Markus Grompe, M.D.
Biography
Dr. Grompe received his medical degree (Dr. med.) in 1982 at the University
of Ulm Medical School in Germany. From 1984-1987 Dr. Grompe was trained in Pediatrics
at Oregon Health Sciences University in Portland, Oregon, USA and then moved
to Baylor College of Medicine in Houston, Texas. There he was a fellow sponsored
by the Pediatric Scientist Training Program in the Institute for Molecular Genetics
from 1987-1991 and worked on gene therapy for inherited diseases, particularly
metabolic liver disorders.
In 1991, Dr. Grompe joined the faculty at Oregon Health & Science University
and he is currently Professor in the Departments of Molecular and Medical Genetics
and Pediatrics. He is a recipient of the E. Mead Johnson award for pediatric
research (2002) and the Merit Award of the Fanconi Anemia Research Foundation
(2002). He is involved in the clinical care of patients with genetic diseases
as well as scientific investigation. In 2004 he became the first director of
the newly founded Oregon Stem Cell Center.
Research Overview
Single gene disorders, although individually rare, cumulatively represent a significant medical burden, particularly in the pediatric age group. Current treatment options are very limited and outcomes remain poor in many cases. Gene transfer and cell therapy (including stem cell transplantation) are hopeful strategies for future therapies. Its is our long-term goal to develop these into clinically useful procedures. Our particular focus are metabolic liver diseases and the DNA repair disease Fanconi Anemia.
METABOLIC LIVER DISEASE AND THERAPY
The level of cell replacement required to achieve physiological benefit in the
treatment of genetic liver disorders depends on which disease is being treated.
The threshold can be as low as only 1% in the hemophilias or as high as 50%
in urea cycle disorders. Even the low threshold is difficult to achieve with
cell therapy or integrating gene transfer vectors required for life-long therapy.
Fortunately, the liver is a highly regenerative organ and in mutant backgrounds
where genetically normal hepatocytes have a selective advantage, extensive repopulation
can be achieved. We first showed in fumarylacetoacetate hydrolase (Fah) deficient
mice that cell replacement levels can reach levels of >98% illustrating the
concept of "therapeutic liver repopulation" (Overturf et al. 1996).
We are using liver repopulation as an assay for the discovery and purification
of hepatocyte progenitors from liver (intrahepatic stem cells), pancreas (hepatopancreatic
stem cell) and bone marrow (bone marrow derived hepatocytes). Cell surface markers
for the prospective isolation of thee cell types are being developed. In addition,
we are working out protocols for hepatic conditioning, which will permit selective
expansion of transplanted cells in any setting.
FANCONI ANEMIA AND INTERSTRAND CROSS-LINKS
Fanconi's anemia (FA) is a genetic disorder that affects multiple stem cells types, particularly hematopoietic stem cells and germline stem cells. Clinically, it is characterized by birth defects, progressive bone marrow failure and/or leukemia. FA cells are hypersensitive to DNA cross-linking agents and have an abnormal cell cycle. At least 11 different FA complementation groups (A, B, C, D1, D2, E, F, G, I, J and L) exist and the corresponding genes for 9 of these have been cloned. Importantly, the gene mutated in FA groups B and D1 is BRCA2, the breast cancer susceptibility gene. The biochemical function(s) of the pathway are unknown. This laboratory is interested in the basic defect in FA cells and therapeutic approaches. Wild-type hematopoietic stem cells have a marked selective growth advantage in FA, marking this disorder an ideal system to explore new strategies for gene therapy in blood stem cells.
Selected References
Liver repopulation
E. Lagasse, H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse,L. Osborne, X. Wang, M. Finegold, I. L. Weissman and M. Grompe (2000)" Purified Hematopoietic Stem Cells Can Differentiate to Hepatocytes In Vivo", Nature Medicine 6: 1229-34
X. Wang, M. Al-Dhalimy, E. Lagasse, M. Finegold and M. Grompe (2002) "Kinetics of liver repopulation by transplanted bone marrow cells", American Journal of Pathology 161(2): 565-74
X. Wang, H. Willenbring, Y. Akkari, Y. Torimaru, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold, S. Olson and M. Grompe (2003) "Cell fusion is the principal source of bone-marrow derived hepatocytes", Nature 422(6934):897-901
X. Wang, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold and M. Grompe (2003) "The origin and liver repopulating capacity of murine oval cells", Proceedings of the National Academy of Sciences USA, 100 Suppl. 1: 11881-8
H. Willenbring, A. S. Bailey, M. Foster, Y, Akkari, C. Dorrell, S. Olson, M. Finegold, W. H. Fleming and M. Grompe (2004) "Myelomonocytic cells are sufficient for therapeutic cell fusion in liver", Nature Medicine 10(7):744-8
Fanconi Anemia
C. Timmers, J. Hejna, C. Reifsteck, L. Lucas, M. Thayer, T. Taniguchi, A. D'Andrea, S. Olson, R.E. Moses and M. Grompe (2001) "Positional cloning of the Fanconi Anemia group D2 gene", Molecular Cell 7: 241-248
M. Noll, K. P. Battaile, R. Bateman, T. P. Lax, K. Rathbun, C. Reifsteck, G. Bagby, M. Finegold, S. Olson and M. Grompe (2002) "Lack of an additive phenotype in mice doubly mutant in the Fanconi Anemia group A and C genes", Journal of Experimental Hematology 30(7): 679-88
S. Houghtaling, C. Timmers, M. Noll, S.N. Jones, M. Finegold, S. Meyn and M. Grompe (2003) "Epithelial cancers in Fanconi Anemia D2 (Fancd2) knockout mice", Genes & Development, 7(16):2021-3
A. Rothfuss and M. Grompe (2004) "Repair Kinetics of Genomic Interstrand DNA Cross-Links: Evidence for DNA Double-Strand Break-Dependent Activation of the Fanconi Anemia,/BRCA pathway", Molecular and Cellular Biology 24(1): 123-34