Sanford Consortium for Regenerative Medicine

San Diego, CA, United States

Sanford Consortium for Regenerative Medicine

San Diego, CA, United States
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News Article | April 21, 2017
Site: www.sciencemag.org

“Who do you side with: scientific community or Donald Trump?” read the Facebook headline of a 15 March article in the San Diego Union-Tribune. In a comment, “March for Science SD” wrote that the headline “unfortunately does very little to help our nonpartisan message.” Many organizers of March for Science events around the world have gone to some lengths to stress that the event is not about U.S. President Donald Trump, and the issues at the fore obviously transcend political parties. But there’s an inconvenient truth: Had Trump not been elected; filled U.S. government slots with people hostile to climate change, evolution, and environmental protection; and crafted a budget that proposes slashing funding for traditional bipartisan darlings like the National Institutes of Health, there would not be more than 600 cities in 69 countries marching for science tomorrow. And clearly there was a Trump elephant in the corner at a small poster-making event held in San Diego on the evening of 20 April. Three dozen people gathered on the patio of the Bella Vista Social Club and Caffé, a popular hangout at the Sanford Consortium for Regenerative Medicine that sports an OMG ocean view. It is neighbored by the University of California, San Diego (UCSD), the Salk Institute for Biological Studies, the Scripps Research Institute, and a dozen biotechs. The poster makers included lab techs, undergrads, Ph.D. hopefuls, postdocs, and nonscientists. The funniest, most provocative signs all had unsubtle anti-Trump references. Jessica Bruhn, a postdoc at Salk who helped organize the event, acknowledged that her own institution was on the fence for some time about supporting the march because it did not want to engage in partisan politics. “There was a fine line we were dancing at the Salk,” said Bruhn, a structural biologist who studies HIV. “The final straw was Trump’s proposed budget.” Salk President Elizabeth Blackburn indeed issued a strong endorsement of the march in the wake of the budget proposal, which “deeply appalled” her, she wrote in an open letter. Scripps grad student Bryan Martin, another structural biologist, took a different tack. He said focusing on Trump obscures the fact that science is apolitical. “Where does it get us?” he asked. The emphasis on inclusiveness and nonpartisanship he thinks combats the divisiveness that’s at the core of the current tension—and shifts the debate away from the exclusively political arena. “There are fights about science budgets, but there are larger issues about science education,” he said. Bridget  Kohlnhofer, a grad student at UCSD, flat out said, “I’m not doing it for political reasons.” Her charmingly straightforward, unquestionably nonpartisan sign could have been waved at a march for science under, say, a Bernie Sanders administration: A few of the nonscientists making posters were unabashed dump Trumpers who saw no reason to downplay their disgust. “We should take away all of Trump’s drugs—including his hair medication,” said Shay Miller, who is currently unemployed. “Who doesn’t like science?” Genie Phillips, who has graying hair highlighted by a hank of pink, was bluntest of all. “The march is all about rejection of Trump and his administration,” said Phillips, who said she’s been an activist her entire adult life. “Some people say we shouldn’t have so many marches. Have as many as you want!” Yet Phillips quickly recognized when she came to this poster-making event that people had come out for a variety of reasons. “I wanted to put #resist on my poster,” she said, referring to a popular anti-Trump meme. But when she looked at other people’s signs, she went with the decidedly more poetic: “Always question, always wonder.”


Cheng J.,Shantou University | Morisaki H.,Japan National Cardiovascular Center Research Institute | Toyama K.,Osaka University of Pharmaceutical Sciences | Sugimoto N.,Osaka University of Pharmaceutical Sciences | And 5 more authors.
BMC Endocrine Disorders | Year: 2015

Background: Insulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle. Methods: Recognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions. Results: Disruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase. Conclusions: Taken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes. © 2014 Cheng et al.; licensee BioMed Central Ltd.


PubMed | University of Pennsylvania, Osaka University of Pharmaceutical Sciences, Osaka University, Tottori University and 3 more.
Type: | Journal: Molecular genetics and metabolism reports | Year: 2016

Mutation of the AMP deaminase 1 (AMPD1) gene, the predominate AMPD gene expressed in skeletal muscle, is one of the most common inherited defects in the Caucasian population; 2-3% of individuals in this ethnic group are homozygous for defects in the AMPD1 gene. Several studies of human subjects have reported variable results with some studies suggesting this gene defect may cause symptoms of a metabolic myopathy and/or easy fatigability while others indicate individuals with this inherited defect are completely asymptomatic. Because of confounding problems in assessing muscle symptoms and performance in human subjects with different genetic backgrounds and different environmental experiences such as prior exercise conditioning and diet, a strain of inbred mice with selective disruption of the AMPD1 was developed to study the consequences of muscle AMPD deficiency in isolation. Studies reported here demonstrate that these animals are a good metabolic phenocopy of human AMPD1 deficiency but they exhibit no abnormalities in muscle performance in three different exercise protocols.


Taylor-Weiner H.,University of California at San Diego | Schwarzbauer J.E.,Sanford Consortium for Regenerative Medicine | Engler A.J.,University of California at San Diego | Engler A.J.,Princeton University
Stem Cells | Year: 2013

Differentiation methods often rely exclusively on growth factors to direct mouse embryonic stem cell (ESC) fate, but the niche also contains fibrillar extracellular matrix (ECM) proteins, including fibronectin (FN) and laminin, which could also direct cell fate. Soluble differentiation factors are known to increase ECM expression, yet ECM's ability to direct ESC fate is not well understood. To address the extent to which these proteins regulate differentiation when assembled into a matrix, we examined mouse ESC embryoid bodies (EBs) and found that their ability to maintain pluripotency marker expression was impaired by soluble serum FN. EBs also showed a spatiotemporal correlation between expression of FN and GATA4, a marker of definitive endoderm (DE), and an inverse correlation between FN and Nanog, a pluripotency marker. Maintenance of mouse ESC pluripotency prevented fibrillar matrix production, but induction medium created lineage-specific ECM containing varying amounts of FN and lami-nin. Mouse ESC-derived matrix was unlike conventional fibroblast-derived matrix, which did not contain laminin. Naïve mouse ESCs plated onto ESC- and fibroblast-derived matrix exhibited composition-specific differentiation. With exogenously added laminin, fibroblast-derived matrix is more similar in composition to mouse ESC-derived matrix and lacks residual growth factors that mouse ESC matrix may contain. Naïve mouse ESCs in DE induction medium exhibited dose-dependent DE differentiation as a function of the amount of exogenous laminin in the matrix in an a3 integrin-dependent mechanism. These data imply that fibrillar FN is necessary for loss of pluripotency and that laminin within a FN matrix improves DE differentiation. © AlphaMed Press.


Akizu N.,University of California at San Diego | Cantagrel V.,University of California at San Diego | Cantagrel V.,French Institute of Health and Medical Research | Schroth J.,University of California at San Diego | And 25 more authors.
Cell | Year: 2013

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease. © 2013 Elsevier Inc.


Vincent L.G.,University of California at San Diego | Engler A.J.,Sanford Consortium for Regenerative Medicine
Nature Materials | Year: 2013

Jason Burdick and colleagues have demonstrated that the differentiation of mesenchymal stem cells (MSCs) encapsulated in degradable, covalently crosslinked hyaluronic hydrogels is mediated by degradation-specific traction stresses. To make their gels degradable, the researchers first incorporated both methacrylate and maleimide functional groups onto the hyaluronic backbone, and used the reactions of the maleimide groups with the thiols on degradable peptides to form a primary gel. The gel could then be covalently crosslinked by radical polymerization of the methacrylate groups in the presence of both a photoinitiator and ultraviolet light. When using the degradable hydrogel, Burdick and co-authors found that local degradability was needed for entrapped cells to be able to rearrange their cytoskeletal structure and undergo osteogenesis. The findings from Burdick and colleagues support the notion that, unlike in two dimensions, in three dimensions matrix-driven cell tension drives cell fate irrespective of cell morphology and spread area.


Fox R.G.,University of California at San Diego | Lytle N.K.,University of California at San Diego | Jaquish D.V.,University of California at San Diego | Park F.D.,University of California at San Diego | And 24 more authors.
Nature | Year: 2016

Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: They preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.


Barrett C.L.,University of California at San Diego | Schwab R.B.,University of California at San Diego | Jung H.C.,University of California at San Diego | Crain B.,University of California at San Diego | And 6 more authors.
PLoS ONE | Year: 2013

Background: The only therapeutic options that exist for squamous cell lung carcinoma (SCC) are standard radiation and cytotoxic chemotherapy. Cancer stem cells (CSCs) are hypothesized to account for therapeutic resistance, suggesting that CSCs must be specifically targeted. Here, we analyze the transcriptome of CSC and non-CSC subpopulations by RNA-seq to identify new potential therapeutic strategies for SCC. Methods: We sorted a SCC into CD133- and CD133+ subpopulations and then examined both by copy number analysis (CNA) and whole genome and transcriptome sequencing. We analyzed The Cancer Genome Atlas (TCGA) transcriptome data of 221 SCCs to determine the generality of our observations. Results: Both subpopulations highly expressed numerous mRNA isoforms whose protein products are active drug targets for other cancers; 31 (25%) correspond to 18 genes under active investigation as mAb targets and an additional 4 (3%) are of therapeutic interest. Moreover, we found evidence that both subpopulations were proliferatively driven by very high levels of c-Myc and the TRAIL long isoform (TRAILL) and that normal apoptotic responses to high expression of these genes was prevented through high levels of Mcl-1L and Bcl-xL and c-FlipL-isoforms for which drugs are now in clinical development. SCC RNA-seq data (n = 221) from TCGA supported our findings. Our analysis is inconsistent with the CSC concept that most cells in a cancer have lost their proliferative potential. Furthermore, our study suggests how to target both the CSC and non-CSC subpopulations with one treatment strategy. Conclusions: Our study is relevant to SCC in particular for it presents numerous potential options to standard therapy that target the entire tumor. In so doing, it demonstrates how transcriptome sequencing provides insights into the molecular underpinnings of cancer propagating cells that, importantly, can be leveraged to identify new potential therapeutic options for cancers beyond what is possible with DNA sequencing. © 2013 Barrett et al.


PubMed | University of Michigan, Parc Recerca Biomedica de Barcelona, University of Chicago, Scripps Research Institute and 2 more.
Type: | Journal: eLife | Year: 2015

Comparative genomics studies in primates are restricted due to our limited access to samples. In order to gain better insight into the genetic processes that underlie variation in complex phenotypes in primates, we must have access to faithful model systems for a wide range of cell types. To facilitate this, we generated a panel of 7 fully characterized chimpanzee induced pluripotent stem cell (iPSC) lines derived from healthy donors. To demonstrate the utility of comparative iPSC panels, we collected RNA-sequencing and DNA methylation data from the chimpanzee iPSCs and the corresponding fibroblast lines, as well as from 7 human iPSCs and their source lines, which encompass multiple populations and cell types. We observe much less within-species variation in iPSCs than in somatic cells, indicating the reprogramming process erases many inter-individual differences. The low within-species regulatory variation in iPSCs allowed us to identify many novel inter-species regulatory differences of small magnitude.


PubMed | University of California at San Diego, University of Nebraska Medical Center, Ionis Pharmaceuticals, Sanford Consortium for Regenerative Medicine and Keio University
Type: Journal Article | Journal: Nature | Year: 2016

Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

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