Harry Heimberg, PhD.
Diabetes Research Center, Vrije Universiteit Brussel, Belgium
Curriculum vitae and current research project
From 1985-1988 Dr. Heimberg carried out undergraduate studies in Biology, outside the diabetes area. First, as an undergraduate researcher at the Department of Genetic Virology (Vrije Universiteit Brussel) under the promotorship of Dr. Mark Van Montagu. He investigated the role of signalling sequences of thaumatine, a sweet tasting protein, by Agrobacterium tumefaciens-mediated gene transfer and TR-promotor-controlled expression of mutant clones in plants.
Then he worked as a research fellow at the Department of Genetics and Microbiology, (Vrije Universiteit Brussel) with Dr. Nicolas Glansdorff as advisor. During that period he isolated and characterized the acetylornithine aminotransferase gene and its product in S. cerevisiae.
In 1989 Dr. Heimberg entered the field of diabetes research. From 1989 to 1994, he was a graduate student at the Department of Biochemistry, which is part of the Diabetes Research Center (Director: Danny Pipeleers) (Vrije Universiteit Brussel).
During the first year of graduate training (promotor: Dr. Frans Schuit), he genotyped HLA-DQ of type 1 diabetic patients using allele-specific amplification of DNA and oligoprobing techniques. Based on this work an extensive registration of patients and their first degree relatives became possible. Today, almost 10.000 individuals, a decent target population for clinical trials, have been registered.
Dr. Heimberg's graduate work was on the early glucose metabolism and functional heterogeneity in pancreatic islet a- and ß-cells. The glucose sensing system was studied at a molecular level in purified rat islet cells. A detailed description of glucose transporter expression and activity in a- and ß-cells revealed that Glut2 only is expressed in ß-cells, and Glut1 in a-cells and that differences in glucose transporter gene expression between rat pancreatic a- and ß-cells are correlated to differences in glucose transport but not in glucose utilization. Analysis of glucose transport and glucose phosphorylating activity in ß-cell subpopulations with different glucose responsiveness added to the concept that glucokinase rather than Glut2 is part of the glucose sensing system in rat ß-cells. Additional evidence was provided when glucokinase was found active in a-cells and, likely, (co)responsible for glucose sensing by this cell type. We then described serious species differences in Glut2 expression: in human islets, Glut2 expression is very low, leaving the possibility open that Glut2 acts as a signalling element in humans, in contrast to rodents where Glut2 expression levels were sky-high under normal phsiological conditions. The resulting Ph.D. thesis was awarded with the tri-annual "Vanderschueren Outstanding Thesis" award of our university.
Support from the Commission for Educational Exchange between Belgium and the USA (Fulbright-Hays Award for research); from the Belgian National Fund for Scientific Research and from the NATO (research awards) allowed him to work as a research associate in the lab of Dr. Mike Mueckler at the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, USA (1994-1997). Together with his colleagues he studied the hexosamine biosynthetic pathway and insulin signalling by treatment of 3T3-L1 adipocytes with glucosamine. This was a popular strategy at the time, until it was discovered that glucosamine-induced insulin resistance in 3T3-L1 adipocytes is caused by depletion of intracellular ATP. During the second year this study was sponsored by a Postdoctoral Fellowship of the Juvenile Diabetes Research Foundation International.
Since 1998, Dr. Heimberg has remained at the Vrije Universiteit Brussel in Brussels, as a senior investigator in the Department of Metabolism and Endocrinology of the Diabetes Research Center (Director: Dr. Danny Pipeleers) and, recently, also as professor in Microbiology. During the last three years he focussed his research on the study of mechanisms that may induce neogenesis of human ß-cells from their ductal precursor cells.
Islet transplantation is a promising alternative treatment for diabetes that avoids the secondary complications caused by insulin but is limited by the insufficient availability of donor organs. The ability to manipulate the ß-cell mass, by transplanting ß-cells procured in vitro or by inducing endogenous regeneration of ß-cells, therefore provides important prospects for diabetes therapy. To approach this goal we are investigating developmental transcription factors that may signal for differentiation of precursors to endocrine islet cells. The pancreatic precursor cell pool is represented by cells lining the pancreatic ducts and the availability of highly purified human post-natal pancreatic duct cells from Beta Cell Transplant (Diabetes Research Center, Brussels) facilitates profiling of transcription factor expression and may allow the characterization of human post-natal endocrine precursor cells. Recent investigations of pancreatic embryogenesis in mice underscored the importance of lateral inhibition for the specific fate selection of epithelial cells in the embryonic pancreas. In collaboration with Drs. Ole Madsen and Palle Serup from the Hagedorn Research Institute (Gentofte, Denmark), a strategy has been developed to induce endocrine differentiation from isolated post-natal pancreatic duct cells by transgenic expression of the transcription factors Ngn-3, NeuroD/ß2, Pdx-1, Nkx-6.1, Nkx-2.2, Pax-6 and Pax-4 by recombinant adenovirus (recAd)-mediated gene transfer. Manipulation of the activity of these transcription factors may make it possible to drive the differentiation of post-natal human ß-cell precursors and thereby provide (i) an increased access to mature human ß-cell (or islets) for patient treatment through ß-cell replacement by transplantation, and (ii) the knowledge to stimulate the process of neoformation of ß-cells from existing precursor cells in vivo in post-natal pancreatic epithelium. In 2000, Dr. Heimberg received a Career Development Award from the Juvenile Diabetes Research Foundation International to explore the feasibility of this project.