| TH E N I H C A T A L Y S T | S E P T E M B E R – O C T O B E R 2008 |
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Leslie Baier is a molecular biologist studying diabetes and obesity among the Pima, a group of Native Americans in southern Arizona who suffer from diabetes rates in excess of 50 percent. Baier is head of the Diabetes Molecular Genetics Section in the Phoenix Epidemiology and Clinical Research Branch (NIDDK). By studying the Pima, Baier hopes to uncover the genetic underpinnings of obesity and diabetes in all peoples.
Obesity and diabetes appear to be polygenetic diseases exacerbated by poor diet and inactivity. Yet identifying which genes underlie these diseases has proven to be challenging, Baier said. Variants of gene TCF7L2, for example, are highly associated with diabetes in Caucasians and many other ethnic groups, but Baier's group has found these variants are rare and do not have a role in increasing diabetes susceptibility in the Pima population. Conversely, Baier's group has found that variants of gene HCRTR2, an orexin receptor that influences eating behavior, are common among Pima but absent among Caucasians.
Baier's current work mostly involves genome-wide association studies. Using a 100,000-SNP chip, her group revealed the HCRTR2 variants as well as variants of A2BP1, involved in body weight. Baier's group is pursuing follow-up studies from genotyping of a million-SNP chip using the same set of approximately 900 subjects. She is also involved in the genotyping of prediabetic patients at the NIH Clinical Research Center, where she and NIDDK colleagues are searching for disease predictors in about 600 patients. By analyzing SNPs of prediabetic patients with known phenotypes such as insulin resistance and decreased insulin secretion, Baier seeks to minimize the number of false-positives in gene-association studies for diabetes and obesity.
The Pima, as with many indigenous groups, have born witness to radical negative lifestyle changes in the past 100 years brought about by an encroaching outside culture. The name "Pima" comes from the word pimo, meaning "I don't understand," something this group said often to Spaniards in their early encounters. Nearly 500 years later, NIDDK is hoping to bring some understanding about diseases affecting the Pima and society at large.
Robert Nelson has worked with the Pima Indians of Arizona for over 20 years, studying type 2 diabetes with a particular focus on kidney disease. He is a member of the Diabetes Epidemiology and Clinical Research Section in NIDDK's Phoenix Epidemiology and Clinical Research Branch.
Nelson has helped identify the course and determinants of kidney disease in persons with type 2 diabetes. In the past, type 2 diabetes was primarily a disease of the elderly, but in recent years, it has increasingly been diagnosed in younger patients, who often develop the end-stage complications of diabetes, including kidney disease, in midlife. Nelson is involved in numerous projects to characterize kidney disease in type 2 diabetes. His early work focused on defining the frequency of kidney disease and its risk factors in the Pima Indians. In the early 1990s he and his colleagues began measuring glomerular function and reported on the hemodynamic changes within the kidney that occurred with the onset of diabetes and with the progression of diabetic kidney disease.
By the late 1990s Nelson was performing kidney biopsies and was conducting morphometric studies of kidney structure that helped identify the loss of podocytes, or visceral epithelial cells, as an early predictor of progressive glomerular injury.
His group is also conducting clinical trials to identify medicines that slow the progression of diabetic kidney disease and outcomes studies that show that improvements in diabetes care are related to slowing in the progression of diabetic kidney disease. This year, Nelson received a Bench-to-Beside award to identify molecular markers of kidney disease development and progression and an ADA Clinical Research Award to complete the morphometry on over 120 kidney biopsies from one of his clinical trials.
[Editor's note: Leslie Baier and Robert Nelson have had long, distinguished careers at NIDDK, and they have become tenure-track investigators as part of a renewed effort by the Intramural Research Program to create a more definable career track for clinical scientists.]
Iain Fraser, a biochemist and molecular biologist interested in mechanisms of cell signaling, arrived at NIH in August to set up a cell and molecular biology group in NIAID's new Program in Systems Immunology and Infectious Disease Modeling (PSIIM). At the heart of Fraser's efforts here will be the design, implementation and interpretation of screening efforts to identify and characterize the interactions among the components in immune-cell signaling networks, that could then be modeled using the software generated by the PSIIM computational biology team. A native of Scotland, Fraser spent the last eight years at Caltech, where in 2005 he became co-director of the Alliance for Cellular Signaling (AfCS) Molecular Biology Laboratory.
At Caltech, Fraser worked on a range of AfCS projects generating comprehensive data sets to model signaling networks in mouse macrophages. He led projects to develop sophisticated nucleic-acid-based reagents for RNA interference, subcellular localization studies, protein-protein interactions and fluorescent biosensors, and applied these technologies to assess how the activity state of the macrophage is altered through G-protein coupled receptor activation with a variety of ligands. He has been interested recently in mechanisms whereby the specificity of signaling crosstalk is controlled through local organization of signaling enzymes by scaffold proteins, drawing on earlier postdoc experience at the Vollum Institute in Portland, Ore.
"The integrated nature of the PSIIM is what appealed to me in accepting this position," Fraser said. His experience with the AfCS emphasized the importance of combining groups with wet lab expertise alongside data analysis and computational teams dedicated to generating quantitative models of cellular responses. This, he said, permits an iterative process of data generation, model development, experimentation directed by model predictions and model refinement, which has great potential to provide new insight to biological processes. He hopes that the PSIIM program will develop a set of quantitative tools and computational approaches that will be invaluable, not only to answering questions in the field of immunology and infectious disease, but to researchers in all biomedical disciplines. "We would like to show the NIH community what is possible by taking this approach," he said.