Keith A. Josephs, M.S.T., M.D., M.S., Associate Professor of Neurology at the Mayo Clinic College of Medicine

in recognition of his work on clinical, pathological and imaging correlates of neurodegenerative and other neurological diseases.

Dr. Keith A. Josephs’ work has focused on correlating clinical manifestations with imaging and pathological findings in patients with neurodegenerative and other neurological diseases.  He has made significant contributions to deciphering the complexity of the pathologies underlying neurodegenerative diseases.  He has identified markers that allow the prediction of brain pathology in these patients, in order to provide definitive diagnosis and hence appropriate treatment.

In addition to his significant contributions to the field of neurodegenerative diseases, Dr. Josephs has made important patient-oriented research contributions in other neurological diseases.  Dr. Josephs identified, for the first time, an important association between dementia and celiac disease.  Similarly, based on a single patient encounter, which lead him to study Manganese neurotoxicity, he identified an association between exposure to welding fumes and the subsequent development of Parkinsonian features.  This finding has had a significant impact on welders by encouraging adequate protection with masks and proper ventilation.

Vamsi Krishna Mootha assistant professor and physician at Massachusetts General Hospital’s Center for Human Genetic Research; assistant professor at Harvard Medical School’s Department of Systems Biology and of Medicine; and senior associate member at the Broad Institute of the Massachusetts Institute of Technology and Harvard University
   

in recognition of his work on genomic approaches to human mitochondrial disorders.
 

Dr. Mootha has been a pioneer in the application of genomics and large-scale biological approaches to understanding the role of mitochondria in human diseases. Trained in mathematics, biochemistry, and internal medicine, Dr. Mootha has utilized a highly multidisciplinary and imaginative approach to systematically characterize the protein composition, gene expression, and assembly of the mitochondrion. He has made several landmark discoveries in mitochondrial medicine.
 

First, he has used proteomics and computational methods to identify 1100 nuclear encoded proteins that comprise human mitochondria. This effort required the development of new proteomics approaches as well as novel computational methodologies. He has integrated this information with linkage intervals for discovering the genes underlying Mendelian mitochondrial disorders, including Leigh syndrome French Canadian variant, hepatocerebral mtDNA depletion syndrome, and three complex I deficiencies.
 

Second, Dr. Mootha has discovered that the common form of type 2 diabetes is associated with a decline in the expression of mitochondrial genes. This high impact discovery required the development of Gene Set Enrichment Analysis, a computational tool for determining whether a pathway exhibits concordant changes in a profiling experiment. This method has been used by thousands of researchers for different biomedical problems.
 

Third, he is using computation and chemical biology to devise strategies for restoring mitochondrial function. He has devised clever computational methods to combine genome-scale expression measures with comparative genome sequence analysis to reconstruct the transcriptional circuits controlling mitochondrial biogenesis. These transcriptional circuits represent excellent drug targets, and Dr. Mootha is currently using a chemical genomics approach to target these factors to target them. Moreover, he is identifying plasma biomarkers of mitochondrial dysfunction, which can eventually be used to monitor the therapeutic response to newly identified drugs.