Recipients of the Judson Daland Prize

2011 AWARD - Shah

Dr. Svati Shah, M.D., M.H.S., Assistant Professor and Medical Director of the Adult Cardiovascular Genetics Clinic at Duke University and Faculty Member at the Duke Center for Human Genetics, Duke Clinical Research Institute, and Sarah W. Stedman Nutrition and Metabolism Center.

in recognition of her work on novel metabolomic biomarkers for cardiovascular events.

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.

 


2009 AWARD - Josephs

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.

 


2009 AWARD - Orange

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.

 

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.

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.

 

 


2008 AWARD

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.

 


2007 AWARD

Victor Velculescu of the Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University Kimmel Cancer Center for his work:

 

in the identification of diagnostic and therapeutic targets through genomic analyses of human cancer.

 

Dr. Velculescu’s work is focused on genomic analyses of human cancer. He has pinpointed PIK3CA as one of the most frequently mutated oncogenes in human cancer and has obtained the first draft sequence of the breast and colorectal cancer genomes. These discoveries have identified a wealth of genes important in tumorigenesis and provide new opportunities for individualized diagnostic and therapeutic approaches in human cancer.

 

Dr. Velculescu received his M.D. in medicine and his Ph.D. in human genetics and molecular biology from Johns Hopkins. Over the past decade he has developed several approaches to investigate genes important to neoplasia, and applied these approaches to systematic mutational analyses of cancer genomes. His genome-wide mutational analysis of breast and colorectal cancers suggested that the number of mutational events occurring during the evolution of human tumors is much larger and affects a wider variety of genes than previously imagined. Dr. Velculescu's studies have paved the way for similar genome-wide mutational analyses in other tumor types and provide a basis for personalized approaches to understanding and treating cancer.

 


2006 AWARD

George Q. Daley of Harvard Medical School, Children's Hospital of Boston and the Dana Farber Cancer Institute for his work:

 

in the area of chronic myeloid leukemia and in the application of stem cell biology to the treatment of leukemia and genetic diseases.

 

While still an MD/PhD student at Harvard Medical School (in the HST division) in the laboratory of David Baltimore, George Daley created a faithful model of human chronic myeloid leukemia by putting the fusion gene of the "Philadelphia chromosome" characteristic of that disorder into the mouse. This proved beyond question the causative role of the fusion gene and indirectly guided development of the remarkably effective inhibitor of the fusion gene product, Gleevec. After completion of full residency training capped off by chief residency at the Massachusetts General Hospital, Daley returned to the laboratory. His studies included investigations into the mechanism of resistance to Gleevec that occurred in some CML patients because of mutation in the active part of the fusion gene. This work prompted him to design small molecules that would overcome resistance and to undertake clinical trials. Following on his seminal work on the pathogenesis and treatment of CML, a paradigm of stem cell disorders, Daley has devoted his efforts in the last five years to the fashioning of blood-cell stem cells that can be corrected genetically and used for bone marrow transplantation in genetic, neoplastic and degenerative disorders. His goal is to reprogram stem cells from patients with genetic diseases and put these cells back into the patient--a combination of gene and cell therapy. This goal was aided by his discovery of two genes that promote specialization into blood cells and their engraftment in the bone marrow. Daley is an active participant in discussions of the ethical and policy issues surrounding stem cell research. Long a leader in the CML field, he has emerged as a leader also in the field of stem cell research, being recently elected president of the International Society for Stem Cell Research.

 


2005 AWARD

Brendan Lee of Baylor College of Medicine for his work:

Skeletal Genetics and Inborn Errors of Metabolism.

 

and to

 

James A. Levine of the Mayo Clinic for his work:

Energy Expenditure and Obesity.

 

Dr. Lee has been a pioneer in the discovery of basic DNA defects in skeletal disorders. He discovered the first such defect in a form of chondrodystrophy: a defect in type II collagen in spondyloepiphyseal dysplasia. Other work has involved a form of Ehlers-Danlos syndrome and Marfan syndrome. His work in genetic metabolic disorders (the so-called urea cycle disorders) has been useful in their diagnosis and treatment.

 

Dr. Lee was the first to identify mutations causing achondrodysplasia and one of the first to associate the fibrillin gene with Marfan syndrome. He also was first to demonstrate mutations causing cleidocranial dysplasia and nail-patella syndrome. He developed stabilized isotope methods from measuring ureagenesis for diagnosis and management urea cycle disorders.

 

Dr. Levine has elucidated the physiologic basis for the individual variation in susceptibility to weight gain in response to overeating. From observations in non-obese volunteers overfed in excess of weight-maintenance requirements, he found a 10-fold difference in fat storage. Two-thirds of the rise in total daily energy expenditure was due to increased non-exercise activity thermogenesis (NEAT), which is associated with fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold differences in fat storage and directly predicted resistance to fat gain with overfeeding. The results were interpreted as indicating that as humans overeat, activation of NEAT dissipates excess energy to preserve leanness and a failure to active NEAT may result in fat gain.

 

Studies quantitating differences in "posture allocation" (fidgeting and so on) indicated that obese individuals were seated, on average, two hours longer per day then lean individuals. Dr. Levine estimated that the NEAT-enhanced behaviors of the lean subjects resulted in their expending an additional 350 calories per day. Posture allocation did not change when the obese individuals lost weight or when the lean individuals gained weight, suggesting that it is biologically determined.

 


2004 AWARD

Ali Gharavi of Columbia University for his work:

 

Genetic Studies of IgA Nephropathy.

 

Dr. Ali Gharavi has demonstrated that a major gene on chromosome 6 affects the risk of IgA nephropathy, changing prevailing concepts about the pathogenesis of this disorder, and showing that disease occurrence and familial aggregation have a significant genetic basis.

 

The biological basis for the development of kidney failure is poorly understood, limiting the development of effective therapeutic or preventive measures. Dr. Gharavi's studies focus on IgA nephropathy, one of the most common causes of kidney failure worldwide. Familial, ethnic and geographic aggregation of IgA nephropathy has usually been considered to have environmental causes. Dr. Gharavi hypothesized that this clustering could be explained by shared genetic factors. He identified and enrolled thirty families in the United States and Italy that had two or more individuals affected, screened other family members and identified individuals with early or mild manifestations, not usually leading to referral for medical evaluation.

 

After performing a genome-wide search, he found that in the majority of families the disease is attributable to a single locus on chomosome 6q22-23. He repeated the findings in a new cohort of patients with IgA nephropathy. urther genealogic work and genetic analysis have led to the discovery of shared chromosomal segments among distantly related patients with no affected immediate family members. His findings provide strong evidence for a gene with large affect of IgA nephropathy.

 

By validating that IgA nephropathy can have a genetic cause, he has made clinicians aware that family history should be routinely investigated, and family members with urinary abnormalities should be referred for nephrologic evaluation for early therapy, before the development of renal failure. Family members with a history of urinary abnormalities are now advised against donating kidneys to affected patients. Dr. Gharavi's work on the genetic basis of IgA nephropathy changes our understanding of the pathogenesis of glomerulonephritis and renal failure.

 


2003 AWARD

Flaura K. Winston of the Children's Hospital of Philadelphia for her work:

 

Biomechanical and Psychological Foundation of Pediatric Trauma Prevention and Treatment.

 

Dr. Flaura Winston has pioneered biomechanical epidemiology, a discipline that combines engineering, medicine, and public health in order to understand, and treat pediatric car crash injuries, the leading cause of death and acquired disability for children in the United States.

 

She identified the first case of air bag-associated child death. In 1998 she created, and heads, the Partners for Child Passenger Safety, which has collected information on 173,000 crashes involving more than 260,000 children. It is the leading resource for data on child passenger injuries, providing information to both vehicle manufacturers and legislative bodies. Her research and advocacy have led to drafting new federal air bag policies. Thirteen states now require booster seats for children after they graduate from child safety seats.

 

Having observed that children in the rear seats of small pick-up trucks are at greater risk of injury and death than those in the front seat, a reversal unique to this type of vehicle, she spurred collaborations between the National Highway Traffic Safety Administration and vehicle manufacturers to develop new test procedures and improved safety designs.

 

She has developed and tested a screening tool to aid emergency physicians in recognizing children and parents at risk of posttraumatic stress disorder, and is currently developing interventions to prevent the development of the disorder.

 


2002 AWARD

James E. Crowe, Jr., of the Vanderbilt University Medical Center for his work:

 

Neonatal Immune Responses to Virus Infection or Immunization.

 

Dr. James Crowe has made outstanding contributions in the areas of immunity to, and prevention of, infectious diseases of children, including the understanding of immunological immaturity in infants and the development of vaccines. His work is an excellent example of taking original basic research from the bench to the patient.

 

His first major contribution was the demonstration that recombined monovalent fragments of antibody molecules (Fab fragments) produced in bacteria could neutralize viruses. This opened the way for further studies of the usefulness of antibodies prepared in the laboratory for use in the therapy and prevention of infectious diseases.

 

His studies elucidated the roles of cellular, humoral, and mucusal immunity in resistance to infection by respiratory syncytial virus (RSV), and showed that maternal antibodies in newborns suppress the development of antibodies in the infant to RSV infection.

 

His most important contribution from the standpoint of clinical medicine was the development of a large number of RSV strains as live attenuated vaccine candidates. These vaccines are now in large scale clinical trials on several continents. In the developing of these vaccines, he first examined the genetic basis for the attenuation of the virus.

 

His work has thus spanned the spectrum from basic virology and immunology to the development of a vaccine that should play a major role in the control of one of the most severe respiratory diseases of infants and young children.

 


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