It was Jean-Martin Charcot working in France in the late 1860s and early 1870s whose lectures and publications were among the first to describe the clinical and pathological features of amyotrophic lateral sclerosis (ALS), and provided the framework for subsequent clinical and experimental endeavors in the ever-expanding field of ALS neurology.
Since the time of Charcot, key discoveries in neurobiology have led to steady advances in our understanding of the pathogenesis of the disease, and there has been modest progress in the management and symptomatic treatment of ALS, as shown in . Accordingly, the ALS research community looks to the future – supported by the strong foundation established by Charcot and the work of those clinicians and scientists who followed – and is poised for major breakthroughs in elucidating pathogenesis and in discovering more effective treatments. Before we press on in these activities, however, it is helpful to pause, and examine what is being done here and now in ALS research, and to what point it has taken us in our understanding of the disease.
Figure 1. Key topics in advancing the understanding and treatment of ALS, alongside Charcot's initial crucial clinical observations.
Today, the ALS community is actively engaged in carrying out therapeutic trials. All current trials are based on hypotheses of possible ALS disease mechanisms, and the majority of these have been inspired by encouraging results in animal models of ALS. The preclinical studies used to justify subsequent human trials have been performed mostly in superoxide dismutase-1 (SOD1) transgenic rodents, with the hope that drugs tested and shown to be effective in these models will also be found to have a positive outcome in patients with ALS. To date, the drugs used in trials have varied widely in terms of their cellular or molecular targets, since there are now multiple viable working hypotheses concerning pathogenesis of ALS, and all of them deserve thorough evaluation. There is no question that the number of therapeutic trials in ALS initiated each year continues to grow, as the stakeholders in the treatment of ALS (patients, doctors, researchers, funding agencies, and pharmaceutical companies) all wish for more effective medications to be available for patients as rapidly as possible. The Northeastern (NEALS), Western (WALS) and European (ENCALS) ALS consortia have made remarkable contributions to the advancement of such trials.
Making the transition from the animal model to the human condition is clearly an important and enduring paradigm for clinical studies, but it might not be the only front in the search for more effective medications. An additional approach to facilitate ALS drug development might be to focus on the patients themselves. While investigations in transgenic mice expressing human mutated SOD1 genes have catalyzed progress in understanding potential disease mechanisms in ALS patients, the knowledge gained from this model has not yet engendered novel therapeutic strategies, with only a single FDA approved medication, riluzole, which slows disease progression only modestly. This situation has led investigators to suspect that more sophisticated models for the human disease are needed. If one accepts that the mystery of ALS resides in the patient, then patient-oriented research to find its causes and discover its disease mechanisms may hold the key to future progress in understanding ALS and discovering more effective treatments. On the other hand, patient-centered research is challenging. Human studies may pose insurmountable limitations, and the clinicians needed to initiate such research endeavors may have little formal research training. However, with huge strides in understanding the basic science of ALS, it is a propitious time to confront these difficulties and bring clinicians and pure scientists together in a common goal.
A first step was to hold a conference in which the best minds in the many fields of ALS (clinician scientists, pure scientists, individuals from patient advocacy groups, funding agencies, and pharmaceutical companies) met to discuss possible ways to facilitate patient-oriented research and explore the widest range possible of potential fronts.
When one of us (HM) pitched his idea for the conference to Annette Kirshner, Program Officer, National Institute of Environmental Health Science, she encouraged him to pursue it. We started by asking clinical leaders in the ALS community if they would be interested in this type of conference. With their encouragement and support, we asked Richard Barohn, Richard Bedlack, Lucie Bruijn, Merit Cudkowicz, Valerie Cwik, Denise Figlewicz, Daragh Heitzman, Chris Henderson, Cathy Lomen-Hoerth, Robert Miller, Ericka Simpson, and Eric Sorenson to serve on the Organizing Committee.
We filed the necessary grant applications to organizations that represent the ALS community, and were most fortunate in receiving generous support from the National Institute of Neurological Diseases and Stoke and Office of Rare Disease Research combined, the Muscular Dystrophy Association, ALS Association (New York Chapter), ALS Society of Canada, The Judith & Jean Pape Adams Charitable Foundation, Ride for Life, Eleanor and Lou Gehrig MDA/ALS Research Center, Bill Spina, Outreach ALS Foundation of Westchester, MND Association UK, ALS Hope Foundation, and Les Turner Foundation. Pharmaceutical companies were equally generous in supporting the conference – Sanofi-Aventis, Knopp Biosciences, Biogen Idec, Avanir, and Pfizer. Without this strong support, such a conference would not have been possible.
Approximately 150 attendees (see listing) discussed topics vigorously in the contexts of the main themes, which included phenotype expression, biomarkers, epidemiology, and genetic/epigenetic issues. More than 60 experts presented their work. All presentations were in a short or ‘blitz-like’ format where the presenters would quickly introduce their specific topic as a springboard for a more extensive discussion that followed. Breakout sessions were also held, to discuss current impediments to clinical research and potential recommendations as to how we might move the field forward. At the conclusion of the conference, we discussed the current infrastructure for patient-oriented research and the resources available, recommendations from funding agencies, breakout session and final summations. David Chad, Andy Eisen, Kurt Fischbeck, Amelie Gubitz, Nigel Leigh, and Steve Ringel most skillfully moderated these sessions to make the conference incredibly productive. The highlight of the conference was an evening talk given by Asao Hirano, titled ‘Personal Recollection from my ALS Research’. His life-long scholarly work dedicated to ALS began in Guam. His talk abounded in enlightenment and wit, and truly inspired all of us who study ALS.
We wanted to share the conference proceedings with the wider clinical and scientific community, and so proposed writing a supplement for Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. We wanted to make sure each topic was written as a high-level review, while also incorporating expert speakers’ presentations and discussion. Ammar Al-Chalabi, David Chad, Pam Factor-Litvak, Amelie Gubitz, John Ravits, Alex Sherman and Martin Turner led the work for each section. We are very grateful for their willingness to undertake this task and help make this supplement a reality. Some of the topics, such as the infrastructure resources, overall recommendations and summaries, have a North American focus, and we wish to reiterate the equal and vital contributions of countries beyond these borders, in particular the large pan-European ALS research efforts. Having completed the entirety of the supplement, we cannot express enough gratitude to Orla Hardiman for her encouragement during the publishing process and for going over all the submitted materials.
We wish to express our heartfelt thanks to the staff of the Eleanor and Lou Gehrig MDA/ALS Research Center: Nicole Armstrong, Christa Campanella, Fondre Goulbourne, Jon Hupf, Jenn Greene, Yei-Won Lee, Meredith Pasmantier, and Regina Youngman, who helped run the conference, and particularly Georgia Christodoulou (executive assistant to HM), who organized the entire conference and supplement development in every aspect.
In summary, the ALS scientific community came together to produce a unique and provocative conference, exceeding our expectations and inspiring all who were present. We sincerely hope this conference, and the supplement it has spawned, will help all of those dedicated to ALS research take further steps forward on the journey of discovery that will eventually delineate the pathogenesis and develop more effective treatment for those living with ALS.
Hiroshi Mitsumoto
Martin R. Turner
List of Attendees
Ammar Al-Chalabi, Institute of Psychiatry, King’s College London
Michael J. Allen, University of Chicago
Jinsy Andrews, Hospital for Special Care
Stanley H. Appel, Methodist Neurological Institute
Carmel Armon, Baystate Medical Center and Tufts University
Alberto Asherio, Harvard School of Public Health
Nazem Atassi, Massachusetts General Hospital
Robert H. Baloh, Washington University in St. Louis
Sami Barmada, University of California San Francisco
Richard J. Barohn, University of Kansas
Richard S. Bedlack, Duke University
Jerry M. Belsh, University of Medicine and Dentistry of New Jersey
Michael G. Benatar, University of Miami
James D. Berry, Massachusetts General Hospital
Sanjay Bidichandani, Muscular Dystrophy Association
Ratna Bhavaraju-Sanka, University of Texas at San Antonio
Robert Bowser, University of Pittsburgh
Kevin B. Boylan, Mayo Clinic Florida
Walter G. Bradley, University of Miami
Mark Bromberg, University of Utah
Benjamin Rix Brooks, Carolinas Medical Center
Lucie Bruijn, ALS Association
Barbara Byer, ALS Worldwide
Stephen Byer, ALS Worldwide
J. Donald Capra, Judith & Jean Pape Adams Charitable Foundation
Patricia Capra, Judith & Jean Pape Adams Charitable Foundation
Greg T. Carter, University of Washington
Jesse M. Cedarbaum, Bristol-Myes Squibb R&D
David A. Chad, Massachusetts General Hospital
Stephen Chan, Columbia University Medical Center
Amy Chen, University of Rochester
Adriano Chiò, University of Turin
Robin Conwit, National Institute of Neurological Disorders and Stroke, NIH
Luc Dupuis, Université Louis Pasteur
Heather Durham, McGill University
Andrew Eisen, University of British Columbia
Jeffrey L. Elliott, University of Texas Southwestern Medical Center
Lauren Elman, University of Pennsylvania
Pam Factor-Litvak, Columbia University Medical Center
John H. Ferguson, Office of Rare Diseases Research, NIH
Denise Figlewicz, ALS Society of Canada
Kenneth H. Fischbeck, National Institute of Neurological Disorders and Stroke, NIH
Mary Kay Floeter, National Institute of Neurological Disorders and Stroke, NIH
Dallas Forshew, California Pacific Medical Center
Melissa Forsythe, Congressionally Directed Medical Research Programs Office (CDMRP) US Army Medical Research & Materiel Command
Ralph M. Garruto, State University of New York at Binghamton
Angela Genge, McGill University
Summer Bell Gibson, University of Utah
Raymond R. Goetz, Columbia University Medical Center
Christopher Grunseich, National Institute of Neurological Disorders and Stroke, NIH
Amelie Gubitz, National Institute of Neurological Disorders and Stroke, NIH
Ali A. Habib, St. Joseph Medical Center
Steve S. Han, Massachusetts General Hospital
Orla Hardiman, Trinity College Dublin
Brent T. Harris, Georgetown University
Kelly D. Hartle, University of Manitoba
Ghazala Hayat, Saint Louis University
Terry Heiman-Patterson, Drexel University
Daragh Heitzman, Texas Neurology, PA
Christopher E. Henderson, Columbia University Medical Center
Asao Hirano, Albert Einstein College of Medicine
Michio Hirano, Columbia University Medical Center
Kevin Horton, Agency for Toxic Substances and Disease Registry (ATSDR)/Centers for Disease Control and Prevention (CDC)
Yasuo Iwasaki, Toho University
Carlayne Jackson, University of Texas Health Science Center
Nanette C. Joyce, University of California, Davis
Freya Kamel, National Institute of Environmental Health Sciences, NIH
Edward J. Kasarskis, University of Kentucky
Jonathan S. Katz, California Pacific Medical Center
Petra Kaufmann, National Institute of Neurological Disorders and Stroke, NIH
Hibiki Kawamata, Weill Cornell Medical College
Suresh Khemani, Knopp Biosciences
Hyun Jeong Kim, Weill Cornell Medical College
Annette Kirshner, National Institute of Environmental Health Sciences, NIH
Lawrence Korngut, University of Calgary
Shin Kwak, MD, Tokyo University
Justin Y. Kwan, University of Maryland
David Lacomis, University of Pittsburgh
Clotilde Lagier-Tourenne, University of California, San Diego
Edward B. Lee, University of Pennsylvania
Peter Nigel Leigh, University of Sussex
Melanie Leitner, Prize4Life
Catherine Lomen-Hoerth, University of California, San Francisco
Albert C. Ludolph, University of Ulm
Jeffrey D. Macklis, Harvard University
Jordi Magrane, Weill Cornell Medical College
Giovanni Manfredi, Weill Cornell Medical College
Nicholas Maragakis, Johns Hopkins University
Jim Mather, Knopp Biosciences
Leo F. McCluskey, University of Pennsylvania
Martin McElhiney, Columbia University Medical Center
Ann McKee, Boston University
Mark F. Mehler, Albert Einstein College of Medicine
Parag Meswani, Biogen Idec
Robert G. Miller, California Pacific Medical Center
Timothy Miller, Washington University in St. Louis
Hiroshi Mitsumoto, Columbia University Medical Center
William Monti, ALS Advocate
Tahseen Mozaffar, University of California, Irvine
Peter L. Nagy, Columbia University Medical Center
Imaharu, Nakano, Jichi Medical University
Sharon Nations, University of Texas Southwestern Medical Center
Lorene Nelson, Stanford University
Mieko Ogino, Kitasato University
Gary L. Pattee, University of Nebraska Medical Center
Ellyn C. Phillips, ALS Association
James Phillips, Congressionally Directed Medical Research Programs Office (CDMRP) US Army Medical Research & Materiel Command
Erik Pioro, Cleveland Clinic
Rahman Pourmand, State University of New York, Stony Brook
Serge Przedborski, Columbia University Medical Center
Seth Pullman, Columbia University Medical Center
Judy Rabkin, Columbia University Medical Center
Denise Rattner, Outreach ALS Foundation of Westchester
John M. Ravits, University of California, San Diego
Steven P. Ringel, University of Colorado School of Medicine
Raymond P. Roos, University of Chicago
Jeffrey D. Rothstein, Johns Hopkins University
Guy A. Rouleau, University of Montreal
Lewis P. Rowland, Columbia University Medical Center
Stacy A. Rudnicki, University of Arkansas
Seward Rutkove, Beth Israel Deaconess Medical Center
Stephen N. Scelsa, Beth Israel Deaconess Medical Center
Pamela J. Shaw, University of Sheffield
Jeremy M. Shefner, SUNY Upstate Medical University
Alexander Sherman, Massachusetts General Hospital
Alvin V. Shih, Pfizer
Neil Shneider, Columbia University Medical Center
Christen Shoesmith, University of Western Ontario
Teepu Siddique, Northwestern University
Zachary Simmons, Penn State Hershey Medical Center
Ericka Simpson, The Methodist Hospital Research Institute
Richard A. Smith, Center for Neurologic Study
Eric J. Sorenson, Mayo Clinic, Rochester
Michael J. Strong, University of Western Ontario
Rup Tandan, University of Vermont
Stacy Topalian, Outreach ALS Foundation of Westchester
John Trojanowski, University of Pennsylvania
John Turnbull, McMaster University
Martin R. Turner, University of Oxford
Yoshiaki Urano, Kitasato University Hospital
Leonard van den Berg, University Medical Center Utrecht
Jean Paul G. Vonsattel, Columbia University Medical Center
Kevin Walton, Division of Neuroscience, Development and Aging, NIH/CSR0
Markus Weber, Kantonsspital St. Gallen
Lorne Zinman, University of Toronto