2008 Autumn General Meeting

Judson Daland Prize for Outstanding Achievement in Clinical Investigation

Vamsi Krishna Mootha

The American Philosophical Society awarded the 2008 Judson Daland Prize for Achievement in Patient-oriented Clinical Investigation to Dr. Vamsi K. Mootha in recognition of his achievements in genomic approaches to human mitochondrial disorders. The award was presented by Clyde F. Barker, Vice President of the Society and new chairman of the prize selection committee.

Vamsi Mootha is an 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. He received his M.D. in 1998 from the Harvard-M.I.T. Division of Health Sciences and Technology and joined the Harvard faculty in 2002.

A gifted physician and researcher, Vamsi Mootha has, through integrated application of mass spectroscopy, genomics, computation and clinical medicine, greatly elucidated the network properties of mitochondria and how these properties go awry in human disease. His efforts have led to the rapid identification of nuclear genes underlying human mitochondrial disease, as well as to the discovery that mitochondrial dysfunction is associated with the common form of type 2 diabetes mellitus. This groundbreaking work has profound implications for virtually all common diseases, including cancer.

The Daland Prize selection committee consisted of chairman Victor A. McKusick, University Professor of Medical Genetics, Johns Hopkins University; Clyde F. Barker, Donald Guthrie Professor, University of Pennsylvania; John N. Loeb, Professor Emeritus of Medicine, Columbia University; Arno Motulsky, Professor Emeritus of Medicine and Genome Sciences, University of Washington; and Thomas E. Starzl, Professor of Surgery, University of Pittsburgh School of Medicine.

2009 Autumn General Meeting

Judson Daland Prize for Outstanding Achievement in Clinical Investigation

Keith A. Josephs and Jordan Orange

The recipients of the 2009 Judson Daland Prize are Dr. 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 and Dr. Jordan Orange, M.D., Ph.D., Director of the Jeffery Modell Diagnostic Center for Primary Immunodeficiency, Attending Physician, Division of Allergy and Immunology at the Children’s Hospital of Philadelphia, and Assistant Professor of Pediatrics at the University of Pennsylvania School of Medicine, in recognition of his work on congenital defects of innate immunity and natural killer cells.  The award was presented by the Chair of the Selection Committee, Clyde F. Barker, Donald Guthrie Professor at the University of Pennsylvania.

Dr. 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.

He has identified a new disease called neurofilament inclusion body disease (NIBD), a neurodegenerative disorder associated with abnormal deposition of intermediate filaments in the brain.  He has also identified a variant of progressive supranuclear palsy, a disease in which abnormal protein deposition within oligodendroglial cells causes destruction of the descending corticospinal tracts.  His research has shown significant overlapping of clinical and pathological features between progressive supranuclear palsy, corticobasal degeneration and the frontotemporal lobar degenerations.  This has led to better understanding, and reclassification, of much of the entire field of neurodegenerative disorders.

In studies of speech and language disorders Dr. Josephs has demonstrated an association between a motor speech disorder and the presence in the brain of the microtubule associated protein.    In addition, he has shown that patients presenting with clinical features of motor neuron disease have a homogeneous underlying pathology.  Clinicians worldwide are now using these clinical markers to help predict the underlying pathology, and hence guide treatment of patients with progressive neurodegenerative disorders.  He has also utilized cutting edge imaging techniques to demonstrate signatures of a number of different neurodegenerative pathologies thus aiding diagnosis.  With these imaging techniques, for example, he showed that the deposition of amyloid in the brain in patients with Alzheimer’s disease is not associated with increased rates of brain atrophy.  This finding has significant impact on the utility of markers of disease progression in future treatments targeting beta-amyloid, one of the abnormal proteins in Alzheimer’s disease.

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.

Dr. Jordan Orange is a pioneer in understanding inborn human defects of the innate immune system.  In studies of human Natural Killer (NK) cell deficiencies he has found novel connections between inborn defects of the immune system and innate immunity.  These have defined paradigms in host defense and given rise to novel therapeutic approaches.

The innate immune system is our initial defense against danger.  It protects us from encounters with pathogens that begin at birth and serves as a first line of defense throughout life.  Without our innate immune system we would be susceptible to many life-threatening infections and malignancies.  So far relevance of the innate immune system to human disease has been demonstrated mainly by congenital deficiencies of innate immunity.  It is in these unusual diseases that Dr. Orange has focused his work.

While working toward his Ph.D., Dr. Orange noted that natural killer (NK) cells, which are a major component of the innate immune system, produce cytokines to participate in antiviral defense.  During his clinical training in Pediatrics at the Children’s Hospital of Philadelphia and fellowship in Allergy and Immunology at Children’s Hospital Boston, Dr. Orange’s interest in the innate immune system and NK cells continued to flourish.  Upon returning to the laboratory, he focused upon defining human deficiencies of NK cells and the innate immune system and in obtaining basic scientific insights from these diseases.

Over the past decade, Dr. Orange has studied human NK cell deficiencies in distinct genetic disorders of immunity.  In these diseases, he has been able to characterize NK cell biology on a mechanistic level.  For example in Wiskott-Aldrich syndrome, he has determined that cytoskeletal reorganization is impaired in NK cells leading to defective formation of the immunological synapse, the critical juncture between an immune cell and its target that enables immune function.  In Wiskott-Aldrich syndrome, this deficiency likely explains the atypical susceptibility to herpes viruses and hematologic malignancies.  He also identified a therapeutic means for bypassing the defect and restoring function of the immunological synapse in the cells of an afflicted patient.  He has recently used this finding to develop and initiate a phase-1 clinical trial with the ultimate objective of restoring NK cell activity and improving outcome in this difficult disease.  He has also identified defects of NK cells and innate immunity in NF-κB essential modulator deficiency.  In this rare disease, he has defined a novel connection between rapidly-induced protein function and innate immune defense, an insight that may not have been possible without studying this disorder.  Dr. Orange’s work has led him from bedside to bench and bench to bedside and has changed the understanding of NK cells, innate immunity and the complex immunologic diseases in which they are affected.

The Daland Prize selection committee consisted of Clyde F. Barker (chair), Donald Guthrie Professor, University of Pennsylvania; John N. Loeb, Professor Emeritus of Medicine, Columbia University; Arno Motulsky, Professor Emeritus of Medicine and Genome Sciences, University of Washington; and Thomas E. Starzl, Professor of Surgery, University of Pittsburgh School of Medicine.

2011 Autumn General Meeting

Judson Daland Prize for Outstanding Achievement in Clinical Investigation

Svati Shah

The 2011 recipient of the American Philosophical Society’s Judson Daland Prize for Outstanding Achievement in Patient-oriented Clinical Investigation is Svati Shah, M.D., M.H.S., in recognition of her work on novel metabolomic biomarkers for cardiovascular events.  Dr. Shah is an assistant professor and Medical Director of the Adult Cardiovascular Genetics Clinic at Duke University.  She is also a member of the faculty at the Duke Center for Human Genetics, Duke Clinical Research Institute, and Sarah W. Stedman Nutrition and Metabolism Center. The award was presented by the Chair of the Selection Committee and President of the American Philosophical Society, Clyde F. Barker, Donald Guthrie Professor at the University of Pennsylvania.

Svati Shah’s clinical research focuses on the molecular epidemiology of cardiovascular disease (CVD).  She has used novel translational technologies to make important discoveries of biomarkers for improved CVD risk prediction.  She is also focusing her efforts on the implications and application of these discoveries to patient care.

Profiling of small-molecule metabolites holds promise for giving a more complete picture of human systems biology. “Unbiased” metabolomic profiling has been used to predict coronary artery disease (CAD), but the non-quantitative nature reduces clinical utility.  Further, the genetic basis of these profiles is not established.  Shah hypothesized that targeted, quantitative metabolomic profiles are heritable; identify patients with CAD and predict subsequent cardiovascular events.

Her research observed that simple metabolomic profiles, in particular branched-chain amino acids and their byproducts, are highly heritable and strongly differentiate patients with CAD and MI, providing improved risk discrimination beyond standard clinical factors.  Metabolite signatures composed of dicarboxylacylcarnitines are independently predictive of subsequent cardiovascular events. These results implicate branched-chain amino acid catabolism and other mitochondrial processes in cardiovascular disease pathogenesis, and could have significant clinical implications for cardiovascular risk prediction, diagnosis, and identification of genetic factors underlying the heritability of cardiovascular disease.

The Daland Prize selection committee consisted of Clyde F. Barker (chair), Donald Guthrie Professor of Surgery, University of Pennsylvania; John N. Loeb, Professor Emeritus of Medicine, Columbia University; Arno Motulsky, Professor Emeritus of Medicine and Genome Sciences, University of Washington; and Thomas E. Starzl, Professor of Surgery, University of Pittsburgh School of Medicine.

2014 Autumn General Meeting

Judson Daland Prize for Outstanding Achievement in Clinical Investigation

Howard Y. Chang

The 2014 recipient of the American Philosophical Society's Judson Daland Prize for Outstanding Achievement in Patient-oriented Clinical Investigation is Howard Y. Chang in recognition of his discovery of the existence and function of a new class of pervasive genes in the human genome, termed long noncoding RNAs (1ncRNAs). Dr Chang's research is focused on mechanisms that coordinate the activities of genes that control cell fate. He has pioneered methods to identify key regulators of large-scale transcriptional programs important in development of cancer, aging and response to infections. His discoveries have introduced the important and pervasive roles of long noncoding RNAs in chromatin regulation. He also invented the first method to map RNA occupancy of chromatin genome-wide, revealing that each lRNA can interact extensively with hundreds or thousands of sites across the genome.

Dr. Chang received a Ph.D. at Massachusetts Institute of Technology in 1998 and an M.D. at Harvard Medical School in 2000. He completed his residency and postdoc in dermatology and genetics at Stanford University School of Medicine in 2004, and became an assistant professor in its Department of Dermatology. He is currently a professor of dermatology at Stanford and Early Career Scientist at Howard Hughes Medical Institute.

The Daland Prize selection committee consisted of Clyde F. Barker (chair), Donald Guthrie Professor of Surgery, University of Pennsylvania; John N. Loeb, Professor Emeritus of Medicine, Columbia University; Arno Motulsky, Professor Emeritus of Medicine and Genome Sciences, University of Washington; and Thomas E. Starzl, Professor of Surgery, University of Pittsburgh School of Medicine.

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