DOCSLIB.ORG

Developing the Yeast Disaggregase Hsp104 As a Treatment for Polyglutamine Disease in Drosophila Mary Cushman Nick University of Pennsylvania, [email protected]

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Developing the Yeast Disaggregase Hsp104 As a Treatment for Polyglutamine Disease in Drosophila Mary Cushman Nick University of Pennsylvania, Mimicnick@Gmail.Com University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 1-1-2013 Developing the Yeast Disaggregase Hsp104 as a Treatment for Polyglutamine Disease in Drosophila Mary Cushman Nick University of Pennsylvania, [email protected] Follow this and additional works at: http://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons Recommended Citation Nick, Mary Cushman, "Developing the Yeast Disaggregase Hsp104 as a Treatment for Polyglutamine Disease in Drosophila" (2013). Publicly Accessible Penn Dissertations. 904. http://repository.upenn.edu/edissertations/904 This paper is posted at ScholarlyCommons. http://repository.upenn.edu/edissertations/904 For more information, please contact [email protected]. Developing the Yeast Disaggregase Hsp104 as a Treatment for Polyglutamine Disease in Drosophila Abstract There is currently no cure for neurodegenerative disease or the underlying burden of protein aggregation that is associated with symptom development. A novel approach to combat this accumulation of misfolded protein species is surprisingly found in a protein disaggregase in yeast, the heat shock protein Hsp104. To investigate whether Hsp104 can be introduced into an animal system and harnessed to attack disease-associated protein inclusions, we created a transgenic Drosophila model expressing Hsp104 and investigated whether this would mitigate toxicity and alter the load of protein accumulations. We found that Hsp104 indeed suppressed toxicity of a disease-associated protein fragment containing an expanded polyglutamine tract. However, we found that Hsp104 worsened toxicity of the full-length pathogenic polyglutamine protein, and this coincided with increased accumulation of amyloid inclusions. This aberrant activity of Hsp104 depended on intact domains in the non-polyglutamine stretches of the protein, and this negative interaction could be prevented by mutation to these neighboring domains. These results indicate that knowing the precise protein state of a disease environment is critical in evaluating potential therapeutics. Moreover, we sequentially activated Hsp104 after the onset of protein aggregation and start of tissue degeneration, to find that Hsp104, but not Hsp70, significantly suppressed progressive degeneration. Thus, the unique ability of Hsp104 to tackle pre- existing amyloid conformers may offer a novel opportunity to reverse disease progression once underway. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Nancy M. Bonini Second Advisor James Shorter Keywords amyloid, chaperone, disaggregase, Drosophila, Hsp104, polyglutamine Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/904 DEVELOPING THE YEAST DISAGGREGASE HSP104 AS A TREATMENT FOR POLYGLUTAMINE DISEASE IN DROSOPHILA Mary Cushman Nick A DISSERTATION in Neuroscience Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2013 Co-Supervisor of Dissertation Co-Supervisor of Dissertation __________________________ __________________________ Nancy M Bonini, PhD James Shorter, PhD Florence R.C. Murray Professor of Biology and Associate Professor of Biochemistry and Investigator, Howard Hughes Medical Institute Biophysics Graduate Group Chairperson __________________________ Joshua I Gold, PhD Associate Professor of Neuroscience Dissertation Committee Harry Ischiropoulos, PhD Virginia M-Y Lee, PhD, MBA Research Professor of Pediatrics and John H Ware 3rd Professor in Alzheimer’s Research Pharmacology and Professor of Pathology and Lab Medicine Erika LF Holzbaur, PhD Robert Fairman, PhD Professor of Physiology Professor of Biology and Associate Provost, Haverford College DEVELOPING THE YEAST DISAGGREGASE HSP104 AS A TREATMENT FOR POLYGLUTAMINE DISEASE IN DROSOPHILA COPYRIGHT 2013 Mary Cushman Nick ACKNOWLEDGEMENT I am so grateful to Jim Shorter and Nancy Bonini for guidance and support throughout the course of this dissertation work. I learned so much from Jim about how to think about science and design experiments, and I greatly appreciate all the time he has invested in training me. Nancy has been a great inspiration to me in how to be a tough scientist and also an encouraging mentor. From her, I have learned how to work efficiently, and will forever be indebted to her for advising me to develop detailed outlines and contingency plans. Moreover, there is no greater group of people than those working in these two labs, and I have been surrounded by exceptional colleagues that I am glad to call my friends. I have also been fortunate to have an outstanding thesis committee, and despite feeling intimidated by such an accomplished group, I have truly enjoyed discussing science with them. I must also acknowledge my family. My husband Jeff has graciously absorbed all of my frustrations and has managed to offer the best advice in return. I could not have completed any of this without his support and reinforcement, and while I am proud of the work presented here, finding him has been my greatest accomplishment. I’m also lucky enough to have three sets of parents to encourage me (and constantly mention that a cure for age-related disease is needed as soon as possible). To my brother and siblings-in-law, I cannot express how pleased I am that I happen to be related to the people I consider my best friends. iii ABSTRACT DEVELOPING THE YEAST DISAGGREGASE HSP104 AS A TREATMENT FOR POLYGLUTAMINE DISEASE IN DROSOPHILA Mimi Cushman-Nick Dr. Nancy M. Bonini Dr. James Shorter There is currently no cure for neurodegenerative disease or the underlying burden of protein aggregation that is associated with symptom development. A novel approach to combat this accumulation of misfolded protein species is surprisingly found in a protein disaggregase in yeast, the heat shock protein Hsp104. To investigate whether Hsp104 can be introduced into an animal system and harnessed to attack disease-associated protein inclusions, we created a transgenic Drosophila model expressing Hsp104 and investigated whether this would mitigate toxicity and alter the load of protein accumulations. We found that Hsp104 indeed suppressed toxicity of a disease-associated protein fragment containing an expanded polyglutamine tract. However, we found that Hsp104 worsened toxicity of the full-length pathogenic polyglutamine protein, and this coincided with increased accumulation of amyloid inclusions. This aberrant activity of Hsp104 depended on intact domains in the non-polyglutamine stretches of the protein, and this negative interaction could be prevented by mutation to these neighboring domains. These results indicate that knowing the precise protein state of a disease environment is critical in evaluating potential therapeutics. Moreover, we sequentially activated Hsp104 after the onset of protein aggregation and start of tissue degeneration, to find that Hsp104, but not Hsp70, significantly suppressed progressive degeneration. Thus, the unique ability of Hsp104 to tackle pre-existing amyloid conformers may offer a novel opportunity to reverse disease progression once underway. iv TABLE OF CONTENTS ACKNOWLEDGEMENT ...................................................................................... iii ABSTRACT .......................................................................................................... iv LIST OF TABLES ................................................................................................ ix LIST OF ILLUSTRATIONS ................................................................................... x CHAPTER 1 : INTRODUCTION ........................................................................... 1 HARNESSING THE MOLECULAR DISAGGREGASE HSP104 TO COMBAT THE AMYLOID ACCUMULATION THAT UNDERLIES NEURODEGENERATIVE DISEASE ............................... 2 Protein aggregation underlies neurodegenerative disease .................................................. 3 Molecular chaperones: a natural defense against protein misfolding ................................ 7 HSPs in treating neurodegenerative disease ....................................................................... 11 Can chaperones reverse neurodegenerative disease? ....................................................... 15 CHAPTER 2 : MANUSCRIPT ............................................................................. 19 HSP104 SUPPRESSES POLYGLUTAMINE-INDUCED DEGENERATION POST ONSET IN A DROSOPHILA MJD/SCA3 MODEL. ............................................................................................ 19 INTRODUCTION ........................................................................................................................... 20 RESULTS ..................................................................................................................................... 24 Hsp104 mitigates toxicity of truncated MJD, but enhances toxicity of the full-length MJD .................................................................................................................................................. 24 The opposite effects of Hsp104 on MJDtrQ78 and MJDnQ78 correspond to distinct modulation of underlying protein accumulations ................................................................ 27 Domains neighboring the expanded PolyQ tract hinder protective Hsp104 activities
Load more

Recommended publications
  • Twists and Turns in Protein Assembly
    Twists and Turns in Protein Assembly Professor Robert Fairman TWISTS AND TURNS IN PROTEIN ASSEMBLY In nerve cells, the accumulation of protein into bundles of insoluble fibres is the underlying cause of a number of neurodegenerative diseases. Professor Robert Fairman and his team at Haverford College are developing cutting edge techniques to unravel this process. Proteins are the building blocks of life. The leads to the death of particularly vulnerable genetic code within each cell of our bodies cells such as neurones – the elaborate and controls the sequence of molecules called sensitive cells in our brain. This is the basic amino acids, which assemble together mechanism that causes the debilitating and to form each protein. But this is only the currently untreatable neurological disorder first step. Amino acids are small charged Huntington’s disease, which is characterised molecules that interact with one another as by a disruption of normal movements and they join together to form strings of peptides a decline in mental ability, resulting in (polypeptides), which spontaneously develop dementia. into different structures known as secondary structures. This can involve the formation ‘The relationship of this aggregation to of sheets or helical spirals following certain disease is poorly understood, and differences rules determined by the order of the amino in protein structure may underlie differences acids. These secondary structures then in toxicity,’ Professor Fairman admits. ‘Many interact with one another to form larger neurodegenerative diseases (Alzheimer’s, tertiary structures of proteins that control Huntington’s, Parkinson’s) have a similar and mediate every aspect of cell function. underlying molecular mechanism of protein aggregation, involving the formation of ‘Ever since I was an undergraduate student, an extended polypeptide chain that can I’ve always been fascinated with a chemical aggregate through ß-sheet formation.’ view of biology,’ Professor Fairman tells As such, it is vital to understand how Scientia.
    [Show full text]
  • From the President's Desk
    Sept | Oct 2009 From the President’s desk: The Increasing Importance of Model Organism Research I’m sure you know this scenario: You’re at a party, and someone hears you’re a biologist, and asks, “What do you work on?” When this happens to me, and I respond that I study yeast, I frequently get the follow-up question that you have probably already anticipated: “Are you learning how to make better beer?” At that point, I offer my explanation about the value of studying model organisms, which in cludes the statement that my daughter, now 17, learned to repeat with me by the time she was 3: “Yeast are actually a lot like people.” If you study a model organism, whether it’s yeast, bacteria, phage, flies, worms, fish, plants, or something else, you probably have been in Fred Winston a similar situation when talking to someone who is not a scientist. There GSA President is little understanding among the general public about the value of studying a model organism. This is also true among some who we might think would better understand this issue. While you wouldn’t be surprised to learn that the person at this party was a lawyer or a businessperson, you might also not be too surprised if that person turned out to be a physician, or even a human biologist. Even among some biologists who understand the history of model organisms, there may be a lack of appreciation for what model organism research can contribute to future scientific understanding. For these scientists, model organi sms appear to be in the twilight of their usefulness with the advent of new sequencing technologies and other genome-wide, high-throughput approaches that can be used in human studies.
    [Show full text]
  • 'Epigenetic Landscape' Is Protective in Normal Aging, Impaired in Alzheimer's Disease 5 March 2018
    'Epigenetic landscape' is protective in normal aging, impaired in Alzheimer's disease 5 March 2018 compaction of chromosomes in the nucleus (called acetylation of lysine 16 on histone H4, or H4K16ac for short). Changes to the way H4K16ac is modified along the genome in disease versus normal aging brains may signify places for future drug development. Because changes in H4K16ac govern how genes are expressed, the location and amount of epigenetic alterations is called the "epigenetic landscape." "This is the first time that we have been able to look at these relationships in human tissue by using donated postmortem brain tissue from the Penn Brain Bank," said Shelley Berger, PhD, a professor of Cell and Developmental Biology in the Perelman School of Medicine and a professor of Biology in the School of Arts and Sciences. "Our results Coronal section of human brain indicating the lateral establish the basis for an epigenetic link between temporal lobe (red circle) used in this study. Credit: aging and Alzheimer's disease." Coronal section of human brain indicating The lab of Shelley Berger, PhD, Perelman School of Medicine, Berger, also the director of the Penn Epigenetics University of Pennsylvania Institute, Nancy Bonini, PhD, a professor of Biology, and Brad Johnson, MD, PhD, an associate professor of Pathology and Laboratory Medicine, are co-senior authors of the new study. Although certain genetic variants increase the risk of Alzheimer's disease (AD), age is the strongest H4K16ac is a key modification in human health known risk factor. But the way in which molecular because it regulates cellular responses to stress processes of aging predispose people to AD, or and to DNA damage.
    [Show full text]
  • St. Geme Symposium Pediatrics, University of Sponsored by the Colorado, AMC Section of Developmental Biology
    Department of St. Geme Symposium Pediatrics, University of Sponsored by the Colorado, AMC Section of Developmental Biology September 10, 2020 2:00pm-4:00pm Speaking Schedule Introduction by Dr. Bruce Appel, Section Head, The St. Geme Symposium Developmental Biology will be held this year in association with the St. 2:00 Caleb Doll, PhD – Fragility in specification; roles for Geme Lectureship, an the RNA binding protein FMRP in gliogenesis annual event in honor of 2:15 Agnese Kocere – RBM8A deficiency in TAR syndrome Dr. Joseph St. Geme, a impacts the lateral plate mesoderm former Dean of the 2:30 Julia Derk, PhD – A critical role for Wnt suppression in School of Medicine. The the development of the arachnoid barrier of the purpose of the meninges Symposium is to 2:45 Kelly Sullivan, PhD – Normalization of Interferon introduce research Receptor Gene Dosage in Mouse Model of Down performed in the Section Syndrome of Developmental Biology 3:00 Yunus Ozekin – Exploring the Effects of Prenatal to our St. Geme Lecturer, ECigarette Exposure on Craniofacial Development Dr. Nancy Bonini, 3:15 Jessica Warns, PhD – Does NF‐Y regulate cilia gene members of the St. Geme networks? family and the Anschutz 3:30 Kayt Scott – Prdm8 regulates pMN progenitor Medical Campus specification for motor neuron and oligodendrocyte community. fates by modulating Shh signaling response 3:45 Peter Dempsey, PhD ‐ Cellular Plasticity of Intestinal Secretory Progenitors in Response to Injury Zoom link https://ucdenver.zoom.us/j/921 40407653 Developmental Biology faculty, post-doctoral fellows About the Section of and student’s biographical information: Developmental Biology: Dempsey, Peter, PhD - Associate Professor Dr.
    [Show full text]
  • Temporal Patterns of Short Non-Coding Rna Modifications And
    TEMPORAL PATTERNS OF SHORT NON-CODING RNA MODIFICATIONS AND EXPRESSION by AMMAR S. NAQVI A dissertation submitted to the Graduate School – Camden Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Computational and Integrative Biology Written under the direction of Dr. Andrey Grigoriev And approved by ________________________ Andrey Grigoriev ________________________ Jongmin Nam ________________________ Nancy Bonini Camden, New Jersey May 2015 ABSTRACT OF THE DISSERTATION Temporal Patterns of non-coding RNA Modifications and Expression by AMMAR S. NAQVI Dissertation Director: Dr. Andrey Grigoriev We investigated the function and properties of small RNAs, particularly microRNAs and tRNA-derived fragments (tRFs) with age. We report the characterization of a novel 3'-to- 5' exonuclease, Nibbler (Nbr), that generates differing isoforms of miRNAs in Drosophila. We developed a robust approach to help identify and characterize 3' heterogeneity in microRNAs controlled by Nbr, which assisted in identifying age- associated traits, including neurodegeneration and lifespan. Subsequently, given the fact Nbr interacts with Ago1 and not Ago2, we observed an accumulation of certain isoforms, which lead us to ask if there were particular patterns and trends that were Ago-specific. Interestingly, we report a novel age-associated change of select isoforms with age that is Ago2 specific. RNA deep-sequencing analysis coupled with experimental evidence reflected an increased loading of miRNA isoforms into Ago2 with age. Essentially, the loss of methylated miRNAs led to accelerated brain degeneration and shortened lifespan. Intriguingly, we also observed and identified Ago-loaded tRFs, which appear to have properties similar to those of miRNAs.
    [Show full text]
  • TFEB/Mitf Links Impaired Nuclear Import to Autophagolysosomal
    RESEARCH ARTICLE TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9- ALS Kathleen M Cunningham1, Kirstin Maulding1, Kai Ruan2, Mumine Senturk3, Jonathan C Grima4,5, Hyun Sung2, Zhongyuan Zuo6, Helen Song2, Junli Gao7, Sandeep Dubey2, Jeffrey D Rothstein1,2,4,5, Ke Zhang7, Hugo J Bellen3,6,8,9,10, Thomas E Lloyd1,2,5* 1Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, United States; 2Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, United States; 3Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, United States; 4Brain Science Institute, School of Medicine, Johns Hopkins University, Baltimore, United States; 5Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States; 6Department of Molecular and Human Genetics, BCM, Houston, United States; 7Department of Neuroscience, Mayo Clinic, Jacksonville, United States; 8Department of Neuroscience, BCM, Houston, United States; 9Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States; 10Howard Hughes Medical Institute, Houston, United States Abstract Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis *For correspondence: [email protected] (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron Competing interest: See microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that page 18 precedes neurodegeneration.
    [Show full text]
  • Polyq Expansions in Ataxin-2—A Risk Factor for Amyotrophic Lateral Sclerosis?
    RESEARCH HIGHLIGHTS MOTOR NEURON DISEASE PolyQ expansions in ataxin-2—a risk factor for amyotrophic lateral sclerosis? ntermediate-length polyglutamine (polyQ) expansions in the ataxin-2 I(ATXN2) gene could confer an increased risk of developing amyotrophic lateral sclerosis (ALS), according to research from a team led by Aaron Gitler and Nancy Bonini at the University of Pennsylvania, USA. Their findings indicate that ataxin-2 enhances the toxicity of TAR DNA-binding protein 43 (TDP-43)—a molecule that has already been strongly implicated in ALS pathogenesis—and the interaction between these two proteins could A combination of approaches involving yeast cells (left), Drosophila (center) and human motor neurons (right) has identified a provide a lead for the development of role for ataxin-2 in amyotrophic lateral sclerosis. Images provided by Professor Nancy Bonini and Professor Aaron Gitler. much-needed new therapies for ALS. Permission obtained from Nature Publishing Group © Elden, A. C. et al. Nature 466, 1069–1075 (2010). Long polyQ expansions (>34 glutamines) in the ATXN2 gene have overexpressed, increased TDP-43 toxicity. degradation, thereby increasing its previously been shown to cause the One of these genes was PBP1, the yeast concentration in the cell. hereditary neurodegenerative disease ortholog of ATXN2. These new findings identify ATXN2 spinocerebellar ataxia type 2 (SCA2). To examine the effects of the ATXN2– as a susceptibility gene for ALS, as well Gitler, Bonini and colleagues measured TDP-43 interaction in the context of as providing a number of avenues for ATXN2 polyQ repeat lengths in 915 the nervous system, the researchers further investigation of the underlying patients with sporadic or familial ALS, switched their attention to a Drosophila disease mechanisms.
    [Show full text]
  • NEWSLETTER VOLUME 35, NUMBER 6 Student/Postdoc- Led Local Meetings NIH Working Group Proposes Page 3 Training Changes More ASCB Award the Recommendations of a U.S
    ASCB J U L Y 2 0 1 2 NEWSLETTER VOLUME 35, NUMBER 6 Student/Postdoc- Led Local Meetings NIH Working Group Proposes Page 3 Training Changes More ASCB Award The recommendations of a U.S. National Institutes of Health (NIH) Working Group on the Announcements biomedical research workforce include changes in the programs offered by academic institutions, Page 8 limits on NIH support for graduate students, and changes in the way graduate students and postdocs are supported. The Working Group, a subcommittee of the Advisory Committee to An Innovative the NIH Director, was formed in January 2011 by NIH Director Francis Collins to examine Approach to Dual- the state of the biomedical research workforce and make recommendations to ensure the future Career Support competitiveness of the U.S. biomedical research enterprise. Page 11 The Biomedical Research Workforce Working Group was co-chaired by Shirley Tilghman and Sally Rockey, NIH Deputy Director for Extramural Research, and included ASCB members Leemor Joshua-Tor and Keith Yamamoto. In June 2012, the Working Group sent its report, with a series of recommendations, to Collins for his review and consideration. Inside Despite low unemployment for biomedical PhDs, the percentage of PhDs who move into President’s Column 3 tenured or tenure-track positions has declined by 8% since 1993. In contrast, science-related Did You Know? 6 occupations that do not involve the conduct of research or do not require graduate training WICB Junior, Senior Awards 8 are seeing increases in employment. According to
    [Show full text]
  • CV Yuanquan 3-23-16
    Yuanquan Song Ph.D. [email protected] Yuanquan Song Ph.D. Department of Physiology University of California San Francisco and HHMI 1550 4th Street RM RH481 San Francisco, CA 94158 (267) 679-9833 [email protected] Positions 05/2016 – Assistant Professor of Pathology and Laboratory Medicine Center for Cellular and Molecular Therapeutics (CCMT) at the Children's Hospital of Philadelphia (CHOP), University of Pennsylvania 09/2009 – 04/2016 Postdoctoral Fellow Dept. of Physiology, Univ. of California San Francisco and HHMI Mentor: Dr. Yuh Nung Jan, Ph.D. Education 05/2015 Spinal Cord Injury Training Program (SCITP) Dept. of Neuroscience, Ohio State University, Columbus, OH 2003 – 2009 Ph.D. in Neuroscience Univ. of Pennsylvania School of Medicine, Philadelphia, PA 1998 – 2002 B.S. in Biotechnology Shanghai Jiao Tong University, Shanghai, China Research Experience 09/2009 – present UCSF Yuh Nung Jan Lab Postdoctoral Fellow Research Projects: Cellular and molecular mechanisms underlying axon and dendrite degeneration and regeneration Neural and molecular substrates for the plasticity of aggression 02/2004 – 08/2009 UPenn Rita Balice-Gordon Lab Graduate Student Research Projects: Cellular and molecular mechanisms underlying neural circuitry formation and function Zebrafish model of MLL leukemogenesis Zebrafish model of neurodegenerative diseases 09/2003 – 12/2003 UPenn Irwin Levitan Lab Pre-dissertation Laboratory Rotation Research Project: Regulation of sodium-potassium ATPase by its binding protein mSlob 06/2003 – 08/2003 UPenn Nancy Bonini Lab Pre-dissertation Laboratory Rotation Research Project: Molecular mechanisms of polyglutamine diseases 07/2002 – 05/2003 Institute of Neuroscience, Academy of Sciences, Shanghai, China Research Assistant in the Lab of Shu-Min Duan, Xiao-Bing Yuan, and Mu-Ming Poo Research Project: Axon guidance and Rho GTPase signaling Awards and Fellowships 1 Yuanquan Song Ph.D.
    [Show full text]
  • From the President's Desk
    JAN - FEB 2008 From the President’s desk: The Urbilateria Book Project Genetics is thriving as never before, spawning in recent years sub- disciplines such as genomics, bioinformatics, evo-devo, systems biology, and more. If genetics were a business, there would be much talk about its growing market share both in basic science, its traditional realm, and increasingly throughout the world of medicine (with significant upside potential). The ageless questions – how genomes evolved on Earth, how genotype programs phenotype, what makes each of us human but unique, how genetic knowledge can better our lives – suddenly seem less daunting, more like practical tasks. Unsurprisingly, some of the brightest young minds on the planet are striving to join this remarkable enterprise in what promises to be among its greatest years. The Genetics Society of America should be at the forefront of all these developments. Genetic advances continue to unify all biological sciences, and a forum is needed to provide wise counsel, to nurture the careers of young geneticists, to communicate with the public, and to improve education, so more individuals can bring a true understanding of the biological world to today’s issues. There are several steps the GSA must take to provide this needed leadership. First, we must reach out and welcome every person who works to understand how genomes operate. We not only want a diverse membership, we need one. Splintering may succeed within ecosystems, but a tropical rainforest of genetics will not advance the future of our science, which is striving for unification. Most of the time we will continue to revel in our favorite realms, but we need a Genetics Society capable of overseeing the full scope of genetic science placing it all in its proper perspective.
    [Show full text]
  • *HDSA/Fall 01/Marker/C
    THE markerHuntington’s Disease Society of America HDSA Research Update 2001 progress hd living in research kids at-risk care a message from n the 1960’s, activist and entertainer In our Nation’s Capital, HDSA advocacy Truly, the answers Woody Guthrie was well known efforts have been unflagging. As a result of we find for Ithroughout the world, but the disease our awareness building efforts, HDSA was Huntington’s that ended his life was not. One of the invited by Connecticut Senator Disease may well greatest challenges that faced Marjorie Christopher Dodd in March to testify serve as the key to Guthrie when she founded the before his Senate Biotechnology caucus. effective therapies organization that was to become the In May, HDSA was invited to partner with or even cures for Huntington’s Disease Society of America the National Institute of Neurological all neuro- was the fact that HD was a “family” Disorders and Stroke (NINDS) in a pilot degenerative secret, misunderstood and often project that was reported in the last issue of and/or hereditary misdiagnosed. Educating healthcare Toward a Cure. In June, HDSA appeared at disorders. professionals, elected officials and the a Health Policy Briefing, hosted by the The HDSA Therapeutics Initiative will general public about Huntington’s National Health Council, along with bring the research, conducted by our Disease, and the challenges faced by several other voluntary health agencies, HDSA Coalition for the Cure those who live with it, has always been to bring issues of concern to the HD investigators and Grant and Fellowship an integral part of HDSA’s mission.
    [Show full text]
  • Enhanced Β Integrin Adhesion Underlies Thrombosis Risk in JAK2
    This Month CD40-targeting HIV vaccine attacks the latent reservoir 2 Neonatal Fc receptor antagonist safely reduces IgGs in healthy adults 3 Reversing B cell impairment in chronic hepatitis B infection 4 Intratumor NK cells respond to PD-1/PD-L1 blockade 5 October 2018 JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight jci.org/this-month Enhanced β integrin adhesion underlies thrombosis risk in JAK2- Scan for the digital version V617F–driven neoplasms p. 2 of JCI This Month. Journal of Clinical Investigation Consulting Editors Soman N. Abraham Richard T. D'Aquila Katherine A. High Terri Laufer Sallie R. Permar Roy L. Silverstein John S. Adams Alan Daugherty Helen H. Hobbs Mitchell A. Lazar David J. Pinsky M. Celeste Simon Qais Al-Awqati Sudhansu Dey Ronald Hoffman Brendan Lee Edward Plow Mihaela Skobe Kari Alitalo Anna Mae Diehl V. Michael Holers William M.F. Lee Catherine Postic Donald Small Dario C. Altieri Harry C. Dietz III Steven Holland Rudolph L. Leibel Alice S. Prince Lois Smith Masayuki Amagai Gianpietro Dotti David Holtzman Wayne I. Lencer Louis J. Ptacek Akrit Sodhi Brian H. Annex Michael Dustin Michael J. Holtzman Jon D. Levine Luigi Puglielli Weihong Song M. Amin Arnaout Connie J. Eaves Lawrence B. Holzman Ross L. Levine Pere Puigserver Ashley L. St. John Alan Attie Dominique Eladari Maureen Horton Klaus Ley Bali Pulendran Jonathan Stamler Jane E. Aubin Joel K. Elmquist Tamas L. Horvath Rodger A. Liddle Ellen Puré Colin L. Stewart Michael F. Beers Stephen G.
    [Show full text]