Dr. James M. Olson

Dr. Olson's laboratory studies the gene expression programs controlling neural differentiation, brain tumor genesis, and neurodegenerative diseases. Translation of laboratory findings to clinical therapeutics is accelerated through an extensive network of academic and industry collaborations.

Pediatric Brain Tumors
Medulloblastoma is the most common malignant brain tumor of childhood. It arises from cerebellar granule cell precursors, in some cases through mutations that lead to excess signaling of the sonic hedgehog pathway. In a multi-institutional collaborative study, we showed that one type of medulloblastoma (desmoplastic histology) overexpresses genes that are downstream of hedgehog and that another type (classic histology) is notable for overexpression of a small group of genes including the transcription factor, neuroD3/neurogenin (Pomeroy, 2001). Based on these studies, we are generating new mouse models of medulloblastoma and testing candidate drugs that interfere with the aberrant signaling pathways. For the latter goal, we lead a national consortium for pre-clinical analysis of new compounds. So far, we have demonstrated efficacy of two drug classes, retinoids and cyclopamine derivatives (Hallahan, 2003; Berman, 2002). Both effectively induce apoptosis in medulloblastoma cells derived from patient surgical samples and in established medulloblastoma cell cultures. We elucidated the mechanism by which retinoids induce apoptosis, providing a basis for understanding why some cells are sensitive to this agent and others are resistant. Based on these data, we are developing a national Phase III clinical trial through the Children’s Oncology Group to assess the efficacy of retinoids in children with high risk medulloblastoma/primitive neuroectodermal tumor.

Brain Development
The neuroD family of transcription factors regulates expression of genes that are necessary for nerve cell development. In collaboration with David Turner, we demonstrated that neuroD proteins were sufficient to convert rapidly dividing embryonal carcinoma cells into nonreplicating, mature neurons (Farah, 1999). In these cells, neuroD2 induced expression of the cell cycle regulator, p27; subsequent cell cycle arrest; and neuronal differentiation. Having demonstrated the neuroD2 was sufficient to induce neurogenic differentiation in mammalian cells, we then assessed the role of neuroD2 in developing brain by generating mice that were heterozygous or nullizygous for neuroD2 (Olson, 2001). NeuroD2-null mice experienced premature death (typically around postnatal day 28) preceded by ataxia, seizures, motor deficits, and weight loss. Cells that normally express neuroD2 underwent excessive apoptosis in the post-natal period in the absence of neuroD2, thus establishing that this transcription factor is important for neuronal survival in addition to its established role in neuronal differentiation. Ongoing studies will determine how neuroD2 is regulated in developing brain and identify transcriptional targets of neuroD2.

Huntington’s Disease
Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein (Hughes, 2001). The mutant protein forms intracellular aggregates that incorporate many other proteins, including transcription factors. We hypothesize that the mutant huntingtin protein causes neuronal dysfunction, in part, by altering transcription of genes that are necessary for neurotransmission. We organized a consortium of 60 investigators from 19 Universities that conducted gene expression profiling studies in models of HD and other neurodegenerative diseases. The results can be seen in a special series of articles in Human Molecular Genetics (issues 11(17) and 11(19), 2002). We identified a number of drugs that reduce aggregate formation in HD models and are currently testing the efficacy of these agents in pre-clinical studies.

Clinical Pharmacology
Dr. Olson is the author of “Clinical Pharmacology Made Ridiculously Simple,” a textbook geared toward medical students making the transition from classroom pharmacology to clinical pharmacology. The principles of pharmacology and the relationships that we have developed in research divisions of pharmaceutical companies accelerate translation of our basic research into clinical practice.