The California Institute for Regenerative Medicine was created in 2004 after 59% of California voters approved California Proposition 71 that governs the allocation of the $3 billion authorized to fund stem cell research in California. The agency was authorized to distribute the money in grants, funded by bonds, over a ten-year period to institutions and scientists throughout California that focused on advancing stem cell research and regenerative medicine. The mission of CIRM is: To support and advance stem cell research and regenerative medicine under the highest ethical and medical standards for the discovery and development of cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease injury. Wikipedia.
News Article | April 17, 2017
CHARLOTTESVILLE, Va., April 13, 2017 - For Mazhar Adli, the little glowing dots dancing about on the computer screen are nothing less than the fulfillment of a dream. Those fluorescent dots, moving in real time, are set to illuminate our understanding of the human genome, cancer and other genetic diseases in a way never before possible. Adli, of the University of Virginia School of Medicine's Department of Biochemistry and Molecular Genetics, has developed a way to track genes inside living cells. He can set them aglow and watch them move in three dimensions, allowing him to map their positions much like star charts record the shifting heavens above. And just as the moon influences the tides, the position of genes influences the effects they have; thus, 3D maps of gene locations could lead scientists to a vastly more sophisticated appreciation of how our genes work and interact -- and how they affect our health. "This has been a dream for a long time," Adli said. "We are able to image basically any region in the genome that we want, in real time, in living cells. It works beautifully. ... With the traditional method, which is the gold standard, basically you will never be able to get this kind of data, because you have to kill the cells to get the imaging. But here we are doing it in live cells and in real time." DNA is often depicted as tidy strands stretched out in straight lines. But in reality, our DNA is clumped up inside the nuclei of our cells like cooked spaghetti. "We have two meters of DNA folded into a nucleus that is so tiny that 10,000 of them will fit onto the tip of a needle," Adli explained. "We know that DNA is not linear but forms these loops, these large, three-dimensional loops. We want to basically image those kind of interactions and get an idea of how the genome is organized in three-dimensional space, because that's functionally important." Thinking about DNA as a neat line, he noted, can create misconceptions about gene interactions. Two genes that are far apart in a linear diagram may actually be quite close when folded up inside the cell's nucleus, and that can affect what they do. He used a map analogy: "That's how we believe an element that appears to be in Los Angeles is regulating an element in Virginia - [when the DNA is folded up,] they're not actually that far apart." Adli's new approach, developed in conjunction with colleagues at UVA and the University of California, Berkeley, uses the CRISPR gene editing system that has proved a sensation in the science world. The researchers flag specific genomic regions with fluorescent proteins and then use CRISPR to do chromosome imaging. If they want, they can then use CRISPR to turn genes on and off, using the imaging approach to see what happens. The new method overcomes longstanding limitations of gene imaging. "We were told we would never be able to do this," Adli said. "There are some approaches that let you look at three-dimensional organization. But you do that experiment on hundreds of millions of cells, and you have to kill them to do it. Here, we can look at the single-cell level, and the cell is still alive, and we can take movies of what's happening inside." The business of growing cells just to kill them is both time consuming and a poor way to figure out what was happening with the DNA inside them, he said. It is like trying to figure out the rules of football by looking at blurry pictures of a game. Adli's new approach, on the other hand, lets him sit back and watch the plays unfold in real time. "It's a super exciting thing to be able to do," he said. Adli and his team have described their new method in an article in the scientific journal Nature Communications, making it available to scientists around the world. The paper was authored by Peiwu Qin, Mahmut Parlak, Cem Kuscu, Jigar Bandaria, Mustafa Mir, Karol Szlachta, Ritambhara Singh, Xavier Darzacq, Ahmet Yildiz and Adli. The work was supported by the V Foundation for Cancer Research; the UVA Cancer Center; the National Institutes of Health, grants U54-DK107980, U01-EB021236 and GM094522; the National Science Foundation; and the California Institute for Regenerative Medicine.
News Article | April 26, 2017
When California voters approved US$3 billion in funding for stem-cell research in 2004, biologists flocked to the state, and citizens dreamed of cures for Parkinson’s disease and spinal-cord injuries. Now, the pot of money — one of the biggest state investments in science — is running dry before treatments have emerged, raising questions about whether Californians will pour billions more into stem-cell research. If they don’t, that could leave hundreds of scientists without support, and strand potentially promising therapies before they reach the market. “It’s an issue of great concern,” says Jonathan Thomas, chair of the board for the California Institute for Regenerative Medicine (CIRM) in Oakland. CIRM is now doling out its final $650 million, and its leaders are seeking money from the private sector to carry projects beyond 2020, when the money will run out. Advocates are also surveying voters to determine whether a new request for funding stands a chance in state elections next year. But critics argue against this way of funding research. California voters saw major opportunities for stem cells in 2004 when they passed Proposition 71, which included an agreement to create the corporation that became CIRM. The move was a reaction to then-US president George W. Bush’s decision in 2001 to restrict federal funds for work on human embryonic stem cells. Since CIRM rolled out its first grants in 2006, it has funded more than 750 projects and reported alluring results from clinical trials. In March, a trial partially funded by CIRM showed that nine out of ten children born with severe combined immunodeficiency — or ‘bubble-boy disease’ — a potentially lethal condition in which a person’s immune system does not function properly, were doing well up to eight years after treatment (K. L. Shaw et al. J. Clin. Invest. http://doi.org/b6bp; 2017). They no longer need injections to be able to go to school, play outside or survive colds and other inevitable infections. A dozen facilities constructed by CIRM have helped to push California to the forefront of research on ageing and regenerative medicine. Many grant recipients were early-career academics who had not been able to enter the stem-cell field previously because of the federal restrictions — which were loosened in 2009 — and the high cost of getting started in this kind of work. That barrier makes it difficult for researchers to gather the preliminary data typically required to win grants from the US National Institutes of Health (NIH). To milk its remaining $650 million, CIRM partnered last year with the contract-research organization QuintilesIMS in Durham, North Carolina, to carry out clinical trials. CIRM leaders hope that this move will help to guide 40 novel therapies into trials by 2020. Bob Klein, the property developer who put Proposition 71 on the ballot and established CIRM, isn’t waiting for the money to run out. He leads an advocacy group, Americans for Cures, which will soon poll voters to see whether they would approve another $5 billion in funding. If it looks like at least 70% of Californians support that plan, he’ll start a campaign to put another initiative on the ballot in 2018. Klein hopes that Californians will rise in support of science at a time when the Trump administration has proposed drastic cuts to the NIH budget. If public enthusiasm is not so strong, Klein says, he’ll aim for the 2020 elections, when voter turnout should be higher because it will coincide with the next presidential race. Currently, CIRM’s leaders are seeking other sources of support. “The majority of our projects will not be ripe for interest from big pharma and the venture-capitalist community by the time we run out of funds,” Thomas says. He has been courting large philanthropic foundations and wealthy individuals to raise money to continue the work. John Simpson, who directs stem-cell oversight work at the advocacy group Consumer Watchdog in Santa Monica, California, plans to oppose any effort to extend CIRM. “I acknowledge their scientific advances, but we should not let a flawed process go further,” he says. Simpson dislikes the model of using a vote to secure research funding through public bonds, because then the state lacks budgetary control. Oversight of CIRM has been a problem in the past. In 2012, the US Institute of Medicine found that some scientists vetting grant proposals for CIRM had conflicts of interest. In response, CIRM altered its procedures — but the public still felt betrayed. Jim Lott, a member of the state board that oversees CIRM’s finances, says that he is not satisfied with the changes. He also argues that CIRM may not have been strategic enough in directing research. “Some people say if they had a better focus, they might have achieved cures.” But researchers argue that expectations for cures after only a decade are unrealistic, given the typical pace of drug development. “It would be a catastrophe for California if people say CIRM did not do what it was expected to do,” says Eric Verdin, president of the Buck Institute for Research on Aging in Novato, California. “They’ve built the foundation for the field and attracted people from around the world — you can’t just now pull the plug.”
News Article | April 25, 2017
Irvine, Calif., April 24, 2017 -- Using human skin cells, University of California, Irvine neurobiologists and their colleagues have created a method to generate one of the principle cell types of the brain called microglia, which play a key role in preserving the function of neural networks and responding to injury and disease. The finding marks an important step in the use of induced pluripotent stem (iPS) cells for targeted approaches to better understand and potentially treat neurological diseases such as Alzheimer's. These iPS cells are derived from existing adult skin cells and show increasing utility as a promising approach for studying human disease and developing new therapies. Skin cells were donated from patients at the UCI Alzheimer's Disease Research Center. The study, led by Edsel Abud, Wayne Poon and Mathew Blurton Jones of UCI, used a genetic process to reprogram these cells into a pluripotent state capable of developing into any type of cell or tissue of the body. The researchers then guided these pluripotent cells to a new state by exposing the cells to a series of differentiation factors which mimicked the developmental origin of microglia. The resulting cells act very much like human microglial cells. Their study appears in the current issue of Neuron. In the brain, microglia mediate inflammation and the removal of dead cells and debris. These cells make up 10- to 15-percent of brain cells and are needed for the development and maintenance of neural networks. "Microglia play an important role in Alzheimer's and other diseases of the central nervous system. Recent research has revealed that newly discovered Alzheimer's-risk genes influence microglia behavior. Using these cells, we can understand the biology of these genes and test potential new therapies," said Blurton-Jones, an assistant professor of the Department of Neurobiology & Behavior and Director of the ADRC iPS Core. "Scientists have had to rely on mouse microglia to study the immunology of AD. This discovery provides a powerful new approach to better model human disease and develop new therapies," added Poon, a UCI MIND associate researcher. Along those lines, the researchers examined the genetic and physical interactions between Alzheimer's disease pathology and iPS-microglia. They are now using these cells in three-dimensional brain models to understand how microglia interact with other brain cells and influence AD and the development of other neurological diseases. "Our findings provide a renewable and high-throughput method for understanding the role of inflammation in Alzheimer's disease using human cells," said Abud, an M.D./Ph.D. student. "These translational studies will better inform disease-modulating therapeutic strategies." Blurton Jones, Abud and Poon are with UCI's Institute for Memory Impairments and Neurological Disorders (UCI MIND). Ricardo Ramirez, Eric Martinez, Cecilia Nguyen, Sean Newman, Vanessa Scarfone, Samuel E. Marsh, Cristhian Fimbres, Chad A. Caraway, Ali Mortazavi, Michael Cahalan, Brian Cummings, Gianna Fote, Andriy Yeromin and Anshu Agrawal with UCI; Luke Healy and Jack Antel with McGill University, Montreal; Rakez Kayed with the University of Texas Medical Branch, Galveston, Texas; Karen Gylys with UCLA; and Abdullah Madany and Monica Carson with UC Riverside contributed to the study. The National Institutes of Health, the California Institute for Regenerative Medicine, and the Susan Scott Foundation provided support.
Knoepfler P.S.,University of California at Davis |
Knoepfler P.S.,California Institute for Regenerative Medicine
Advanced Drug Delivery Reviews | Year: 2015
The phrase "bench-to-bedside" is commonly used to describe the translation of basic discoveries such as those on stem cells to the clinic for therapeutic use in human patients. However, there is a key intermediate step in between the bench and the bedside involving governmental regulatory oversight such as by the Food and Drug Administration (FDA) in the United States (US). Thus, it might be more accurate in most cases to describe the stem cell biological drug development process in this way: from bench to FDA to bedside. The intermediate development and regulatory stage for stem cell-based biological drugs is a multifactorial, continually evolving part of the process of developing a biological drug such as a stem cell-based regenerative medicine product. In some situations, stem cell-related products may not be classified as biological drugs in which case the FDA plays a relatively minor role. However, this middle stage is generally a major element of the process and is often colloquially referred to in an ominous way as "The Valley of Death". This moniker seems appropriate because it is at this point, and in particular in the work that ensues after Phase 1, clinical trials that most drug product development is terminated, often due to lack of funding, diseases being refractory to treatment, or regulatory issues. Not surprisingly, workarounds to deal with or entirely avoid this difficult stage of the process are evolving both inside and outside the domains of official regulatory authorities. In some cases these efforts involve the FDA invoking new mechanisms of accelerating the bench to beside process, but in other cases these new pathways bypass the FDA in part or entirely. Together these rapidly changing stem cell product development and regulatory pathways raise many scientific, ethical, and medical questions. These emerging trends and their potential consequences are reviewed here. © 2014 Elsevier B.V.
Yuen B.T.K.,University of California at Davis |
Yuen B.T.K.,California Institute for Regenerative Medicine |
Knoepfler P.S.,University of California at Davis |
Knoepfler P.S.,California Institute for Regenerative Medicine
Cancer Cell | Year: 2013
A host of cancer types exhibit aberrant histone modifications. Recently, distinct and recurrent mutations in a specific histone variant, histone H3.3, have been implicated in a high proportion of malignant pediatric brain cancers. The presence of mutant H3.3 histone disrupts epigenetic posttranslational modifications near genes involved in cancer processes and in brain function. Here, we review possible mechanisms by which mutant H3.3 histones may act to promote tumorigenesis. Furthermore, we discuss how perturbations in normal H3.3 chromatin-related and epigenetic functions may more broadly contribute to the formation of human cancers. © 2013 Elsevier Inc.
Dimmeler S.,Goethe University Frankfurt |
Ding S.,University of California at San Francisco |
Rando T.A.,Stanford University |
Trounson A.,California Institute for Regenerative Medicine
Nature Medicine | Year: 2014
The scientific community is currently witnessing substantial strides in understanding stem cell biology in humans; however, major disappointments in translating this knowledge into medical therapies are flooding the field as well. Despite these setbacks, investigators are determined to better understand the caveats of regeneration, so that major pathways of repair and regrowth can be exploited in treating aged and diseased tissues. Last year, in an effort to contribute to this burgeoning field, Nature Medicine, in collaboration with the Volkswagen Foundation, organized a meeting with a panel of experts in regenerative medicine to identify the most pressing challenges, as well as the crucial strategies and stem cell concepts that can best help advance the translational regenerative field. Here some experts who participated in the meeting provide an outlook at some of those key issues and concepts. © 2014 Nature America, Inc.
News Article | February 15, 2017
LA JOLLA--(February 14, 2017) Not everyone is Fred Astaire or Michael Jackson, but even those of us who seem to have two left feet have got rhythm--in our brains. From breathing to walking to chewing, our days are filled with repetitive actions that depend on the rhythmic firing of neurons. Yet the neural circuitry underpinning such seemingly ordinary behaviors is not fully understood, even though better insights could lead to new therapies for disorders such as Parkinson's disease, ALS and autism. Recently, neuroscientists at the Salk Institute used stem cells to generate diverse networks of self-contained spinal cord systems in a dish, dubbed circuitoids, to study this rhythmic pattern in neurons. The work, which appears online in the February 14, 2017, issue of eLife, reveals that some of the circuitoids--with no external prompting--exhibited spontaneous, coordinated rhythmic activity of the kind known to drive repetitive movements. "It's still very difficult to contemplate how large groups of neurons with literally billions if not trillions of connections take information and process it," says the work's senior author, Salk Professor Samuel Pfaff, who is also a Howard Hughes Medical Institute investigator and holds the Benjamin H. Lewis Chair. "But we think that developing this kind of simple circuitry in a dish will allow us to extract some of the principles of how real brain circuits operate. With that basic information maybe we can begin to understand how things go awry in disease." Nerve cells in your brain and spinal cord connect to one another much like electronic circuits. And just as electronic circuits consist of many components, the nervous system contains a dizzying array of neurons, often resulting in networks with many hundreds of thousands of cells. To model these complex neural circuits, the Pfaff lab prompted embryonic stem cells from mice to grow into clusters of spinal cord neurons, which they named circuitoids. Each circuitoid typically contained 50,000 cells in clumps just large enough to see with the naked eye, and with different ratios of neuronal subtypes. With molecular tools, the researchers tagged four key subtypes of both excitatory (promoting an electrical signal) and inhibitory (stopping an electrical signal) neurons vital to movement, called V1, V2a, V3 and motor neurons. Observing the cells in the circuitoids in real time using high-tech microscopy, the team discovered that circuitoids composed only of V2a or V3 excitatory neurons or excitatory motor neurons (which control muscles) spontaneously fired rhythmically, but that circuitoids comprising only inhibitory neurons did not. Interestingly, adding inhibitory neurons to V3 excitatory circuitoids sped up the firing rate, while adding them to motor circuitoids caused the neurons to form sub-networks, smaller independent circuits of neural activity within a circuitoid. "These results suggest that varying the ratios of excitatory to inhibitory neurons within networks may be a way that real brains create complex but flexible circuits to govern rhythmic activity," says Pfaff. "Circuitoids can reveal the foundation for complex neural controls that lead to much more elaborate types of behaviors as we move through our world in a seamless kind of way." Because these circuitoids contain neurons that are actively functioning as an interconnected network to produce patterned firing, Pfaff believes that they will more closely model a normal aspect of the brain than other kinds of cell culture systems. Aside from more accurately studying disease processes that affect circuitry, the new technique also suggests a mechanism by which dysfunctional brain activity could be treated by altering the ratios of cell types in circuits. Other authors included: Matthew J. Sternfeld, Christopher A. Hinckley, Niall J. Moore, Matthew T. Pankratz, Kathryn L. Hilde, Shawn P. Driscoll, Marito Hayashi, Neal D. Amin, Dario Bonanomi, Wesley D. Gifford, and Martyn Goulding of Salk; and Kamal Sharma of the University of Illinois, Chicago. The work was funded by the National Cancer Institute at the National Institutes of Health; the Rose Hills Foundation; the H. A. and Mary K. Chapman Charitable Trust; the University of California, San Diego, Neurosciences Graduate Program; a U.S. National Research Service Award fellowship from the U.S. National Institutes of Health National Institute of Neurological Disorders and Stroke; the National Science Foundation; the Japanese Ministry of Education, Culture, Sports, Science, and Technology Long-Term Student Support Program; the Timken-Sturgis Foundation; the California Institute for Regenerative Medicine; the Howard Hughes Medical Institute; the Christopher and Dana Reeve Foundation; the Marshall Heritage Foundation; and the Sol Goldman Charitable Trust. Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
News Article | March 2, 2017
In June 2016, on the day before his high school graduation, nineteen-year-old Jake Javier suffered a terrible diving accident that left him paralyzed. The incident was covered widely across Bay Area news media and residents quickly mobilized to support Jake and his family. In the March issue of Diablo Magazine, Senior Editor Pete Crooks revisits the story of Jake’s bravery and trailblazing medical care. Crooks caught up with Jake and his parents to discuss life after the accident and explore the life-saving treatments he received at John Muir’s Walnut Creek Medical Center and Santa Clara Valley Medical Center. As part of his therapy, Jake participated in a groundbreaking stem cell procedure by the California Institute for Regenerative Medicine in Oakland. Jake was one of five people in the world to receive an injection of 10 million embryonic stem cells. “This story needed to be revisited.” says Crooks. “Diablo magazine is the town square of the East Bay, and we needed to give Jake’s story time to develop and really share how brave and pioneering he is.” The article details the days and months following the accident and how the community rallied around Jake. Friends, classmates and even strangers joined forces to organize fundraising drives and provide support for the Javier family. To read about the incredible support from the community, Jake’s plans for a future as a college freshman, and view a link to support Jake through the JaviStrong54 Foundation, visit diablomag.com. About Diablo Magazine Covering topics ranging from travel, culture, and personalities to entertainment, recreation, and food, Diablo magazine is written specifically for the San Francisco East Bay market—from Central Contra Costa, into the Oakland and Berkeley hills, and throughout the Tri-Valley. With locally driven editorial content, beautiful photography, and resource listings, Diablo is a unique celebration of the San Francisco East Bay. Published since 1979, Diablo has been recognized for its editorial and design with numerous awards, including previous Maggie Awards for Best Overall Publication and Best Regional and State Magazine in the consumer category. About Diablo Publications For 35 years, Diablo Publications has been creating award-winning publications, including Diablo magazine, Napa Sonoma magazine, Diablo Weddings, the Oakland Visitors' Guide, Diablo Arts, and the Tri-Valley California Visitors Guide. Covering travel, theater, lifestyle, and home design, Diablo Publications celebrates the people, places, and pleasures of the East Bay and North Bay. Diablo Publications’ custom content division, Diablo Custom Publishing (DCP), provides complete print and online marketing communications and customer publishing services for corporate clients nationwide. For more information, visit diablomag.com or dcpubs.com. Diablo Publications is an employee-owned company.
Trounson A.,California Institute for Regenerative Medicine |
Shepard K.A.,California Institute for Regenerative Medicine |
DeWitt N.D.,California Institute for Regenerative Medicine
Current Opinion in Genetics and Development | Year: 2012
In the past few years, cellular programming, whereby virtually all human cell types, including those deep within the brain or internal organs, can potentially be produced and propagated indefinitely in culture, has opened the door to a new type of disease modeling. Importantly, many diseases or disease predispositions have genetic components that vary from person to person. Now cells from individuals can be readily reprogrammed to form pluripotent cells, and then directed to differentiate into the lineage and the cell type in which the disease manifests. Those cells will contain the genetic contribution of the donor, providing an excellent model to delve into human disease at the level of individuals and their genomic variants. To date, over fifty such disease models have been reported, and while the field is young and hurdles remain, these tools promise to inform scientists about the cause and cellular-molecular mechanisms involved in pathology, unravel the role of environmental versus hereditary factors driving disease, and provide an unprecedented tool for screening therapeutic agents that might slow or halt disease progression. © 2012 Elsevier Ltd.
Trounson A.,California Institute for Regenerative Medicine |
Grieshammer U.,California Institute for Regenerative Medicine
Cell | Year: 2012
In this issue, Tachibana et al. report the generation of the first chimeras from a nonhuman primate, the rhesus monkey. Unlike mice, rhesus chimeras fail to form when embryonic stem cells are injected into blastocysts. Instead, chimera formation is achieved by aggregation of several four-cell embryos. © 2012 Elsevier Inc.