News Article | November 28, 2016
An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression. Led by investigators at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, the team's report on its development of the network called InWeb_InBioMap (InWeb_IM) is receiving advance online publication in Nature Methods. "Modern genetic technologies allow us to routinely sequence the genomes of people with, for example, cancer or psychiatric diseases, but understanding the cellular systems that are affected by disease-causing genetic variations remains a major challenge," says Kasper Lage, PhD, of the MGH Department of Surgery and the Stanley Center for Psychiatric Research at the Broad Institute, project leader and co-corresponding author of the Nature Methods report. "Having more complete maps of the physical interactions of human proteins will enable us to start exploring cellular processes affected in disease at a higher resolution than is currently possible." While the importance of mapping large-scale protein-protein interaction networks is widely recognized, the most recent experimental efforts have identified fewer than 30,000 direct interactions, representing well under a quarter of the most conservative estimates of the total number of interactions. Lage's team, in collaboration with researchers in Denmark and the U.K., developed a computational framework to integrate data from more than 43,000 published articles, including data from eight established protein-protein interaction databases. They applied stringent quality control in creating InWeb_IM, which consisted of almost 586,000 interactions when the paper was submitted in February 2015 and now includes more than 625,500 interactions. Co-lead author Taibo Li from Lage's team explains, "Just like people, proteins like to work in groups to carry out their functions, and they do this by physically interacting in protein networks. If you compare protein-protein interaction networks to human social networks, just as platforms like Facebook can infer people who may know each other or share interests based on patterns of interaction with others in the network, constructing networks of protein interactions can infer gene groups and molecular pathways that can improve our understanding of processes that occur in human cells." Lage adds, "The rapidly declining cost of genome sequencing has far outpaced our ability to interpret the gene variants we identify in patients with undiagnosed diseases. By exploring interaction networks at the level of proteins and of the genes that may be causing a disease, clinicians may begin to see patterns of genetic data that would otherwise be difficult to discern, which we illustrate in the article for cancers and autism. For example, around 30 genes appear to be involved in cardiomyopathies, but many individuals with the condition do not have mutations in any of those genes. By looking at interaction partners at the protein level of the 30 cardiomyopathy genes, we can start to identify new candidate genes based on the 'cardiomyopathy network,' potentially leading to new molecular insights into the disease. It is our hope that InWeb_IM can be a resource that contributes to interpreting clinical exome sequencing data and play a part in enabling clinical action in patients with an unknown cause of disease." The team is continuing to develop ways of using InWeb_IM to explain large-scale genomic datasets; to improve understanding of complex biological systems in a tissue-specific manner by integrating proteomic, transcriptomic and genomic data; and - in collaboration with several groups at MGH - applying that information to the understanding of cardiovascular diseases, birth defects, cancers, reproductive disorders and psychiatric disease. InWeb_IM will be maintained and updated quarterly and is fully accessible to academic users at http://www. or http://www. . Lage is an assistant professor of Surgery at Harvard Medical School. The co-lead authors of the Nature Methods paper are Rasmus Wernersson, PhD, and Rasmus B. Hansen, PhD, of Intomics A/S, Lyngby, Denmark. The co-corresponding author is Thomas S. Jensen, PhD, MSc, of Intomics A/S. Support for the study includes National Institutes of Health grant 1R01 MH109903, a Broadnext10 grant from the Broad Institute, and grants from the Stanley Center for Psychiatric Research at the Broad Institute, the Lundbeck Foundation and the Novo Nordisk Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | January 15, 2016
Strengthening and weakening the connections between neurons, known as synapses, is vital to the brain’s development and everyday function. One way that neurons weaken their synapses is by swallowing up receptors on their surfaces that normally respond to glutamate, one of the brain’s excitatory chemicals. In a new study, MIT neuroscientists have detailed how this receptor reabsorption takes place, allowing neurons to get rid of unwanted connections and to dampen their sensitivity in cases of overexcitation. “Pulling in and putting out receptors is a dynamic process, and it’s highly regulated by a neuron’s environment,” said Elly Nedivi, a professor of brain and cognitive sciences and member of MIT’s Picower Institute for Learning and Memory. “Our understanding of how receptors are pulled in and how regulatory pathways impact that has been quite poor.” Nedivi and colleagues found that a protein known as CPG2 is key to this regulation, which is notable because mutations in the human version of CPG2 have been previously linked to bipolar disorder. “This sets the stage for testing various human mutations and their impact at the cellular level,” said Nedivi, who is the senior author of a Jan. 14 Current Biology paper describing the findings. The paper’s lead author is former Picower Institute postdoc Sven Loebrich. Other authors are technical assistant Marc Benoit, recent MIT graduate Jaclyn Konopka, former postdoc Joanne Gibson, and Jeffrey Cottrell, the director of translational research at the Stanley Center for Psychiatric Research at the Broad Institute. Neurons communicate at synapses via neurotransmitters such as glutamate, which flow from the presynaptic to the postsynaptic neuron. This communication allows the brain to coordinate activity and store information such as new memories. Previous studies have shown that postsynaptic cells can actively pull in some of their receptors in a phenomenon known as long-term depression (LTD). This important process allows cells to weaken and eventually eliminate poor connections, as well as to recalibrate their set point for further excitation. It can also protect them from overexcitation by making them less sensitive to an ongoing stimulus. Pulling in receptors requires the cytoskeleton, which provides the physical power, and a specialized complex of proteins known as the endocytic machinery. This machinery performs endocytosis — the process of pulling in a section of the cell membrane in the form of a vesicle, along with anything attached to its surface. At the synapse, this process is used to internalize receptors. Until now, it was unknown how the cytoskeleton and the endocytic machinery were linked. In the new study, Nedivi’s team found that the CPG2 protein forms a bridge between the cytoskeleton and the endocytic machinery. “CPG2 acts like a tether for the endocytic machinery, which the cytoskeleton can use to pull in the vesicles,” Nedivi said. “The glutamate receptors that are in the membrane will get pinched off and internalized.” They also found that CPG2 binds to the endocytic machinery through a protein called EndoB2. This CPG2-EndoB2 interaction occurs only during receptor internalization provoked by synaptic stimulation and is distinct from the constant recycling of glutamate receptors that also occurs in cells. Nedivi’s lab has previously shown that this process, which does not change the cells’ overall sensitivity to glutamate, is also governed by CPG2. “This study is intriguing because it shows that by engaging different complexes, CPG2 can regulate different types of endocytosis,” said Linda Van Aelst, a professor at Cold Spring Harbor Laboratory who was not involved in the research. When synapses are too active, it appears that an enzyme called protein kinase A (PKA) binds to CPG2 and causes it to launch activity-dependent receptor absorption. CPG2 may also be controlled by other factors that regulate PKA, including hormone levels, Nedivi said. In 2011, a large consortium including researchers from the Broad Institute discovered that a gene called SYNE1 is number two on the hit list of genes linked to susceptibility for bipolar disorder. They were excited to find that this gene encoded CPG2, a regulator of glutamate receptors, given prior evidence implicating these receptors in bipolar disorder. In a study published in December, Nedivi and colleagues, including Loebrich and co-lead author Mette Rathje, identified and isolated the human messenger RNA that encodes CPG2. They showed that when rat CPG2 was knocked out, its function could be restored by the human version of the protein, suggesting both versions have the same cellular function. Rathje, a Picower Institute postdoc in Nedivi’s lab, is now studying mutations in human CPG2 that have been linked to bipolar disorder. She is testing their effect on synaptic function in rats, in hopes of revealing how those mutations might disrupt synapses and influence the development of the disorder. Nedivi suspects that CPG2 is one player in a constellation of genes that influence susceptibility to bipolar disorder. “My prediction would be that in the general population there’s a range of CPG2 function, in terms of efficacy,” Nedivi said. “Within that range, it will depend what the rest of the genetic and environmental constellation is, to determine whether it gets to the point of causing a disease state.” The research was funded by the Picower Institute Innovation Fund and the Gail Steel Fund for Bipolar Research.
News Article | September 14, 2016
In an unprecedented move, the group that selects the winners of the Nobel Prize in Physiology or Medicine — the Nobel Assembly — has asked two of its members to resign following a scandal at the institute that supplies the assembly’s members. But scientists around the world don’t see the events at the Karolinska Institute (KI) in Stockholm as a threat to the reputation of the medical prize. They say that the assembly is sufficiently separate to the KI and has handled the affair well so far. “Everything is exploding now, but the long-term credibility won’t be affected,” says cancer researcher Julio Celis, associate scientific director of the Danish Cancer Society Research Center in Copenhagen. The scandal involves the surgeon Paolo Macchiarini. Multiple inquiries have alleged that he committed scientific misconduct and subjected patients to unethical, experimental tracheal transplant operations, three of which occurred at the affiliated Karolinska University Hospital. Two of the patients have since died, and the third has required continuous hospital care since the transplant. In June, Swedish public prosecutors opened investigations following preliminary charges against Macchiarini of involuntary manslaughter and causing grievous bodily harm. Macchiarini has denied the allegations. On 5 September, an independent report that revealed institutional problems at the KI mentioned Nobel Assembly members Harriet Wallberg-Henriksson and Anders Hamsten — both former KI vice-chancellors — for their roles in hiring Macchiarini in 2010 and subsequently extending his contracts. (Hamsten resigned as vice-chancellor in February after acknowledging that he had misjudged Macchiarini; the KI dismissed Macchiarini in March.) The call for Wallberg-Henriksson and Hamsten to resign came a day after the report and is a first for the 115-year-old panel, says neuroscientist Thomas Perlmann, secretary of the Nobel Committee, whose fixed-term members are elected from the more permanent assembly. “The professionalism of some of the faculty at the Karolinska Institute has been called into question, and this won’t go away,” says Erwin Neher of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, who won the medicine prize in 1991. “But I don’t think this discredits the Nobel prize — they are two different things.” When Alfred Nobel died in 1896, he left the bulk of his fortune — amassed from his explosives businesses — to the Nobel prizes. His will specified which institutions would select each prize, and declared the KI in charge of medicine. The first prizes were awarded in 1901. At first, the entire KI faculty selected the medicine winners, but by the 1970s it had grown too large for this to be practical — and a new law made all documents at state institutions accessible to the public, ruling out secret deliberations. So in 1977, the Nobel Assembly was created, comprising 50 KI professors; the Nobel Foundation pays for its operations. The Nobel Committee has also done a good job of separating itself from the Macchiarini affair since it began, says neuroscientist Eero Castrén at the University of Helsinki. KI geneticist Urban Lendahl, who participated in the decision to hire Macchiarini, resigned his position as secretary-general of the Nobel Committee in February, notes Castrén. (Lendahl stepped down because he anticipated that he would be involved in the investigation.) Two other assembly members — clinical immunologist Katarina Le Blanc, who co-authored a paper with Macchiarini that is under investigation by the Central Ethical Review Board, and Hans-Gustaf Ljunggren, who was dean of research at the KI from 2013 until February — have not been asked to resign because there is still “uncertainty over their roles” in the Macchiarini affair, says Perlmann. “To protect the brand”, he adds, none of the three, nor Wallberg-Henriksson, nor Hamsten, has participated in assembly activities since February. Perlmann says that the Nobel Committee is not taking further action, but will monitor perceptions of the prize to see whether it needs to do more. “It is important that institutions deal in a fair way with those whose judgement or moral probity has been called into question,” says Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute in Boston, Massachusetts, who has nominated prize candidates to the Nobel Committee. “The Nobel Assembly seems to be doing this.” He adds: “There is no benefit to the world, or to patients who have been harmed, by using a very serious incident to undercut a globally important institute.” The assembly has survived other challenges, usually relating to complaints about its choices. In 1994, it encountered accusations — quickly discredited — that it had allowed a drug company to buy the 1986 medicine prize for Italian neuroscientist Rita Levi-Montalcini. Just as the Swedish king never comments on politics, the Nobel Assembly never comments on such complaints. But during its 100th anniversary celebrations, it acknowledged some regrets — such as awarding a share of the 1923 prize for the discovery of insulin to John Macleod, whose role is now questioned, and the failure to recognize Oswald Avery, who identified DNA as the genetic material in the 1940s. “The prize has survived many things,” says cell biologist Måns Ehrenberg of Uppsala University, who has served on the committee that selects the Nobel Prize in Chemistry. “The standard of evaluation no one can criticize.”
News Article | December 20, 2016
Dublin, Dec. 20, 2016 (GLOBE NEWSWIRE) -- Research and Markets has announced the addition of the "HDAC Inhibitors Market, 2016 - 2026" report to their offering. The HDAC Inhibitors Market, 2016-2026 report was commissioned to examine the current landscape and the future outlook of the growing pipeline of products in this area. HDACs have been studied in cellular processes such as apoptosis, autophagy, metabolism, DNA damage repair, cell cycle control and senescence. Altered expression of HDACs has been observed in different tumors; this makes them a potential target for treatment of cancer and other genetic or epigenetic related disorders. Inhibition of HDACs has shown positive results in disruption of multiple cell signaling pathways and prevention of tumor growth. The study provides a detailed market forecast and opportunity analysis for the time period 2016-2026. The research, analysis and insights presented in this report include potential sales of the approved drugs and the ones in late stages of development (phase III and phase II). To add robustness to our model, we have provided three scenarios for our market forecast; these include the conservative, base and optimistic scenarios. Our opinions and insights, presented in this study were influenced by several discussions we conducted with experts in this area. All actual figures have been sourced and analyzed from publicly available information forums and primary research discussions. Financial figures mentioned in this report are in USD, unless otherwise specified. Example Highlights - Nearly 90 HDAC inhibitors are currently in clinical / preclinical stages of development; the clinical molecules account for over 30% of the pipeline while over 60% is captured by molecules in the preclinical / discovery stage. - With 66% of the pipeline molecules targeting oncological indications, cancer remains one of the most widely studied field for HDAC inhibitors. Within oncology, hematological malignancies such as PTCL and CTCL are popular targets; three HDAC inhibitors (Zolinza, ISTODAX® and BELEODAQ®) are approved for these indications. Other therapeutic areas such as autoimmune disorders, infectious diseases, inflammatory disorders, neurological disorders, are also gradually gaining traction. - Although the market was initially led by the large-size pharma players (such as Celgene, Merck, Novartis), the current market is characterized by the presence of several small / mid-sized pharma players. Notable examples of the small and mid-sized firms include 4SC, Chroma Therapeutics, CrystalGenomics, Curis, Evgen Pharma, FORUM Pharmaceuticals, Karus Therapeutics, Mirati Therapeutics, MEI Pharma, Shenzhen Chipscreen Biosciences, Syndax Pharmaceuticals and TetraLogic Pharmaceuticals. - In addition, there are several non-industry institutes and universities that are primarily carrying out preclinical research. Examples of these include Harvard Medical School (BG45), Imperial College London (C1A), Kyoto University (Jd, Sd), National Taiwan University (Quinazolin-4-one derivatives), Taipei Medical University (MPT0E028), University of Messina (MC-1575, MC-1568). - Four of the five approved drugs are pan-HDAC inhibitors targeting HDAC isoforms non-specifically. However, in the past few years, several class selective HDAC inhibitors have entered the clinic; these are associated with a higher efficacy and result in decreased toxicity from the treatment. Of the total HDAC inhibitors identified, 52% of the molecules are class specific; of these, 33% molecules target Class I specific isoforms and the rest target Class II specific isoforms of HDACs. Notable examples of molecules targeting class-specific HDACs includeentinostat (phase III), resminostat (phase II), SHP-141 (phase II), mocetinostat (phase II), CHR-3996 (phase I/II) and ricolinostat (phase I/II). - The HDAC inhibitors market is expected to grow at a healthy annual rate of 32% over the next decade.With multiple potential target indications, Istodax® is expected to capture the largest market share (close to 21%) in 2026, followed by entinostat, Farydak® and Beleodaq®. Key Topics Covered: 1. Preface 1.1. Scope Of The Report 1.2. Research Methodology 1.3. Chapter Outlines 2. Executive Summary 3. Introduction 3.1. The Central Dogma of Molecular Biology and Cell Cycle 3.2. DNA: Structure and Functions 3.3. Fundamentals of Epigenetics 3.3.1. Effect of Histone Modification on DNA Based Processes 3.3.2. Chromatin Structure Modification and its Enzymes 3.4. Histone Deacetylases (HDACs) 3.4.1. Classification of HDACs 3.4.2. Role of HDACs and HDAC Inhibitors in Cellular Processes 3.5. HDAC Inhibitors 3.5.1. Structure and Classification 3.5.2. Different Types of HDAC Inhibitors 3.5.3. Therapeutic Applications of HDAC Inhibitors 4. HDAC Inhibitors: Market Landscape 4.1. Chapter Overview 4.2. Development Pipeline of HDAC Inhibitors 4.3. Distribution by Phase of Development 4.4. Distribution by Therapeutic Area 4.5. Distribution by Class Specificity 4.6. Distribution by Type of Developer 4.7. Distribution by Geography 4.8. Active Industry Players 5. Drug Profiles: Marketed And Late-Stage HDAC Inhibitors 5.1. Chapter Overview 5.2. Company and Drug Profiles: Marketed and Phase III Molecules 5.2.1. Celgene Corporation 5.2.3. Novartis 5.2.4. Shenzhen Chipscreen Biosciences 5.2.5. Syndax Pharmaceuticals 5.3. Drug Profiles: Phase II Molecules 5.3.1. Abexinostat (PCI-24781) 5.3.2. CUDC-907 5.3.3. FRM-0334 (EVP-0334) 5.3.4. Givinostat (ITF2357) 5.3.5. Mocetinostat (MGCD103) 5.3.6. Pracinostat (SB939) 5.3.7. Resminostat (4SC-201) 5.3.8. SFX-01 5.3.9. SHAPE (SHP-141) 5.3.10. Tefinostat (CHR-2845) 6. Key Insights: Therapeutic Area, Class Specificity, Clinical Endpoints 6.1. Clinical Development Analysis: Class Specificity and Therapeutic Areas 6.2. Clinical Development Analysis: Developer Landscape 6.3. Clinical Development Analysis: Trial Endpoint Comparison 7. Market Forecast And Opportunity Analysis 7.1. Chapter Overview 7.2. Scope and Limitations 7.3. Forecast Methodology 7.4. Overall HDAC Inhibitors Market 7.5. HDAC Inhibitors Market: Individual Forecasts 7.5.1. Zolinza (Merck) 7.5.2. Istodax® (Celgene Corporation) 7.5.3. Beleodaq® (Onxeo) 7.5.4. Farydak® (Novartis) 7.5.5. Epidaza® (Shenzhen Chipscreen Biosciences) 7.5.6. Entinostat (Syndax Pharmaceuticals) 7.5.7. Abexinostat (Pharmacyclics) 7.5.8. CUDC-907 (Curis) 7.5.9. FRM-0334 (FORUM Pharmaceuticals) 7.5.10. Mocetinostat (Mirati Therapeutics) 7.5.11. Pracinostat (MEI Pharma) 7.5.12. Resminostat (4SC, Menarini, Yakult Honsha) 7.5.13. SFX-01 (Evgen Pharma) 7.5.14. SHP-141 (TetraLogic Pharmaceuticals) 7.5.15. Tefinostat (Chroma Therapeutics) 8. Publication Analysis 8.1. Chapter Overview 8.2. HDAC Inhibitors: Publications 8.3. Publication Analysis: Quarterly Distribution 8.4. Publication Analysis: Distribution by HDAC Inhibitor Class 8.5. Publication Analysis: Distribution by Drugs Studied 8.6. Publication Analysis: Distribution by Therapeutic Area 8.7. Publication Analysis: Distribution by Journals 8.8. Publication Analysis: Distribution by Phase of Development 8.9. Publication Analysis: Distribution by Type of Therapy 9. Social Media: Emerging Trends 9.1. Chapter Overview 9.1.1. Trends on Twitter 9.1.2. Trends on Facebook 10. Conclusion 10.1. The Pipeline is Healthy with Several Molecules in Preclinical Stages of Development 10.2. HDAC Inhibitors Cater to a Wide Spectrum of Disease Areas 10.3. Class Specific HDAC Inhibitors Have Been Explored for a More Targeted Approach 10.4. The Interest is Gradually Rising Amongst Both Industry and Non-Industry Players 10.5. Supported by a Robust Preclinical Pipeline, HDAC Inhibitors are Expected to Emerge as A Multi-Billion Dollar Market 11. Interview Transcripts 11.1. Chapter Overview 11.2. Dr. Simon Kerry, CEO, Karus Therapeutics 11.3. Dr. James Christensen, CSO and Senior VP, Mirati Therapeutics 11.4. Dr. Hyung J. Chun, MD, FAHA, Associate Professor of Medicine, Yale School of Medicine 12. Appendix 1: Tabulated Data 13. Appendix 2: List Of Companies And Organizations Companies Mentioned - 4SC - AACR - AbbVie - Acceleron Pharma - Acetylon Pharmaceuticals - Active Biotech - Agios Pharmaceuticals - ASH - Arno Therapeutics - Astellas Pharma - Bayer Schering Pharma - Baylor College of Medicine - BioMarin - Bionor Immuno - bluebird bio - Case Comprehensive Cancer Center - Celera Genomics - Celgene - Celleron Therapeutics - Centre de Recherche en Cancérologie - CETYA Therapeutics - CHDI Foundation - Chipscreen Biosciences - Chong Kun Dang Pharmaceutical - Chroma Therapeutics - Croix-Rousse Hospital - CrystalGenomics - Curis - DAC - Diaxonhit - DNA Therapeutics - Duke University - ECOG-ACRIN Cancer Research Group - Eddingpharm - Eisai - Epizyme - Errant Gene Therapeutics - European Calcified Tissue Society - Evgen Pharma - FORMA Therapeutics - FORUM Pharmaceuticals - Fudan University - Genentech - Genextra - Gilead - Gloucester Pharmaceuticals - GNT Biotech - GSK - Harvard Medical School - Henan Cancer Hospital - HUYA Biosciences - Ikerchem - Imperial College London - In2Gen - International Bone and Mineral Society - Israel Cancer Association and Bar Ilan University - Italfarmaco - Johnson and Johnson - Kalypsys - Karus Therapeutics - King's College, University of London - Kyoto Prefectural University of Medicine - Kyoto University - Kyowa Hakko Kirin - Leukemia and Lymphoma Society - Lymphoma Academic Research Organization - Massachusetts General Hospital - Mayo Clinic - MedImmune - MEI Pharma - Memorial Sloan-Kettering Cancer Center - Menarini - Merck - MethylGene - Mirati Therapeutics - Morphosys - Mundipharma-EDO - National Brain Research Centre - National Comprehensive Cancer Network - National Taiwan University - NCI - Novartis - NuPotential - Oceanyx Pharma - Oncolys Biopharma - Onxeo - Onyx - Orchid Pharma - Paterson Institute for Cancer Research - Pfizer - Pharmacyclics - Pharmion Corporation - Quimatryx - Quintiles - Repligen - Respiratorius - Roche - Rodin Therapeutics - Royal Veterinary College, University of London - Ruijin Hospital - S*Bio - Sarcoma Alliance for Research through Collaboration - Seattle Genetics - Servier Canada - Shape Pharmaceuticals - Sidney Kimmel Comprehensive Cancer Center - Sigma Tau Pharmaceuticals - Signal Rx - SpeBio - Spectrum Pharmaceuticals - Stanley Center for Psychiatric Research - Sutro Biopharma - Syndax Pharmaceuticals - Synovo GmbH - Taipei Medical University - TetraLogic Pharmaceuticals - University of Liverpool - University of Messina - University of Miami - Vanderbilt University School of Medicine - Ventana Medical Systems - Vilnius University - Yakult Honsha - Yale University - Yonsei University College of Medicine For more information about this report visit http://www.researchandmarkets.com/research/srvj3j/hdac_inhibitors
News Article | December 1, 2016
Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops. Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now, scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs. The scientists demonstrated that Zika infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus. "Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells," said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University, and co-corresponding author on a paper reporting the research in Cell Stem Cell. "It's very important for the research community to learn that targeting the AXL protein alone will not defend against Zika," agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for BioMedical Research (NIBR). Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain. "We were thinking that the knocked-out NPCs devoid of AXL wouldn't get infected," said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. "But we saw these cells getting infected just as much as normal cells." Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain "organoids" containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice. "We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect," said Kaykas. "For the first few months, the organoids do a really good job in recapitulating normal brain development." Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish. The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika. The Harvard/NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika's global challenge, as the virus has spread to more than 70 countries and territories. "At the genesis of the project, my wife was pregnant," Eggan remarked. "One can't read the newspapers without being concerned." The collaboration grew out of interactions at the Broad Institute of MIT and Harvard's Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders. "Zika seemed to be a big issue where we could have an impact, and we all shared that interest," Eggan said. "It's been great to have this public, private collaboration." The researchers are studying other receptor proteins that may be open to Zika infection, in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus. This research was funded by the Stanley Center for Psychiatric Research and the Harvard Stem Cell Institute.
News Article | March 24, 2016
More than 3 million Americans suffer from attention deficit hyperactivity disorder (ADHD), a condition that usually emerges in childhood and can lead to difficulties at school or work. A new study from MIT and New York University links ADHD and other attention difficulties to the brain’s thalamic reticular nucleus (TRN), which is responsible for blocking out distracting sensory input. In a study of mice, the researchers discovered that a gene mutation found in some patients with ADHD produces a defect in the TRN that leads to attention impairments. The findings suggest that drugs boosting TRN activity could improve ADHD symptoms and possibly help treat other disorders that affect attention, including autism. “Understanding these circuits may help explain the converging mechanisms across these disorders. For autism, schizophrenia, and other neurodevelopmental disorders, it seems like TRN dysfunction may be involved in some patients,” said Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute. Feng and Michael Halassa, an assistant professor of psychiatry, neuroscience, and physiology at New York University, are the senior authors of the study, which appears in the March 23 online edition of Nature. The paper’s lead authors are MIT graduate student Michael Wells and NYU postdoc Ralf Wimmer. Feng, Halassa, and their colleagues set out to study a gene called Ptchd1, whose loss can produce attention deficits, hyperactivity, intellectual disability, aggression, and autism spectrum disorders. Because the gene is carried on the X chromosome, most individuals with these Ptchd1-related effects are male. In mice, the researchers found that the part of the brain most affected by the loss of Ptchd1 is the TRN, which is a group of inhibitory nerve cells in the thalamus. It essentially acts as a gatekeeper, preventing unnecessary information from being relayed to the brain’s cortex, where higher cognitive functions such as thought and planning occur. “We receive all kinds of information from different sensory regions, and it all goes into the thalamus,” Feng said. “All this information has to be filtered. Not everything we sense goes through.” If this gatekeeper is not functioning properly, too much information gets through, allowing the person to become easily distracted or overwhelmed. This can lead to problems with attention and difficulty in learning. The researchers found that when the Ptchd1 gene was knocked out in mice, the animals showed many of the same behavioral defects seen in human patients, including aggression, hyperactivity, attention deficit, and motor impairments. When the Ptchd1 gene was knocked out only in the TRN, the mice showed only hyperactivity and attention deficits. At the cellular level, the researchers found that the Ptchd1 mutation disrupts channels that carry potassium ions, which prevents TRN neurons from being able to sufficiently inhibit thalamic output to the cortex. The researchers were also able restore the neurons’ normal function with a compound that boosts activity of the potassium channel. This intervention reversed the TRN-related symptoms but not any of the symptoms that appear to be caused by deficits of some other circuit. “The authors convincingly demonstrate that specific behavioral consequences of the Ptchd1 mutation — attention and sleep — arise from an alteration of a specific protein in a specific brain region, the thalamic reticular nucleus. These findings provide a clear and straightforward pathway from gene to behavior and suggest a pathway toward novel treatments for neurodevelopmental disorders such as autism,” said Joshua Gordon, an associate professor of psychiatry at Columbia University, who was not involved in the research. Most people with ADHD are now treated with psychostimulants such as Ritalin, which are effective in about 70 percent of patients. Feng and Halassa are now working on identifying genes that are specifically expressed in the TRN in hopes of developing drug targets that would modulate TRN activity. Such drugs may also help patients who don’t have the Ptchd1 mutation, because their symptoms are also likely caused by TRN impairments, Feng said. The researchers are also investigating when Ptchd1-related problems in the TRN arise and at what point they can be reversed. And, they hope to discover how and where in the brain Ptchd1 mutations produce other abnormalities, such as aggression. The research was funded by the Simons Foundation Autism Research Initiative, the National Institutes of Health, the Poitras Center for Affective Disorders Research, and the Stanley Center for Psychiatric Research at the Broad Institute.
News Article | January 28, 2016
Researchers have identified a gene that increases the risk of schizophrenia, and they say they have a plausible theory as to how this gene may cause the devastating mental illness. After conducting studies in both humans and mice, the researchers said this new schizophrenia risk gene, called C4, appears to be involved in eliminating the connections between neurons — a process called "synaptic pruning," which, in humans, happens naturally in the teen years. It's possible that excessive or inappropriate "pruning" of neural connections could lead to the development of schizophrenia, the researchers speculated. This would explain why schizophrenia symptoms often first appear during the teen years, the researchers said. Further research is needed to validate the findings, but if the theory holds true, the study would mark one of the first times that researchers have found a biological explanation for the link between certain genes and schizophrenia. It's possible that one day, a new treatment for schizophrenia could be developed based on these findings that would target an underlying cause of the disease, instead of just the symptoms, as current treatments do, the researchers said. "We're far from having a treatment based on this, but it's exciting to think that one day, we might be able to turn down the pruning process in some individuals and decrease their risk" of developing the condition, Beth Stevens, a neuroscientist who worked on the new study, and an assistant professor of neurology at Boston Children's Hospital, said in a statement. The study, which also involved researchers at the Broad Institute's Stanley Center for Psychiatric Research at Harvard Medical School, is published today (Jan. 27) in the journal Nature. [Top 10 Mysteries of the Mind] From previous studies, the researchers knew that one of the strongest genetic predictors of people's risk of schizophrenia was found within a region of DNA located on chromosome 6. In the new study, the researchers focused on one of the genes in this region, called complement component 4, or C4, which is known to be involved in the immune system. Using postmortem human brain samples, the researchers found that variations in the number of copies of the C4 gene that people had, and the length of their gene, could predict how active the gene was in the brain. The researchers then turned to a genome database, and pulled information about the C4 gene in 28,800 people with schizophrenia, and 36,000 people without the disease, from 22 countries. From the genome data, they estimated people's C4 gene activity. They found that the higher the levels of C4 activity were, the greater a person's risk of developing schizophrenia was. The researchers also did experiments in mice, and found that the more C4 activity there was, the more synapses were pruned during brain development. Previous studies found that people with schizophrenia have fewer synapses in certain brain areas than people without the condition. But the new findings "are the first clear evidence for a molecular and cellular mechanism of synaptic loss in schizophrenia," said Jonathan Sebat, chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego, who was not involved in the study. Still, Sebat said that the studies in mice are preliminary. These experiments looked for signs of synaptic pruning in the mice but weren't able to directly observe the process occurring. More detailed studies of brain maturation are now needed to validate the findings, Sebat said. In addition, it remains to be seen whether synaptic pruning could be a target for antipsychotic drugs, but "it's promising," Sebat said. There are drugs in development to activate the part of the immune system in which C4 is involved, Sebat noted. Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
News Article | November 2, 2016
The US National Institute of Mental Health (NIMH) has a new director. On 12 September, psychiatrist Joshua Gordon took the reins at the institute, which has a budget of US$1.5 billion. He previously researched how genes predispose people to psychiatric illnesses by acting on neural circuits, at Columbia University in New York City. His predecessor, Thomas Insel, left the NIMH to join Verily Life Sciences, a start-up owned by Google’s parent company Alphabet, in 2015. Gordon says that his priorities at the NIMH will include “low-hanging clinical fruit, neural circuits and mathematics — lots of mathematics", and explains to Nature exactly what that means. I won’t be doing anything radical. I am just going to listen to and learn from all the stakeholders — the scientific community, the public, consumer advocacy groups and other government offices. But I can say two general things. In the past twenty years, my two predecessors, Steve Hyman [now director of the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts] and Tom Insel, embedded into the NIMH the idea that psychiatric disorders are disorders of the brain, and to make progress in treating them we really have to understand the brain. I will absolutely continue this legacy. This does not mean we are ignoring the important roles of the environment and social interactions in mental health — we know they have a fundamental impact. But that impact is on the brain. Second, I will be thinking about how NIMH research can be structured to give payouts in the short, medium and long terms. The advent of incredibly powerful tools to observe and alter activity in a subset of neurons, such as optogenetics, has been transformational. It is allowing us to get at questions of how neural circuits produce behaviour — a research approach that may soon generate new treatments for psychiatric disorders. One is the Human Connectome Project. The project has scanned the brains of more than 1,000 healthy people to generate individual maps of their neural circuitry, the ‘wiring’ in their brains that accounts for their particular personalities. At the NIMH, we have created standardized databases, designed by the scientific community, to store this information. The Human Connectome Project is going to be a tremendous resource for the field — maybe not quite as impactful as the Human Genome Project, but on that scale, I think. A clinical programme that deserves as much attention, but perhaps doesn’t get it, is the Coordinated Specialty Care project for individuals facing their first psychotic episode. Some small studies have shown that coordinating different clinical and social-support programmes helps individuals to cope better. Yes. We are now looking for similarly significant clinical problems where good, evidence-based interventions exist but are not widely adopted. For example, we have a range of screening tools that we think can help reduce the suicide rate, which has been rising in the United States for unclear reasons. It could be advantageous to incorporate universal suicidality screening as a matter of routine into all emergency rooms. People often present in emergency rooms with injuries that result from suicide attempts but don’t admit to it — unless they are explicitly asked. Neural circuits could be delivering treatments in 10 or 15 years. We don’t yet know exactly which circuits we would want to modify to treat psychiatric disorders in humans. But now is the time to start thinking about which tools we are going to need to make this translational step possible, and invest in them. Most work on neural circuits has been done in genetically modified mice, where it is relatively easy to control the activity of a few very specific cells in a particular brain area using tools such as optogenetics. We’ll need safe methods for humans. Should we be thinking in terms of viruses that can be directed to, and change activity in, specific neurons? Or should we be thinking of ways to stimulate or inhibit these cells indirectly, using transcranial magnetic stimulation or deep-brain stimulation, for example? The really transformative treatments that are going to change mental-health care in the long term will depend on us learning how the brain works as a whole. We are all tempted to reduce the huge complexity of the brain into understandable chunks. But to appreciate and exploit that complexity, we will need to be able to integrate everything we know, from molecular biology to behaviour, into our models of how the brain works. That requires serious math. How does the structure of a neuron affect its integration into a circuit? How does that circuit affect the neural system that it fits into? How does the dynamic activity in these neural systems drive behaviour? Fully characterizing each of these levels and then integrating them across scales requires a level of mathematical rigour that most of us, including myself, have not really brought to bear on the problem. It’s not so difficult — I’m not saying that we are going to need string theorists! It’s just a question of appropriate training in math for students. In the future, I hope that every experimentalist will also be a theoretician. But at this stage we need to encourage experimental neurobiologists to form long-term interdisciplinary collaborations with theoreticians, mathematicians or physicists. We need to inject more math into every level of the NIMH portfolio. Math can also have a short-term impact in psychiatry for things such as predicting individual responses to drugs and improving precision medicine more generally. Clinical neuroscience has typically tried to identify the neurobiology that underlies diagnoses [such as depression]. That hasn’t got us very far. Maybe if we instead try to understand the neurobiology underlying the various domains of behaviour [such as apathy], we’ll get better insight. I see RDoC as something potentially very valuable, something I am likely to keep — although it may need a few tweaks to extract the most value out of it. Most of our knowledge about the brain has been gained in mice. It is hard for me to believe that we’ll really be able to translate the knowledge that we have won in mice into the design of new treatments for humans without going through an intermediate species with an elaborated prefrontal cortex and a large brain. So unfortunately, yes, I think we do still need to use non-human primates. We need to do so judiciously, though — the welfare of animals is fundamental, and we need to minimize the numbers of all of the animals that we use.
News Article | April 6, 2016
CAMBRIDGE, MA — Intel and the Broad Institute of MIT and Harvard announced at the Bio-IT World Conference & Expo that they are co-developing new tools, and advancing fundamental capabilities, so large genomic workflows can run at cloud scale. Broad Institute also announced collaborations with cloud providers to enable cloud-based access to its Genome Analysis Toolkit (GATK) software package. This is expected to expand access to the GATK Best Practices pipeline. The new tools Broad is developing with Intel aim to simplify the execution of large genomic workflows such as GATK, and to improve the storage, scalability, and processing of genomic data. This has the potential to not only speed variant detection and biomarker discovery, but enable discoveries that would not have been detected with smaller cohorts. Broad’s workflow execution engine, called “Cromwell,” is designed to launch genomic pipelines on private or public clouds in a portable and reproducible manner. Broad is working with Intel to extend Cromwell’s capabilities to support multiple input languages and execute on multiple back ends simultaneously, enabling researchers to run jobs anywhere. This integrated workflow engine has built-in intelligence capable of finding the optimal way to execute tasks, the most appropriate hardware resources to run those tasks on, and methods to avoid redundant steps. “Orchestrating genomic workflows at cloud scale is complex,” said Dr. Eric Banks, Senior Director of Data Sciences and Data Engineering at Broad and a creator of the GATK software package. “We wanted to simplify the execution of common genomic data types like reads and variants and to create an environment that allows any researcher to do this at scale in an easy-to-use way.” Another area of joint innovation is in the processing and storing of genomic variant datasets, which often consist of large, sparse data matrices. Gene sequence variation data is commonly stored as text files for bioinformatics. The declining cost of DNA sequencing has driven an increase in the volume of genomic data sets that researchers want to incorporate, making it increasingly difficult to jointly analyze large volumes of data from text files. Large scale reads and writes of variant call data, joint genotyping, or variant recalibration require next-generation databases that are built and optimized for genomic data. Broad and Intel are collaborating on a faster, more flexible, and scalable solution. ‘GenomicsDB’ is a novel way to store vast amounts of patient variant data and to perform fast processing with unprecedented scalability. Built and optimized for the management of genomic variant data, GenomicsDB runs on top of an array database system optimized for sparse data called ‘TileDB.’ TileDB was developed by MIT and Intel researchers working at the Intel Science and Technology Center for Big Data, which is based at MIT's Computer Science and Artificial Intelligence Lab. GenomicsDB is now used in the Broad’s production pipeline running on an Intel Xeon processor based cloud environment to perform joint genotyping. “The time it now takes to perform the variant discovery process went from eight days to 18 hours,” Banks said. “However, that’s with 100 whole genomes. We routinely process projects with thousands of samples, so that speedup itself is truly transformative. We recently needed to abandon our attempt to run variant discovery on an eight thousand sample project, because we estimated it would take 90 days without GenomicsDB. With GenomicsDB, however, it should take under a week. This means we can say ‘yes’ to our researchers far more often, on far more ambitious projects.” “With the integration of these two tools into the genomic pipeline that we are running on a cloud environment, the orchestration and execution of the workflow is not only simplified but significantly accelerated,” said Ben Neale, an institute member at the Broad Institute’s Stanley Center for Psychiatric Research and the Broad’s Program in Medical and Population Genetics. “We are excited that the research community will be able to start testing GenomicsDB and Cromwell.” Intel is releasing TileDB and GenomicsDB as open source tools. Engineers building the ‘Collaborative Cancer Cloud,’ a precision medicine network including Oregon Health Sciences University (OHSU), Dana-Farber Cancer Institute (DFCI), and Ontario Institute for Cancer Research (OICR) are already using these tools across their collective data sets. Long-term goals are to expand upon these tools to enable joint genotyping with other large genomic research centers in a federated and secure model, regardless of the location of data. Broad will continue to work with Intel on next-generation computing technologies that address the size, speed, security and scalability challenges associated with large scale genomic sequencing data and analytics. “The progress that we’re seeing in our development work with Broad represents another step in the moonshot goal of taming cancer and other maladies,” said Eric Dishman, Intel Vice President, Health and Life Sciences. “Harnessing and analyzing massive amounts of genomic data may eventually be a key factor in enabling people around the world to live longer, healthier lives.”
News Article | December 2, 2016
Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops. Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now, scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs. The scientists demonstrated that Zika infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus. "Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells," said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University, and co-corresponding author on a paper reporting the research in Cell Stem Cell. "It's very important for the research community to learn that targeting the AXL protein alone will not defend against Zika," agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for BioMedical Research (NIBR). Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain. "We were thinking that the knocked-out NPCs devoid of AXL wouldn't get infected," said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. "But we saw these cells getting infected just as much as normal cells." Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain "organoids" containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice. "We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect," said Kaykas. "For the first few months, the organoids do a really good job in recapitulating normal brain development." Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish. The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika. The Harvard/NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika's global challenge, as the virus has spread to more than 70 countries and territories. "At the genesis of the project, my wife was pregnant," Eggan remarked. "One can't read the newspapers without being concerned." The collaboration grew out of interactions at the Broad Institute of MIT and Harvard's Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders. "Zika seemed to be a big issue where we could have an impact, and we all shared that interest," Eggan said. "It's been great to have this public, private collaboration." The researchers are studying other receptor proteins that may be open to Zika infection, in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus.