The 2023 speakers are:
Ype Elgersma, Dept Neuroscience, Rotterdam, NL
« Neurodevelopmental disorders: Understanding the mechanisms and identifying treatments »
Neurodevelopmental disorders (i.e. intellectual disability, autism) affect 1% of the population, and often have a genetic basis. Our lab seeks to get insight in the molecular and cellular mechanisms underlying these disorders, with the ultimate goal to develop treatments. Our research is divided into three research lines: (1) Improving genetic diagnosis, (2) Understanding the mechanisms underlying neurodevelopmental disorders (3) Translational studies (i.e. clinical trials) to improve the quality of life of the affected individuals.
To improve genetic diagnosis, we have developed together with van Woerden lab a functional genomics screen (PRiSM) to rapidly determine if a genetic variant is pathogenic. This screen is not only important for providing a diagnosis, but also allows us to get more insight in the genes underlying neurodevelopment.
Understanding the mechanisms underlying neurodevelopmental disorders
To get more insight in the pathophysiology of neurodevelopmental disorders, we typically make use of genetically engineered mouse models. Mouse models are analyzed at the biochemical, cellular (electrophysiological) and behavioral level. By analyzing the mouse models at all these levels we try to understand the specific function of these genes and proteins in brain development and learning and memory. Besides mouse models, we are currently also exploring the value of iPS cells to study these disorders. The genes and proteins that we specifically focus on are proteins associated with the RAS-ERK-MTOR signaling pathway and the proteasome.
To translate our findings to the patients, we are part of the ENCOREexpertise center for neurodevelopmental disorders, for which Ype Elgersma is the scientific director. ENCORE has large expertise outpatient clinic for Angelman Syndrome, Neurofibromatosis (NF1), Tuberous Sclerosis (TSC), Fragile X and genetic forms of autism.
Michael F. Clarke, Standford Medecine, USA
« Stem Cell Biology and Regenerative Medicine«
In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. A central issue in stem cell biology is to understand the mechanisms that regulate self-renewal of hematopoietic stem cells, which are required for hematopoiesis to persist for the lifetime of the animal. Until recently, the molecular mechanisms that regulate adult stem cell self-renewal were not known. His laboratory recently found that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. By investigating the pathways upstream and downstream of Bmi1, the laboratory is actively investigating the molecular pathways that regulate self-renewal.
Cancers arise as a result of a series of genetic mutations. A better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help to focus the development of more effective therapies. Solid tumors such as breast cancers contain heterogeneous populations of neoplastic cells. Dr. Clarkes group has developed a technique that allows the isolation and characterization of tumorigenic and non-tumorigenic populations of cancer cells present in human breast, colon and head and neck cancer tumors. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. The tumorigenic cells displayed stem cell-like properties in that they were capable of generating new tumors containing additional stem cells as well as regenerating the phenotypically mixed populations of non-tumorigenic cells present in the original tumor. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. The laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. Dr. Clarkes laboratory will provide other members of the program with the expertise to identify and isolate cancer stem cells from solid tumors of epithelial origin. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells.