rejection of these cells confirms our suspicions that they do cause an immune response.” Embryonic stem cells form all cells in an embryo. Many researchers have suggested that these cells may receive a kind of “free pass” from the normally vigilant immune system in order to allow the growth of a foetus that contains both maternal and paternal genetic material. Such an immunological exemption could alleviate many concerns about using cells for therapy that don’t exactly match the recipient’s immune system — such as existing embryonic stem cell lines that are not directly derived from the recipient. “We all want to know what’s going to happen if you transplant these stem cells into a person,” said Mark Davis, MD, PhD, the Burt and Marion Avery Family Professor and professor of microbiology and immunology. But because unmodified embryonic stem cells can cause cancer, the researchers transplanted the cells into mice rather than people. Davis, who is also an investigator for the Howard Hughes Medical Institute, is a co-author of the paper, published Aug. 18 in the online early edition of the Proceedings of the National Academy of Sciences. Wu is the senior author of the research. Wu, Davis and their colleagues injected human embryonic stem cells into the leg muscles of mice with either normal or compromised immune systems. They followed the fate of the transplanted cells with a novel molecular imaging technique that can visualize whole, living animals. Previous studies of this type relied on microscopic examination of tissue samples from sacrificed animals, but this new approach allows researchers to watch the life or death of cells in real time. Although the cells died within about seven to 10 days in mice with functioning immune systems, they survived and proliferated in the immunocompromised mice. Repeated injections of cells into the immune-normal mice led to more rapid cell death, indicating that the immune system was becoming more efficient at recognizing and rejecting the cells. “The data is quite convincing,” said Wu. “Based on these results, we believe that transplanting these cells into humans would also cause an immune response.” It’s not known what triggers the immune system to attack the embryonic stem cells, but the scientists believe it may be a protein that begins to appear on the surface of the cells as they differentiate into more specialized tissues. Once the immune system has been primed to recognize the foreign molecules, it responds even more quickly to repeated invasion. “That’s the beauty of this kind of non-invasive imaging system,” said Wu. “It allows us to assess the response of one animal to a variety of conditions and gives us much more valuable information.” Because the aggressive reaction of the immune system somewhat mimics the way the body reacts to transplanted organs, the researchers wondered if common anti-rejection medications would increase cell survival. They found that a combination of two compounds — tacrolimus and sirolimus — allowed the cells to survive for up to 28 days in the mice with normal immune systems. Wu and his colleagues will continue to investigate whether different combinations can more effectively mitigate the immune response in mice. They also plan to conduct similar experiments in a mouse model that more closely approximates what would happen in humans. “A lot of research efforts are devoted to the basic science of stem cells,” said Davis. “This work is focused on the immediate practicalities of actually using these cells therapeutically.” Other Stanford authors include postdoctoral scholars Rutger-Jan Swijnenburg, MD; Johannes Govaert, MD; Feng Cao, MD, PhD, and Ahmad Sheikh, MD; as well as Sonja Schrepfer, MD, PhD, clinical instructor of cardiothoracic surgery; Katie Ransohoff, undergraduate; Andrew Connolly, MD, PhD, associate professor of pathology, and Robert Robbins, MD, professor and chair of cardiothoracic surgery. The work was supported by the National Institutes of Health, the Burroughs Wellcome Foundation, the California Institute of Regenerative Medicine, the Howard Hughes Medical Institute, the International Society for Heart & Lung Transplantation and a European Society for Organ Transplantation-Astellas Study and Research Grant. Astellas Pharma US, Inc. manufactures tacrolimis, which was used in this study. Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu/. ......... ZenMaster

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CIRM Award Funds to Build California Stem Cell Labs

Next big investment in stem cell research in California Wednesday, 07 May 2008 CIRM, Donors and 12 California Institutions Commit $1.1 Billion to Stem Cell Research in California. The governing board of the California Institute for Regenerative Medicine (CIRM), the state’s stem cell agency, voted today to distribute $271 million to 12 institutions to build stem cell research facilities throughout California. The institutions committed an additional $560 million from charitable donations and their internal reserves, bringing the total state-wide investment in new research space to $831 million. This leverage of the state’s stem cell funds was further increased by additional institutional commitments for faculty recruitment packages and other related capital costs. In total, the state funding will have leveraged $1.1 billion in new resources to accelerate the pace toward therapies for patients with chronic and debilitating disease and injury. Investment in research infrastructure to extend California’s state-of-the-art research capacity is a critical part of the agency’s scientific strategic plan to sustain and build California’s global leadership in stem cell research and to accelerate the field as a whole. All the institutions have agreed to expedited construction schedules that will deliver nearly 800,000 square feet of facilities with researchers in the labs within two years. This accelerated schedule should create thousands of construction jobs at a time when the state economy needs them. “This Prop. 71 stem cell research facilities program is one of the largest building programs ever dedicated for a new field of medical science and it will deliver an impact that will be felt world-wide,” commented Robert N. Klein, chairman of the governing board of the state stem cell agency. “As a patient advocate, I am inspired by the amount of leverage California research institutions have contributed from their charitable donors and from their reserves. Their incredible commitment underscores the promise that stem cell research holds for patients suffering from chronic disease and injury.” In a statement issued today, Governor Schwarzenegger said: “This will go a long way toward medical research that could save lives and improve them for people with chronic diseases. But also, this kind of public-private investment in a growing jobs sector is exactly the kind of good news our economy needs right now.” The Major Facilities Grant program was launched in August 2007 as a two-part application process. In the fall, the agency’s Scientific and Medical Research Grants Working Group evaluated the scientific merit of 17 proposals submitted in response to the request for application. On January 16, 2008 the ICOC approved Part 1 of the applications, inviting 12 institutions to advance to the second and final part of the application process. Part 2 of the application focuses on the technical aspects of an applicant’s building program and how the scientific program aligns with the CIRM’s objectives, and why the program represents a good value for California taxpayers’ investment. The review was conducted by the 10-member Scientific and Medical Research Facilities Working Group (Facilities Working Group) made up of real estate experts, patient advocates and the chairman of the ICOC. This meeting was open to the public. “These facilities will house basic and clinical researchers working collaboratively, with stem-cell-specific core labs literally ‘down the hall’ – an arrangement that is instrumental to our ability to accelerate the pace of research toward clinical application” said Dr. Alan Trounson, president of CIRM. “Because of this, we believe these facilities will be an instrumental part of advancing one of CIRM’s primary objectives of helping to speed the delivery of stem-cell based therapies and cures into the clinic and to patients.” CIRM had originally pledged to award $262 million in this round of grants, which would have taken the facilities grants by CIRM to the maximum allowed for “bricks and mortar” under Proposition 71. Today’s total of $271 million results from asking the institutions to breakout costs for scientific equipment, which CIRM routinely funds from the research portion of its bond allocation. This allowed CIRM to supplement its facilities total with $9 million from the research pool. “I was very pleased that the review process allowed us to make complete, thorough and fair evaluations of the applications,” said David Lichtenger, Chair of the CIRM Facilities Working Group (FWG), and President and CEO of Integrated Facilities Solutions (IFS) in Palo Alto. “I was also very encouraged to see that many of the applicants are at the forefront in designing innovative research space that efficiently used open and common areas to foster collaboration and flexibility in use.” “I am thrilled that there appears to be sufficient funds that all 12 proposals can move forward to completion because these facilities should dramatically accelerate the pace of getting new therapies to patients,” said David Serrano Sewell, vice chair of the CIRM FWG and Deputy City Attorney in the San Francisco City Attorney’s Office. The 12 institutions had originally requested $336 million in funding from CIRM. At its April 4 - 5 meeting the FWG scored each proposal on set criteria and then reduced each institution’s request by the percentage their score was below 100. For example, if a proposal received a 92, the institution’s request was reduced by eight percent. That reduced the funding gap from $74 million to $27 million. Moving $9 million of the requests into equipment costs reduced the gap to $18 million. This remaining gap was mitigated by offering institutions the chance to receive their award this summer at a discounted rate, rather than two years from now at completion of the projects as was initially contemplated. Eight institutions decided it was financially advantageous for them to take the award now with a nine percent reduction. This closed the gap and the remaining, relatively new and emerging institutions, could get the full funding recommended by the FWG. “California is at the epicenter of stem cell research,” said Eli Broad, founder of The Eli and Edythe Broad Foundation, which has committed more than $50 million to stem cell research at the Broad Institute for Integrative Biology and Stem Cell Research at USC and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “By creating new research centers and attracting the very best scientists from around the world, we will enable the rapid progress of one of the most promising areas of scientific and medical research today. The partnership between public institutions, the state, private foundations and donors demonstrates the unprecedented commitment California is making to stem cell research. The Broad Foundation is pleased to be the largest private donor to stem cell research in California.” "The important thing to me is that stem cells might not only extend life, but also improve the quality of life, as so many people suffer in their later years. But I think stem cells will have applications across the entire life span" stated Lorry Lokey, a donor to Stanford University’s project. Edward Thorp, a donor to the University of California, Irvine project states: "Vivian and I believe that private donations like ours in support of stem cell research at UCI will have a benefit both to our community and to our country that is immeasurably greater than the amount of the gift. Stem cell research promises to transform the treatment of disease and to give us longer, healthier lives. We expect donor support will allow continuing breakthroughs by UCI's stellar research team and that this will be leveraged by attracting many times as much in continuing state support." Ray Dolby, a donor to the University of California San Francisco project stated: “Dagmar and I are very happy to see the ongoing progress of CIRM activities and wish the project continued success." Li Ka-shing, a Hong Kong philanthropist and entrepreneur and donor to the University of California, Berkeley project stated: “When I made a gift to support the establishment of the Li Ka Shing Center for Biomedical and Health Sciences at Berkeley, I was inspired by the passage of Prop. 71 and the promise of significant advances in stem cell research. I am pleased to partner with UC Berkeley and with CIRM to support focused efforts targeting the root causes of some of today's most devastating diseases and translate discoveries into new therapies.”

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(Press the picture for larger version)

The table above details the amount of funding (in US$) each applicant will receive from CIRM, the donor and institutional funds, the total building cost, the additional funds committed for faculty recruitment and other project costs, and total project costs.

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Major Facilities Grants The objectives of the CIRM Major Facilities Grant Program are:

• Funding new facilities – and encouraging investments by others in new facilities – that are free of any federal funding so as to allow research and development of therapies based on human embryonic stem cell (hESC) and other stem cell approaches to proceed in California without restrictions imposed by the federal government.
• Developing stem cell research centers that will expand research capacity and capabilities in California while bringing stem cell-related researchers together in a collaborative setting.
• Funding new facilities and improvements where research institutions have determined that existing facilities are inadequate or are lacking altogether and thus pose a challenge to the development of therapies and cures for diseases being addressed at these institutions.

The applications seek funding to establish one of three types of CIRM facilities:

• CIRM Institutes to carry out stem cell research in three categories: basic and discovery stem cell research, preclinical (translational) research, and preclinical development and clinical research. CIRM funding for these projects will be up to $50 million.
• CIRM Centers of Excellence to conduct stem cell research in any two of the three categories listed above. CIRM funding for these project will be up to $25 million.
• CIRM Special Program to conduct specialized stem cell projects in one of the categories listed above. CIRM funding for these project will be up to $10 million.

CIRM Grants Awarded Since the Start: Since April 2006 when the CIRM awarded its first scientific grants under the California Stem Cell Research and Cures Initiative, the Institute has funded 168 grants totalling more than $530 million for investigator-initiated research grants and training to 22 California non-profit and academic institutions.

• The first grants directed $37.5 million for training 169 pre-doctoral, post-doctoral, and clinical fellows at 16 non-profit and academic research institutions.
• In 2007 the ICOC approved 73 Leon J. Thal SEED Grants totalling more than $46 million to bring new ideas and new investigators into the field of human embryonic stem cell (hESC) research;
• 28 Comprehensive Research Grants totalling nearly $72 million to support mature, ongoing studies on hESCs by scientists with a record of accomplishment in the field;
• 17 Shared Research Laboratory Grants totalling more than $50 million;
• 22 New Faculty Awards of more than $54 million to encourage the next generation of clinical and scientific leaders in stem cell research;
• and today’s Major Facilities grants to 12 institutions totalling $271 million.

About CIRM: CIRM was established in 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The state-wide ballot measure, which provided $3 billion in funding for stem cell research at California universities and research institutions, was overwhelmingly approved by voters, and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research opportunities. To date, the CIRM governing board has approved 168 research and facility grants totalling more than $530 million, making CIRM the largest source of funding for human embryonic stem cell research in the world. .........

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Mitochondrial DNA mutations can cause degenerative heart and muscle disease

UCI study provides insights into age-related diseases and proof that mitochondrial DNA is central to health 
Friday, 15 February 2008

A single change in the DNA of mitochondria – the cellular power plants that generate energy in all human cells – has been found to cause degenerative heart and muscle disease, according to University of California, Irvine researchers. The study provides new insights into age-related disease and further proof that the mitochondria play a central role in human health. Study results appear in the Feb. 15 issue of Science. (More about mitochondria, see below.) 

Douglas Wallace, director of the Center for Molecular and Mitochondrial Medicine and Genetics at UC Irvine and study leader, says the findings also address a core dilemma facing efforts to cure and treat inherited degenerative diseases, including chronic heart and muscle disease. 

“While these diseases traditionally have been assumed to result from mutations in the genes encoded by DNA in the cell’s nucleus,” he said, “most common degenerative diseases frequently do not exhibit inheritance patterns wholly consistent with our understanding of these nuclear DNA genetics. Our demonstration that mutations in the mitochondrial DNA can also cause the same diseases means that both nuclear and mitochondrial DNA genes that affect mitochondrial function can contribute to disease risk.” 

A complete understanding of the importance of mitochondrial defects caused by either mitochondrial or nuclear DNA mutations could lead to treatments effective for age-related diseases that affect millions worldwide, Wallace added. To prove the importance of mitochondrial DNA mutations for health, the UC Irvine researchers generated a relatively mild mitochondrial DNA mutation in mouse cells, which reduced a key enzyme of mitochondrial energy production by 50 percent. They then used female mouse embryonic stem cells to create mice in which this mitochondrial DNA energy deficiency mutation was inherited through the female germ line, which is the reproductive cells and other genetic material passed to offspring. Mice harbouring the mutant mitochondrial DNA appeared normal early in life, but by one year they developed marked muscle and heart disease, similar to disease that can develop in humans. 

“Consequently, mitochondrial DNA mutations and their related energy defects are sufficient to cause age-related disease,” said Wallace, the Donald Bren Professor of Biological Sciences and Molecular Medicine and a National Academy of Sciences member. 

“Therefore, mitochondrial energy deficiency may be a common factor in these diseases.” 
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Weiwei Fan, Katrina Waymire, Navneet Narula, Peng Li, Christophe Rocher, Pinar Coskun, Mani Vannan, Jaget Narula and Grant MacGregor of UC Irvine also participated in this study, which is supported by the National Institutes of Health and the California Institute of Regenerative Medicine.

About mitochondria: Mitochondria exist in all human cells and have their own DNA. They generate energy by burning the calories that we eat with the oxygen that we breathe, much like a coal-burning power plant. In addition to energy, mitochondrial combustion generates “smoke” in the form of oxygen radicals. These oxygen radicals damage the mitochondrial DNA giving it a very high mutation rate, both in the tissues of our bodies and also in the cells of the female germ line. Since the mitochondrial DNA is outside of the cell’s nucleus and not associated with its DNA, it is inherited exclusively from the mother and is present in thousands of copies per cell. As the mitochondrial DNA of our cells accumulates damage with age, the blueprints required to sustain energy production are lost, the body’s equivalent of a brownout. The resulting age-related decline in cellular energy production ultimately leads to tissue and organ failure and the development of clinical disease or illness. Thus the accumulation of mtDNA damage may explain aging and the delayed-onset and progressive course of age-related diseases and aging. 
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One More Group Reprogram Fibroblasts to Stem Cells

UCLA stem cell scientists reprogram human skin cells into embryonic stem cells Tuesday, 12 February 2008 UCLA stem cell scientists have reprogrammed human skin cells into cells with the same unlimited properties as embryonic stem cells without using embryos or eggs. Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells. The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appears Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences. The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient’s skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types – beta islet cells to treat diabetes, hematopoietic cells to create a new blood supply for a leukaemia patient, motor neuron cells to treat Parkinson’s disease. “Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells,” said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. “Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications.” The UCLA work was completed at about the same time the Yamanaka and Thomson reports were published. Taken together, the studies demonstrate that human iPS cells can be easily created by different laboratories and are likely to mark a milestone in stem cell-based regenerative medicine, Plath said. These new techniques to develop stem cells could potentially replace a controversial method used to reprogram cells, somatic cell nuclear transfer (SCNT), sometimes referred to as therapeutic cloning. To date, therapeutic cloning has not been successful in humans. However, top stem cell scientists worldwide stress that further research comparing these reprogrammed cells with stem cells derived from embryos, considered the gold standard, is necessary. Additionally, many technical problems, such as the use of viruses to deliver the four genes for reprogramming, need to be overcome to produce safe iPS cells that can be used in the clinic. “Reprogramming normal human cells into cells with identical properties to those in embryonic stem cells without SCNT may have important therapeutic ramifications and provide us with another valuable method to develop human stem cell lines,” said Lowry, an assistant professor of molecular, cell and developmental biology, a Broad Stem Cell Center researcher and first author of the study. “It is important to remember that our research does not eliminate the need for embryo-based human embryonic stem cell research, but rather provides another avenue of worthwhile investigation.” The combination of four genes used to reprogram the skin cells regulate expression of downstream genes and either activate or silence their expression. The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells. The UCLA research team included four young scientists recruited to UCLA’s new stem cell center in the wake of the passage of Proposition 71 in 2004, which created $3 billion in funding for embryonic stem cell research. The scientists were drawn to UCLA in part because of California’s stem cell research friendly atmosphere and the funding opportunities created by Proposition 71. In addition to Plath and Lowry, the team included Amander Clarke, an assistant professor of molecular, cell and developmental biology, and April Pyle, an assistant professor of microbiology, immunology and molecular genetics. The creation of the human iPS cells is an extension of Plath’s work on mouse stem cell reprogramming. Plath headed up one of three research teams that were able to successfully reprogram mouse skin cells into mouse embryonic stem cells. That work appeared in the inaugural June 2007 issue of the journal Cell Stem Cell. ......... ZenMaster

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CIRM Gets 57 Applications for New hESC Lines Grants

CIRM Gets 57 Applications for New Embryonic Stem Cell Lines Grants Wednesday, 16 January 2008 The California Institute for Regenerative Medicine (CIRM) today announced that it has received and accepted 57 letters of intent for the New Cell Lines Awards. 42 applications were received from non-profit organizations and 15 from for-profit companies. The CIRM New Cell Lines Awards will provide up to $25 million to support the derivation and propagation of new lines of pluripotent human stem cells that will have important research and clinical application for understanding, diagnosing and treating serious injury and disease. Pluripotent stem cells have the potential to play a key role in regenerative medicine and in cell replacement therapies because of their unique ability to renew themselves and their potential to form almost all of the cell types of the body, including muscle, nerve, heart and blood. “We are particularly excited to note that based on the letters of intent we have received there is a good balance between research that derives pluripotent stem cell lines from human embryonic stem cell lines as well as new, highly novel methods such as iPS” stated Alan O. Trounson, Ph.D., the newly appointed president of CIRM. The Awards will fund qualified investigators to conduct research in California that will address the need for new types and sources of human pluripotent stem cell lines and the methods for deriving them. CIRM expects to fund up to 16 New Cell Lines Awards for three years and will support a broad range of research that uses the full spectrum of human cell types and experimental approaches. The Awards will support two categories of research and will give particular consideration to research applications that cannot be currently funded by federal programs:

• Derivation of new human embryonic stem cell lines using excess or rejected early-stage human embryos generated by in vitro fertilization.
• Derivation of pluripotent human stem cell lines from other sources using alternative methods such as, but not limited to, somatic cell nuclear transfer (SCNT) or reprogramming of neonatal or adult cells (iPS cells).

Completed applications for the New Cell Lines Awards are due on February 5, 2008. Review of applications by the Grants Working Group is anticipated for March or April of 2008, with review and approval by the Independent Citizen’s Oversight Committee (ICOC), CIRM’s governing board, projected for June 2008. .........

ZenMaster

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Alan Trounson named California's new stem cell chief

Alan Trounson named California's new stem cell chief Saturday, 15 September 2007 The California Institute of Regenerative Medicine (CIRM), based in San Francisco, has been searching for a science chief since its first president, Zach Hall, retired at the end of April. On Friday, the California's stem cell agency named the Australian stem cell scientist Alan Trounson as its new president. Twenty members of the 29-person committee that oversees the agency were in attendance at Friday's monthly meeting in Los Angeles. All 20 voted for Trounson's appointment, instantly propelling him to the forefront of stem cell research. Trounson, 61, said he is ready to start a new scientific chapter to a career spent in the laboratory. "It's just a wonderful conclusion to a career in science," said Trounson. "These things don't happen often to us colonials down under." Trounson earned undergraduate degrees from the University of New South Wales in Sydney and his doctorate in embryology from Sydney University in 1974. He is currently director of Monash University's stem cell program in Melbourne. Trounson founded the Australia's Stem Cell Center in 2003, and is well known globally for his work in stem cell and human fertilization. He has also launched eight biotechnology companies, including Singapore-based Embryonic Stem Cell International. Trounson said he is no longer an investor in that company, or any other, working with human embryonic stem cells. Trounson will oversee a staff of about 30 and help the agency meet its goals laid out in a 150-page plan Hall helped draft before he departed. The most ambitious goal of the plan is to move the research out of the laboratory and into tests on people within 10 years. ......... ZenMaster

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California Supreme Court Clears the Way for Stem Cell Grants

CA Supreme Court Clears the Way for Stem Cell Grants Thursday, 17 May 2007 Finally the battle over the Californian stem cell program is over. The California Supreme Court on Wednesday refused to take up the case, already decided in the lower courts. In this way they cleared the way for the state to start selling their proposed $3 billion in bonds. This will finance the research grants distributed by CIRM over the next ten years. ………….. ZenMaster

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UCI Scientist to Start Therapeutic Cloning

UCI Scientist to Start Therapeutic Cloning Tuesday, 15 May 2007 UC Irvine neurobiologist Hans Keirstead and his research team today launched a project to develop stem cell lines that genetically match human patients. These lines would allow scientists to better study conditions ranging from diabetes to Parkinson’s disease, and they would provide the basis for potential patient-specific stem cell treatments. ………….. ZenMaster For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html