News Article | November 8, 2016
JUPITER, FL, November 8, 2016 - The Celia Lipton Farris and Victor W. Farris Foundation has made a $1.135 million gift to The Scripps Research Institute (TSRI) to create the Farris Foundation Endowed Graduate Fellowship on the Jupiter, Florida campus. "I want to thank the Farris Foundation for its generous gift to support our graduate program," said TSRI President Peter Schultz. "Gifts like this will help train the next generation of scientists who are critical to the future of biomedical research--and to build a lasting legacy of scientific excellence." The new Farris Foundation Endowed Graduate Fellowship will provide annual support for doctoral students at Scripps Florida in perpetuity. "Our gift is an investment in the continued strength of biomedical research at Scripps Florida," said Christine Koehn, executive director of the Farris Foundation, "so that young scholars will be able to reach their full potential as world-class scientists." TSRI's graduate program is consistently rated by U.S. News and World Report as in the top 10 of its kind in the nation for chemistry and biology. Scripps Florida established a branch of the graduate program in 2005; the campus has since graduated 28 PhDs, and 49 doctoral students are currently enrolled. The Celia Lipton Farris and Victor W. Farris Foundation, created in 1986 by a merger of the Victor W. Farris Foundation and the Celia Lipton Farris Foundation, seeks to support projects that provide the structure, encouragement and incentive that enable people to help themselves lead more successful, inspired and fulfilling lives. More information on The Celia Lipton Farris and Victor W. Farris Foundation and TSRI's graduate program is available on their respective websites. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .
News Article | February 15, 2017
JUPITER, FL, Feb. 14, 2017 - A pair of scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to $3.3 million from the National Cancer Institute of the National Institutes of Health (NIH) to create the next generation of breast cancer treatments for the thousands of patients whose current treatment options are limited. Ben Shen, TSRI professor and co-chair of the Department of Chemistry, and Christoph Rader, TSRI associate professor in the Department of Immunology and Microbiology, will co-lead the new five-year study. The researchers aim to develop a potent type of therapy known as an antibody-drug conjugate (ADC). This new class of anti-cancer drugs combines the specificity of antibodies, which attack only cells they recognize, with a highly toxic payload designed to kill specific cancer cells with far greater efficiency than most currently available treatments. So far, only three of these combination therapies have been approved by the U.S. Food and Drug Administration (FDA). The new ADC approach targets HER2-postive and ROR1-positive breast cancers, which are often aggressive and harder to treat with conventional chemotherapy and hormone drugs. The new grant builds on the work done in both the Shen and Rader labs. Shen and his colleagues recently uncovered a new class of natural products called tiancimycins, (TNMs) which kill selected cancer cells more rapidly and more completely compared with the toxic molecules already used in FDA-approved ADCs. Rader, who has spent most of his scientific career at TSRI and the NIH, has been studying and developing site-specific ADCs to treat cancer. "This grant matches my lab's work on advancing antibody engineering and conjugation technologies with the world-class natural product-based drug discovery in Ben Shen's lab," Rader said. "It's precisely what I came to Scripps Florida for: to build new molecules at the interface of chemistry and biology that can advance medicine. I'm very pleased that the NIH continues to invest in our ideas." Since HER2 and ROR1 expression is highly complementary, the new collaboration could provide new treatment options for at least 50 percent of breast cancer patients, Shen noted. "At Scripps Florida we not only do great science, but we have even greater opportunities to collaborate on projects like this," Shen added. "The combination of Christoph Rader's antibody technology and the tiancimycins, which have been proven to be exquisitely potent, should produce an antibody drug conjugate that we hope to move very quickly into the clinic." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .
Choi J.Y.,Scripps Florida |
Podust L.M.,University of California at San Francisco |
Roush W.R.,Scripps Florida
Chemical Reviews | Year: 2014
CYP51 is considered one of the most ancient P450 protein families. structure guided lead development has proven to be a productive strategy for generating highly potent antiparasitic CYP51 inhibitors. Lead selectivity can also be assessed in silico at early stages of drug discovery via molecular docking and comparative modeling of newly designed inhibitors against the structures for human CYP enzymes. Drugs of the azole class have been developed as antifungal agents for human diseases. Substantial efforts have been made to repurpose approved antifungal azole drugs for treatment of Chagas disease. It is likely that parasite-specific inhibitors, optimized by structure-based drug-design criteria with close monitoring of PK parameters and inhibition of human drug-metabolizing CYPs, will be more effective in developing efficacious treatments of human T. cruzi and other protozoan infections than the antifungal agents. The long-term success of these efforts will depend on the ability to develop potent therapeutic agents ensuring parasitological cure with minimal or no harm to the human host.
Dorronsoro A.,Scripps Florida |
Robbins P.D.,Scripps Florida
Stem Cell Research and Therapy | Year: 2013
Transplantation of adult stem cells is being used to facilitate repair or regeneration of damaged or diseased tissues. However, in many cases, the therapeutic effects of the injected stem cells are mediated by factors secreted by stem cells and not by differentiation of the transplanted stem cells. Recent reports have identified a class of microvesicles, termed exosomes, released by stem cells that are able to confer therapeutic effects on injured renal and cardiac tissue. In this issue of Stem Cell Research & Therapy, Zhou and colleagues demonstrate the ability of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs), but not non-stem cell-derived exosomes, to improve acute kidney injury induced by cisplatin in rats. The authors demonstrate that hucMSC exosomes can reduce cisplatin-mediated renal oxidative stress and apoptosis in vivo and increase renal epithelial cell proliferation in culture. These results suggest that stem cell-derived exosomes, which are easy to isolate and safer to use than the parental stem cells, could have significant clinical utility. © 2013 BioMed Central Ltd.
Weissmann C.,Scripps Florida |
Li J.,Scripps Florida |
Mahal S.P.,Scripps Florida |
Browning S.,Scripps Florida |
Browning S.,Cytonics Corporation
EMBO Reports | Year: 2011
Prions consist mainly, if not entirely, of PrP Sc, an aggregated conformer of the host protein PrP C. Prions come in different strains, all based on the same PrP C sequence, but differing in their conformations. The efficiency of prion transmission between species is usually low, but increases after serial transmission in the new host, suggesting a process involving mutation and selection. Even within the same species, the transfer of prions between cell types entails a selection of favoured 'substrains', and propagation of prions in the presence of an inhibitory drug can result in the appearance of drug-resistant prion populations. We propose that prion populations are comprised of a variety of conformers, constituting 'quasi-species', from which the one replicating most efficiently in a particular environment is selected. © 2011 Euroopeean Moleolecullar Bioloology Organnization.
Weissmann C.,Scripps Florida
Biochemical and Biophysical Research Communications | Year: 2013
Major advances in science are usually launched by new methods or techniques. Because this essay is not intended as a history of science, I shall not invoke the invention of the microscope or telescope as the gateways to inner and outer space, but will restrict myself to developments I have witnessed, or almost witnessed, during my scientific lifetime. © 2013 Elsevier Inc. All rights reserved.
Wang M.,University of Massachusetts Medical School |
Fuhrmann J.,Scripps Florida |
Thompson P.R.,University of Massachusetts Medical School
Biochemistry | Year: 2014
Protein arginine methyltransferase 5 (PRMT5) is a histone-modifying enzyme whose activity is aberrantly upregulated in various cancers and thereby contributes to a progrowth phenotype. Indeed, knockdown of PRMT5 leads to growth arrest and apoptosis, suggesting that inhibitors targeting this enzyme may have therapeutic utility in oncology. To aid the development of inhibitors targeting PRMT5, we initiated mechanistic studies geared to understand how PRMT5 selectively catalyzes the symmetric dimethylation of its substrates. Toward that end, we characterized the regiospecificity and processivity of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5), insect cell-expressed human PRMT5 (hPRMT5), and human PRMT5 complexed with methylosome protein 50 (MEP50), i.e., the PRMT5·MEP50 complex. Our studies confirm that arginine 3 is the only site of methylation in both histone H4 and H4 tail peptide analogues and that sites distal to the site of methylation promote the efficient symmetric dimethylation of PRMT5 substrates by increasing the affinity of the monomethylated substrate for the enzyme. Additionally, we show for the first time that both cPRMT5 and the hPRMT5·MEP50 complex catalyze substrate dimethylation in a distributive manner, which is assisted by long-range interactions. Finally, our data confirm that MEP50 plays a key role in substrate recognition and activates PRMT5 activity by increasing its affinity for protein substrates. In total, our results suggest that it may be possible to allosterically inhibit PRMT5 by targeting binding pockets outside the active site. © 2014 American Chemical Society.
Halvorsen G.T.,Scripps Florida |
Roush W.R.,Scripps Florida
Tetrahedron Letters | Year: 2011
A stereoselective synthesis of the decahydrofluorene core of the hirsutellones was accomplished in eight steps and in 43% overall yield. The key step of the synthesis is the highly stereoselective intramolecular Diels-Alder cyclization of the siloxacyclopentene-constrained tetraene 1. © 2010 Elsevier Ltd. All rights reserved.
Li J.,Scripps Florida |
Mahal S.P.,Scripps Florida |
Demczyk C.A.,Scripps Florida |
Weissmann C.,Scripps Florida
EMBO Reports | Year: 2011
Murine prions transferred from brain to cultured cells gradually adapt to the new environment. Brain-derived 22L prions can infect neuroblastoma-derived PK1 cells in the presence of swainsonine (swa); that is, they are ('swa resistant'). PK1 cell-adapted 22L prions are swa sensitive; however, propagation in swa results in selection of swa-resistant substrains. Cloned, PK1 cell-adapted 22L prions were initially unable to develop swa resistance ((swa incompetent)); however, after serial propagation for 30-90 doublings, four of nine clones became swa competent, showing that swa-resistant (mutants) arose during replication. Mutations in the case of prions are attributed to heritable changes in PrP Sc conformation. One clone remained swa incompetent even after 10 35-fold expansion; surprisingly, after propagation in brain, it yielded swa-resistant prions, indistinguishable from the original 22L population. Thus, cell-adapted 22L prions assumed either mutable or virtually immutable conformations; however, when passaged through the brain all became mutable. Mutability is thus a substrain-specific attribute. © 2011 European Molecular Biology Organization.
News Article | November 22, 2016
Sleepiness after a large meal is something we all experience, and new research with fruit flies suggests higher protein and salt content in our food, as well as the volume consumed, can lead to longer naps. Writing in the journal eLife, scientists from The Scripps Research Institute, US, have for the first time found a way to study 'food comas' in the fruit fly Drosophila melanogaster and explained some of the causes behind this phenomenon. They created a system that can measure both the sleep and feeding behaviors of individual fruit flies and discovered that, in much the same way as humans, the animals sleep for longer periods following larger meals. Further studies also revealed that certain types of food can promote post-meal sleep. "In Drosophila, there is a well-documented interaction between sleep and metabolism, whereby flies suppress sleep or increase their activity when starved," says senior author William Ja, PhD, Associate Professor in the Department of Metabolism and Aging at Scripps Florida. "However, the acute effects of food consumption on sleep have not yet been tested, largely because there was no system available to do so." To better understand this relationship, Ja and his team created the Activity Recording CAFE (ARC), the first system for flies that enables visual tracking of food consumption and animal motion. Recordings of fruit flies' behavior from this system reveal that, after eating a meal, the animals sleep more before returning to a normal state of wakefulness. The sleep period generally lasts around 20 to 40 minutes, with flies that eat larger portions generally sleeping more. To determine if individual nutrients could modulate post-meal sleep, the team gave the flies food consisting of protein, salt or sugar. They found that only protein and salt were effectors of post-meal sleep, suggesting that this form of sleep can indeed be regulated by specific food types. "We next sought to identify a neuronal mechanism by which feeding drives post-meal sleep," explains first author Keith Murphy. "By using genetic tools to turn neurons on and off in the fly brain, we were surprised to find a number of circuits that play a role in controlling this behavior." A previous study has shown that leucokinin (Lk) neurons are involved in meal-size regulation, indicating that this system acts rapidly during feeding to signal a behavioral shift. Building on this work, the authors of the current study demonstrate that the Lk system plays a role in post-meal sleep. "A subset of leucokinin receptor (Lkr) neurons was necessary to initiate post-meal sleep in the presence of protein specifically," Murphy says. "While we expected that flies defective in protein sensing would experience post-meal sleep in a similar way to those fed only sucrose, we found instead that they had a waking response. Our analysis suggests that ingested protein promotes both sleep and wakefulness, and that the wakefulness is counterbalanced by Lkr neuronal activity." They also found that other brain circuits are sensitive to the fruit fly's internal clock, reducing post-meal sleepiness only around dusk. Taking these results together, the team concludes that post-meal sleepiness can be regulated in a number of different ways in flies and humans alike. "The ARC provides a starting point for future studies aimed at uncovering the exact genes and circuits that enable meal size, protein and salt to drive sleep," Ja adds. "As sleep is a vulnerable state for animals in nature, it will be interesting to discover why post-meal naps are necessary." The paper 'Postprandial sleep mechanics in Drosophila' can be freely accessed online at http://dx. . Contents, including text, figures, and data, are free to reuse under a CC BY 4.0 license. eLife is a unique collaboration between the funders and practitioners of research to improve the way important research is selected, presented, and shared. eLife publishes outstanding works across the life sciences and biomedicine -- from basic biological research to applied, translational, and clinical studies. All papers are selected by active scientists in the research community. Decisions and responses are agreed by the reviewers and consolidated by the Reviewing Editor into a single, clear set of instructions for authors, removing the need for laborious cycles of revision and allowing authors to publish their findings quickly. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Learn more at elifesciences.org.