Ann Romney Tackling Neurological Disease – Interview with Ann Romney Center Directorsby Shaheen E Lakhan, MD, PhD, MEd, MS, FAAN | December 1, 2014
The Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital launched just one month ago. It is poised to be a global research operation to tackle five neurological diseases: multiple sclerosis (MS), Alzheimer’s disease (AD), Lou Gehrig’s disease (ALS), Parkinson’s disease (PD), and brain tumors. Here, I interview the two co-directors.
The Center is co-directed by two pioneering neurologists. Dr. Dennis J. Selkoe and Dr. Howard Weiner. Dr. Selkoe, Professor at Harvard Medical School, isolated the tangles of AD and co-discovered their antigenic relationship to tau. His research on amyloid beta-protein and APP led to the “amyloid hypothesis” of AD, which has helped provide the underpinning of numerous clinical trials, including the world’s first prevention trial in older individuals at risk for developing AD.
Dr. Howard Weiner, Robert L. Kroc Professor of Neurology at Harvard Medical School, pioneered the use of immunotherapy and the drug cyclophosphamide for the treatment of MS and has investigated immune abnormalities in the disease, including the role of the innate immune system and regulatory T cells. Based on his work, vaccines are being tested in MS, diabetes, and most recently in AD.
Lakhan: Can you elaborate on your work that led to the amyloid hypothesis of Alzheimer’s disease?
Selkoe: Beginning around 1983, the focus of my research was on biochemical experiments on the amyloid plaques, which are one of the two pathological hallmarks of AD (I had been working on the other one – the neurofibrillary tangles – prior to that). My lab conducted extensive experiments on amyloid plaques and then the Amyloid Precursor Protein (APP) during this time. This work increasingly convinced me that amyloid protein build-up was perhaps the key early event in AD. After 8 years of extensive research, I wrote an article for the journal Neuron that proposed a stepwise mechanism for AD that began with amyloid build-up. This article, along with a similar paper from another scientist (John Hardy in London), represented the formal written formulation of the “amyloid hypothesis” of AD. But a great deal of work lay ahead to try to prove it.
Lakhan: What have been the most impressive applications of your research on amyloid and on tauin Alzheimer’s disease?
Selkoe: For amyloid, our discovery in 1992 (Nature) of the normal production of the amyloid beta-protein (A-beta) by all cells throughout life provided the first method to screen for and identify amyloid-lowering drugs. This cell culture method has been widely used in academia and biotechnology and has allowed many pharmaceutical companies to identify compounds that lower amyloid beta-protein and appear to have therapeutic potential in slowing down AD.
For tau, in 1986, our lab co-discovered that tau is the protein that makes up the neurofibrillary tangles. This discovery enabled many subsequent studies of how the biochemistry of tau is altered in AD and certain other dementias.
Lakhan: Where do you see the future of dementia therapy?
Selkoe: Dementia research is a very broad area, with AD being the most common of the dementias (about 60% of cases). I think that the molecular dissection of AD (as discussed above) is steadily leading to novel drugs and antibodies, some of which have already been shown to slow memory decline in mild AD patients. But treating people even earlier than at the mild state, namely before significant memory symptoms (called “secondary prevention”), seems to be the most promising approach.
Lakhan: Can you elaborate on your 21 point unifying hypothesis for multiple sclerosis?
Weiner: The 21 point unifying hypothesis is aimed at taking various pieces of information about MS and unifying them into one coherent explanation of the disease. For example, it integrates viruses, immune system and the environment. This allows for a more simplified understanding of the complex nature of the disease.
Lakhan: What have been the greatest advancements in multiple sclerosis research in the past decade?
Weiner: The greatest advancements relate to the following: 1) new therapies that have become available; 2) a better understanding of how the environment influences MS; and 3) advanced MRI imaging that has allowed us to understand the disease better.
Lakhan: Where do you see the future of MS therapy?
Weiner: The future will relate to individualized treatment based on profiles of the MS patient. I also envision development of prevention strategies and the ultimate development of an MS vaccine. The other area of major importance is the gut and stimulating the natural gut immune system to help protect against MS.
Lakhan: What will the Ann Romney Center offer to both patients and the biomedical community?
Selkoe: In a word: collaboration. We will use a broad range of collaborative approaches to help patients, beginning with highly accurate diagnosis and advanced brain imaging, then counseling and detailed advice about the most promising clinical trials, depending on the individual’s stage and symptoms. For the biomedical community, we offer an unprecedented emphasis on research collaboration both within our multi-disciplinary AD team and with many outside scientists in this country and abroad. A great example of the latter is the new “A4 trial” (Anti-Amyloid in Asymptomatic Alzheimer’s), whose development was led by our Brigham and Women’s Hospital colleague, Dr. Reisa Sperling. It is now being offered at 62 AD clinical centers around the US as the first secondary prevention trial for older people heading toward AD.
Weiner: What makes this center different is our integrated approach. By convening a global consortium of researchers and scientists working together across each of the five disease states, we will create a novel and collaborative approach for biomedical research, which will lead to new breakthroughs, therapies and clinical trials for patients. This approach has the potential to change outcomes for future generations and advance our understanding of neurological disease.
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