Author Interviews, Genetic Research, Nature, Scripps / 21.06.2017

MedicalResearch.com Interview with: [caption id="attachment_35494" align="alignleft" width="146"]Michael Farzan PhD Co-chair and Professor Department of Immunology and Microbiology  Florida Campus  The Scripps Research Institute Jupiter, Florida Dr. Farzan[/caption] Michael Farzan PhD Co-chair and Professor Department of Immunology and Microbiology Florida Campus The Scripps Research Institute Jupiter, Florida MedicalResearch.com: What is the background for this study? What are the main findings? Response: CRISPR is system for immune protection of bacteria.  It has now been widely adopted for use in editing mammalian cells.  The most commonly used CRISPR effector protein is Cas9.  Cas9 binds a guide RNA to recognize a DNA target, for example an incoming virus infecting a bacterium, or a gene in a human chromosome.  In bacteria, Cas9 requires a second protein to clear the guide RNA from a longer "CRISPR array", basically a string of guide RNAs. We have been studying a CRISPR effector protein related to Cas9 called Cpf1.  In bacteria it was know that, unlike Cas9, Cpf1 could cleave a CRISPR array by itself, without assistance from a second protein.  We knew that if it could do the same thing in human cells, it would help to simplify a number of gene-editing applications.  We were able to show that Cas9 could indeed excise multiple guide RNAs from a single message RNA in human cells.  We further showed that this approach was more efficient than the previous ways that guide RNAs were generated for gene editing, even more so when multiple guide RNAs were needed.
Author Interviews, Pharmacology, Scripps, Weight Research / 15.11.2016

MedicalResearch.com Interview with: [caption id="attachment_29284" align="alignleft" width="133"]Ken Fujioka M.D. Director of the Center for Weight Management Scripps Clinical Department of Endocrinology La Jolla CA Dr. Ken Fujioka[/caption] Ken Fujioka M.D. Director of the Center for Weight Management Scripps Clinical Department of Endocrinology La Jolla CA MedicalResearch.com: What is the background for this study? Response: Obesity is an odd disease that has many causes (overeating, underactivity, the patient being placed on a medication that drives up weight and a whole lot of other causes that result in a higher weight) so trying to find the right treatment, in this case a weight loss medication, for a particular patient is not an easy task. If there is a way to find out if you’ve picked the right medication (a weight loss of at least 5%) then this can help you decide whether you should keep the patient on the medication or stop the medication. There are two huge benefits to this: 1. Is that you find your responders (patients) that will go on to lose weight and do well and 2. When you stop the medication in the non-responders you eliminate any potential adverse events from the weight loss medication. Thus this study was designed to find out if early weight loss can predict who will go on to lose a significant amount of weight on Liraglutide. And yes those who lose weight go on to lose weight.
Author Interviews, Memory, Scripps / 23.09.2016

MedicalResearch.com Interview with: [caption id="attachment_28286" align="alignleft" width="144"]Ron L. Davis, PhD Professor and Chair Department of Neuroscience Florida campus of The Scripps Research Institute Dr. Ron Davis[/caption] Ron L. Davis, PhD Professor and Chair Department of Neuroscience Florida campus of The Scripps Research Institute MedicalResearch.com: What is the background for this study? What are the main findings? Response: While calcium’s importance for our bones and teeth is well known, its role in neurons—in particular, its effects on processes such as learning and memory—has been less well defined. Our new study, published in the journal Cell Reports, offers new insights how calcium in mitochondria—the powerhouse of all cells—can impact the development of the brain and adult cognition. Specifically, we show in fruit flies, a widely used model system, that blocking a channel that brings calcium to the mitochondria called “mitochondrial calcium uniporter” causes memory impairment but does not alter learning capacity. That surprised us – we thought they wouldn’t be able to learn at all. This is important because defects in the same calcium channel function have been shown to be associated with intellectual disability in humans.
Author Interviews, Memory, Scripps / 19.09.2016

MedicalResearch.com Interview with: [caption id="attachment_28094" align="alignleft" width="144"]Ron L. Davis, PhD Professor and Chair Department of Neuroscience Florida campus of The Scripps Research Institute Dr. Ron L. Davis[/caption] Ron L. Davis, PhD Professor and Chair Department of Neuroscience Florida campus of The Scripps Research Institute MedicalResearch.com: What is the background for this study? What are the main findings? Response: While calcium’s importance for our bones and teeth is well known, its role in neurons—in particular, its effects on processes such as learning and memory—has been less well defined. Our new study, published in the journal Cell Reports, offers new insights how calcium in mitochondria—the powerhouse of all cells—can impact the development of the brain and adult cognition. Specifically, we show in fruit flies, a widely used model system, that blocking a channel that brings calcium to the mitochondria called “mitochondrial calcium uniporter” causes memory impairment but does not alter learning capacity. That surprised us – we thought they wouldn’t be able to learn at all. This is important because defects in the same calcium channel function have been shown to be associated with intellectual disability in humans.
Alcohol, Author Interviews, PNAS, Scripps / 19.05.2015

Interview of Candice Contet, Ph.D. Assistant Professor The Scripps Research Institute, La Jolla, CAMedicalResearch.com Interview with: Interview of Candice Contet, Ph.D. Assistant Professor The Scripps Research Institute, La Jolla, CA MedicalResearch: What is the background for this study? Dr. Contet: Alcohol changes the activity of numerous proteins in the brain. One of them is an ion channel found in neurons, the G-protein activated inwardly rectifying potassium (GIRK) channel. It is however unknown whether the ability of alcohol to open GIRK channels matters for its effects in vivo, i.e. how tipsy we feel or how motivated we are to drink alcohol. To address this question, we studied mice that are lacking one of the components of GIRK channels, the GIRK3 subunit. These mice behave normally in the absence of alcohol, and we sought to determine whether they respond differently to alcohol. MedicalResearch: What are the main findings? Dr. Contet: We found that the absence of GIRK3 did not impact how fast the mice clear alcohol from their body nor how sensitive they are to alcohol intoxication. Alcohol reduced their motor coordination, made them sleepy and lowered their body temperature to the same extent as in normal mice. GIRK3-deficient mice also drank as much alcohol as normal mice when they were given continuous access to alcohol, a situation in which mice sporadically drink throughout the day but rarely get intoxicated. By contrast, when mice are given access to alcohol only for a couple hours per day at a specific time of the day, they drink to the point of intoxication. Under these conditions, which emulate “binge drinking”, the GIRK3-deficient mice drank more than normal mice. The next step was to locate the region of the brain responsible for the effect of GIRK3 on binge drinking. We turned our attention to the mesocorticolimbic dopaminergic pathway, a neural circuit that facilitates reward seeking. This pathway originates in an area of the midbrain called the ventral tegmental area (VTA) and releases the neurotransmitter dopamine in two forebrain areas: the ventral striatum and the prefrontal cortex. Alcohol, like other drugs of abuse, activates this pathway. When we reintroduced GIRK3 in the VTA of GIRK3-deficient mice, their alcohol intake dropped down to normal levels. Increasing the levels of GIRK3 in the VTA of normal mice reduced their alcohol consumption even further. We concluded that GIRK3 in the VTA keeps binge drinking in check: the more GIRK3, the less binge drinking. We then wanted to understand how GIRK3 controls binge drinking: do the GIRK3-deficient mice drink more because alcohol is more rewarding to them, or because more alcohol is needed for them to experience the same level of reward? To answer this question, we measured the activity of VTA neurons in brain slices. Alcohol usually make VTA neurons fire more – but in the absence of GIRK3, these neurons were completely insensitive to alcohol, even at a very high concentration. We also measured the levels of dopamine in the ventral striatum. Injecting mice with a moderate dose of alcohol usually causes a rise in dopamine levels – but again, GIRK3-deficient mice were completely unresponsive. These results may seem paradoxical. If the canonical “reward pathway” of the brain cannot be activated by alcohol, these mice should not have any motivation to drink alcohol. But the mesocorticolimbic dopaminergic pathway is not the only brain circuit responsible for the rewarding properties of alcohol, and we think that GIRK3-deficient mice end up drinking more alcohol to activate alternative circuits more strongly than normal mice would.
Author Interviews, HIV, Nature, Scripps / 04.03.2015

Dr. Michael Farzan PhD Vice Chairman Department of Immunology and Microbial Science Florida Campus The Scripps Research InstituteMedicalResearch.com Interview with: Dr. Michael Farzan PhD Vice Chairman Department of Immunology and Microbial Science Florida Campus The Scripps Research Institute Medical Research: What is the background for this study? Dr. Farzan: The key points are that HIV-1 needs two receptors – CD4 and CCR5 – to infect cells.  CD4’s primary job is to initially bind the viral entry protein, which upon CD4 binding, uncloaks its CCR5 binding site.   A number of years ago we observed that CCR5 had an unusual modification that was really important to HIV-1.  We later showed that antibodies – protein your body makes to protect from pathogens – mimics CCR5 by incorporating this modification.  We develop a peptide from one of these antibodies that mimics CCR5. Medical Research: What are the main findings? Dr. Farzan: By combined a soluble form of CD4 with this CCR5-mimicking peptide, we created a protein that neutralizes all HIV-1 isolates tested, including the hardest-to-stop viruses, as well as distantly related viruses found in monkeys.  It does so better than the best HIV-1 antibodies.  We expressed this protein using a commonly used gene-therapy vector, and showed that after a one-time inoculation we could protect from doses much higher than most humans are likely to see, and we did so 34 weeks after the inoculation.
Author Interviews, Breast Cancer, Scripps / 25.01.2015

Dr. Patrick Griffin PhD Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute Scripps Research Institute, Jupiter, FloridaMedicalResearch.com Interview with: Dr. Patrick Griffin PhD Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute Scripps Research Institute, Jupiter, Florida MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Griffin: We identified a novel synthetic compound known as SR1848 that sharply inhibits the activity and expression of “liver receptor homolog-1” or LRH-1, a protein that plays an important role in the progression of breast and pancreatic cancers. Our new study shows that SR1848 removes LRH1 from DNA, shutting down expression of LRH-1 target genes, and halts cell proliferation. It’s a novel compound that appears to be a promising chemical scaffold for fighting tumors that are non-responsive to standard therapies.
Author Interviews, Genetic Research, Mental Health Research, Scripps / 25.01.2015

Dr. Gavin Rumbaug Professor (Associate) The Scripps Research InstituteMedicalResearch.com Interview with: Gavin Rumbaug Professor (Associate) The Scripps Research Institute Medical Research: What is the background for this study? What are the main findings? Response: We have developed a genetic approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels. The findings focus on treating the effects of mutations to a gene known as Syngap1. In our new study, we examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth—a period between the first and third postnatal weeks in mouse models. We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits. These findings help explain why genetic treatments in adult mice are not very effective.
Aging, Author Interviews, Nature, Scripps / 27.12.2014

Paul Schimmel, Ph.D. Professor The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, California MedicalResearch.com Interview with: Paul Schimmel, Ph.D. Professor The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, California Medical Research: What is the background for this study? What are the main findings? Dr. Schimmel: Resveratrol (RSV) is thought to provide health benefits by activating a protective stress response. In the paper we described a new, previously missed mechanism for its action. This mechanism is activated at much lower concentrations of resveratrol than previously described or imagined. Consequently, other mechanisms, which appear to act at higher concentrations of resveratrol, are layered over a preexisting foundation set by the newly revealed mechanism.
Author Interviews, Genetic Research, Neurological Disorders, PNAS, Scripps / 26.12.2014

Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research InstituteMedicalResearch.com Interview with: Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research Institute   Medical Research: What is the background for this study? What are the main findings? Response: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression, and in turn, influence resistance or susceptibility to disease.  Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, and are being proposed for therapeutic use in several neurological disorders.  Our previous studies have shown that selective HDAC inhibitors can cause beneficial effects in mouse models of Huntington’s disease, improving symptoms, and reducing severity of the disease.  Our current studies show that one such compound can alter DNA methylation, an epigenetic mark that can be inherited, leading to changes in gene expression that are seen in the parent mouse exposed directly to the drug, as well as in offspring from the drug-treated male mice.  Concurrent with these changes, we observed that offspring from drug-treated males shown improved disease symptoms, showing a delay in disease onset and a reduction of motor and cognitive symptoms that included improved performance in tests of balance, speed and memory. These finding have significant implications for human health as they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease outcome in a subsequent generation.  One exciting aspect of our study is that the parental drug treatment made the offspring better, not worse, like other compounds known to cause transgenerational effects.
Author Interviews, Neurological Disorders, Scripps / 30.10.2014

Srinivasa Subramaniam, Ph.D., Assistant Professor Department of Neuroscience The Scripps Research Institute Jupiter, Florida 33458MedicalResearch.com Interview with: Srinivasa Subramaniam, Ph.D., Assistant Professor Department of Neuroscience The Scripps Research Institute Jupiter, Florida 33458   Medical Research: What is the background for this study? What are the main findings? Dr.  Subramaniam: Huntington’s disease (HD) is a genetic disorder occurs due to a mutation in a protein called huntingtin (mHtt), which affects 5-10 people per 100000 populations worldwide. Our research revolves around the question— why mutant huntingtin despite its ubiquitous expression through out the body selectively affects brain regions such as striatum, a region that regulates voluntary movement. We now found that mHtt activates a protein kinase complex, mammalian target of rapamycin complex 1 (mTORC1), which is required for normal functions such as translation of genes into proteins and also organelle recycling. We found the mTORC1 activation is so robust and sustained in the striatum that lead to the severe motor disabilities and premature death of HD mice. Our study indicates a functional relationship between huntingtin and mTOR the developmentally important genes with implication in Huntington’s disease pathogenesis.
Author Interviews, Case Western, Heart Disease, Scripps / 29.09.2014

MedicalResearch.com Interview with: Philip Gorelick, M.D., M.P.H, F.A.C.P. Medical Director of the Hauenstein Neuroscience Center Saint Mary’s Health Care, Grand Rapids, MI; Professor, Translational Science and Molecular Medicine Michigan State University College of Human Medicine; Board member of the National Stroke AssociationPhilip Gorelick, M.D., M.P.H, F.A.C.P. Medical Director of the Hauenstein Neuroscience Center Saint Mary’s Health Care, Grand Rapids, MI; Professor, Translational Science and Molecular Medicine Michigan State University College of Human Medicine; Board member of the National Stroke Association and Judy Lenane, R.N., M.H.A. Chief Clinical Officer of iRhythm Technologies, Inc. Judy Lenane, R.N., M.H.A. Chief Clinical Officer of iRhythm Technologies, Inc.   Medical Research: What is atrial fibrillation and how common a problem is it among US adults? Dr. Gorelick: Nearly 3 million people in the US suffer from Atrial Fibrillation or “Afib,” an abnormal heart rhythm that causes the heart to beat rapidly and irregularly. While Afib can occur at any age, the incidence increases with age and the number of cases is expected to increase significantly in the coming years as the population ages. Approximately 5 percent of people 65 years and older and one in every 10 people over 80 years of age have Afib. It is more common in those with high blood pressure, heart disease or lung disease.
Diabetes, Scripps / 20.06.2014

Athena Philis-Tsimikas, M.D. Corporate Vice President Scripps Whittier Diabetes Institute, a subsidiary of Scripps HealthMedicalResearch.com Interview with: Athena Philis-Tsimikas, M.D. Corporate Vice President Scripps Whittier Diabetes Institute, a subsidiary of Scripps Health MedicalResearch: What are the main findings of the study? Dr. Philis-Tsimikas: Findings from the Dulce Digital study suggest that a text message-based self-management intervention improves glycemic control in high risk Latinos with type 2 diabetes. Researchers recruited 126 Latinos with type 2 diabetes and HbA1c greater than 7.5% from federally-qualified health centers (FQHCs) that serve disadvantaged populations to investigate the impact of a diabetes self-management intervention delivered via mobile text messaging. Cell phones were provided to patients who did not have them, along with text messaging instructions. Patients were randomized after completing clinical and self-reported measurements at baseline and these assessments were then repeated at 3 and 6 months. Both Dulce Digital and control groups received usual care.   The Dulce Digital group received three types of text messages — educational and motivational; medication reminders; and blood glucose monitoring prompts — two to three messages each day initially, with frequency tapering over 6 months. Project Dulce staff then monitored blood glucose responses, assessed reasons for hyperglycemia or hypoglycemia and encouraged follow up with providers as needed. Still ongoing, the current analyses included 106 completed participants (mean age= 49.25±9.49 years, 74% female), 52 of which were Dulce Digital participants. Findings showed significantly greater decreases in HbA1c with text messages compared with usual care only (9.4% to 8.4%, vs. 9.5% to 9.3%, P<.05) at 6 month follow-up. No significant group differences, however, have been observed for lipids, weight or blood pressure.
Addiction, Author Interviews, Memory, Methamphetamine, Scripps / 11.09.2013

MedicalResearch.com Interview with: Ph.D., Neurobiology & Behavior and Center for the Neurobiology of Learning & Memory (2005), University of California, Irvine, CaliforniaCourtney A. Miller, PhD Assistant Professor Department of Metabolism & Aging Department of Neuroscience The Scripps Research Institute Jupiter, FL 33458 MedicalResearch.com: What are the main findings of the study? Dr. Miller: The relapse rate for drug abusers, smokers and alcoholics is high because abstinence is so difficult. A major factor is the craving that drug associations can trigger. These range from seeing the neighborhood where someone used to buy, in the case of illicit drugs, to social drinking for a smoker. We’ve found a way to disrupt these drug-associated memories without affecting other, more benign memories.