In August 2001, a diverse group of academic and industry investigators from within and outside of Alzheimer's disease research participated in this workshop in Bar Harbor, Maine. The goal was to identify critical knowledge gaps that slow down the search for diagnostics and treatments, and to develop a strategy for directing new approaches and technologies towards bridging these gaps.
The first day was spent summarizing the current state of knowledge. Following a primer on AD biology by Brad Hyman, scientists gave presentations on topics including AD genetics and epidemiology and the role of the cell cycle, inflammation, and cell death in the nervous system. Two scientists introduced "maverick" ideas: that AD is an autoimmune rather than a degenerative disease, and that epigenetic changes to DNA underlie some sporadic cases of AD. This day also included presentations of novel technologies that have matured sufficiently to become useful to AD research, including RNA arrays, high-throughput transfection in cultured brain slices, MR imaging of gene expression, multiphoton imaging in live animals, mass spectrometry, as well as high-throughput screening for drug discovery and medium-throughput functional assays in mammalian neurons. Rounding off the first day were a talk on the management of mouse genetic information and two perspectives from representatives of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.
The second day saw discussions of biological research priorities and of bioinformatics requirements to enable high-level analysis of information gathered in the course of collective research. In the afternoon, Dennis Selkoe led a discussion in which he suggested that a new Alzheimer Research Institute be launched, in which a permanent staff of scientists would work with rotating groups of visiting scientists to pursue research projects identified in the workshop. This proposal sparked lively debate on Friday and Saturday, without consensus.
On the third morning, the group distilled their discussions into an action plan, which they presented to foundation representatives.
- Robert Balaban, Chief, Laboratory of Cardiac Energetics, National Heart, Lung and Blood Institute
- James Basilion, Assistant Professor, Center for Molecular Imaging Research, Massachusetts General Hospital
- Robert Baughman, Associate Director for Technology Development, National Institute for Neurologic Disorders and Stroke
- Judith A. Blake, Mouse Genome Informatics, Jackson Laboratory
- Harvey Cantor, Chair, Dept. of Cancer Immunology, Dana-Farber Cancer Institute
- Timothy Clark, Director of Bioinformatics, Millennium Pharmaceuticals, Inc.
- Paul D. Coleman, Professor, Department of Neurobiology and Anatomy, Director, Alzheimer's Disease Center, University of Rochester Medical Center
- Peter Davies, Department of Pathology & Neuroscience, Albert Einstein College of Medicine
- C. Forbes Dewey, Professor of Mechanical Engineering/Bioengineering, Massachusetts Institute of Technology
- Peter DiStefano, Senior Director of Neurobiology, Millennium Pharmaceuticals, Inc.
- Alison Goate, Department of Psychiatry, Washington University School of Medicine
- James Heywood, Executive Director, ALS-Therapy Development Foundation
- Bradley T. Hyman, Professor of Neurology, Mass. General Hospital
- Rudolph Jaenisch, Professor of Biology, Whitehead Institute
- June Kinoshita, Executive Editor, Alzheimer Research Forum
- Peter T. Lansbury, Associate Professor of Neurology, Brigham and Women's Hospital
- Donald C. Lo, Chief Scientific Officer, Cogent Neuroscience
- Richard Mayeux, Director, Behavioral Neurology, Sergievsky Center, Columbia-Presbyterian Medical Center
- Marcelle Morrison-Bogorad, Associate Director, National Institute on Aging
- Dennis J. Selkoe, Professor of Neurologic Diseases, Neurology-BWH, Harvard Institutes of Medicine
- Gabrielle Strobel, Managing Editor, Alzheimer Research Forum
- Rong Wang, Department of Human Genetics, Mt. Sinai School of Medicine
Summary of Recommendations
The working groups need a tight management structure, a clear work plan, and mechanisms for accountability and follow-up on initiated projects and collaboration. Their composition is key to success. They need administrative resources and decision-making power. The working groups must have regularly scheduled phone conferences. The Dana-Farber Harvard Cancer Center and Harvard Center for Neurodegeneration and Repair can model the structure of technology cores interacting with disease-based groups.
The working groups will:
1. Define specific AD research questions in their area and match them with technologies that can address these questions.
2. Draw up an inventory of available resources as well as those that need to be developed or purchased.
3. Identify institutions and people best suited to addressing the defined problems.
4. Initiate projects to generate pilot data that can attract subsequent industry investment.
5. Serve as a mediator between resources (e.g. well-characterized samples from epidemiological studies) and scientists who can analyze these resources with novel assays to assure that available samples are more widely used. In general, the working groups should set up mechanisms to improve communication between scientists that do not usually talk to one another.
The Biomarkers Working Group needs to develop strict standards for what constitutes a quality biomarker. This requires novel research information from the Pathways Working Group. In cancer, effort was wasted developing ultimately worthless biomarkers early on when there was not yet good understanding of underlying mechanisms. First, research opportunities in basic neurobiology and development must be identified. Exploit Patterson's in-vitro systems for neurons to avoid chasing poor biomarkers. Then focus on imaging as a next step. Imaging techniques are ready but awaiting good AD biomarkers.
Some additional short-term steps
- Explore modus operandi of Hereditary Disease Foundation in identifying knowledge gaps and funding postdoc salaries for them.
- On ARF website: in cooperation with the technology core, list available technologies, explain what they can do for AD research, who has them and is willing to use them for AD questions brought up by others. List equipment review, asking people who have expensive equipment to share info on what works and what does not.
- Create an on-line directory of Alzheimer specimen resources available from laboratories and centers around the world.
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