July 1, 2004
[QUICK SUMMARY: In June, the San Francisco Bay Area Chapter hosted the Young Investigators Workshop. Investigators new to ALS research collaborated with seasoned investigators to discuss promising areas to focus future research.]
The ALS Association holds a Young Investigators Workshop every two years in June to encourage collaboration and discussion among scientists new to the ALS field or those who have just received their first grant from The Association. This year’s meeting was held in San Francisco and was hosted by the Bay Area Chapter. Both their attention to detail as hosts and the wonderful San Francisco location set the stage for what promised to be an exciting workshop. We are grateful to The Linden Foundation for their generous support of these workshops. Indeed, the workshop was a great success with lively debate and discussion among the participants and sound input and suggestions from the more senior investigators. The day and a half of focused presentations led to exciting new collaborations and project proposals.
The ALS Association funds young scientists internationally, and representatives from the United Kingdom and France attended to present their data. In addition to the stimulating scientific program, scientists had the opportunity to meet with ALS patients and their families at a social gathering in the Genentech Hall at the new University of California San Francisco (UCSF) campus. The highlight of the evening was the presentation of the post-doctoral fellowship awards. Jonathan Lin, Ph.D. received the Lawrence and Isabel Barnett Post-Doctoral Fellowship for 2003. Christine Haenggeli, Ph.D. received The Milton Safenowitz Post-Doctoral Fellowship for 2004.
The workshop opened with a presentation by Dr. Richard Olney who described the clinical aspects of ALS. For many academic investigators who have not worked directly with people with ALS, this is an invaluable part of the program, putting their own research work into context. This was followed by excellent presentations on a variety of cell-based systems that are currently being developed not only to understand disease mechanism but to test therapies.
Much focus has been placed on the therapeutic potential of stem cells. Dr. Nicholas Maragakis described his study exploiting stem cell biology to develop model systems to understand disease mechanisms and test therapeutic approaches. Dr. Brigitte Pettman described her work to develop organotypic cultures from adult mice, a novel technique that has been difficult to do. Together with her expertise in cell culture systems and the support from Dr. Fred Gage’s laboratory using the most sophisticated imaging systems, this culture system has been developed into an invaluable model system to test disease mechanism and potential therapeutic interventions. In particular, Dr. Pettman will replicate some of her early studies with Dr. Chris Henderson looking at cell death pathways in embryonic cultures using a more relevant model for the human adult onset disease.
Dr. Lin introduced an exciting new area for ALS research. His studies in Dr. Peter Walters’ laboratory will focus on the unfolded protein response-signaling pathways. To date no one has demonstrated that these processes are altered in ALS, but due to the increased attention of aberrant protein folding in the disease, this will certainly be an intriguing area of research, which may lead to important new targets for the disease. It is invaluable for a young investigator such as Dr. Lin to have the opportunity to interact with a group of peers and review the current status of ALS research so early in his career.
Dr. Jonathan Wood described the zebra fish as a model system for studying disease and his preliminary work in generating mutant SOD1 zebra fish. He has already developed the model for a disease called Hereditary Spastic Paraplegia in humans and described some of his interesting results. Zebra fish embryos are optically transparent, and one can readily visualize internal structures and fluorescent markers in living and fixed whole specimens. Motor neuron development is well-characterised in the zebra fish; they have a short life cycle and are ideal models for both loss and gain of function diseases and amenable to high-throughput drug screening.
Classical ALS affects both the upper and lower motor neurons. There are rare forms of motor neuron disease that affect either the upper or lower motor neurons. Some of these forms may at later stage develop both upper and lower motor disease. In a large family known as the Maryland kindred the disease has both upper and lower motor neuron involvement but is distinguished from classical ALS by a lack of respiratory muscle involvement and a normal life span.
Dr. Craig Bennet and his team reported in this month’s edition of the American Journal of Human Genetics the discovery of the gene mutations linked to this family. The function of the gene named senataxin is currently unknown. The ALS Association contributed to the funding of this project recognizing the importance of finding more genes linked to motor neuron disease providing clues for disease mechanism and therapeutic targets. Although this form of motor neuron disease is different from classical ALS, understanding how the gene product functions normally in cells may provide clues to why motor neurons are vulnerable in this disease and other motor neuron diseases. Dr. Bennet’s continuing studies are focusing on the function of senataxin and developing new models of motor neuron disease.
Continuing the theme of why motor neurons may be susceptible to injury, Dr. George Haase has been investigating a cell death pathway using the SOD1 mutant mouse models and a mouse that has a spontaneous mutant leading to motor neuron death. This latter mutation was identified to be an autosomal recessive mutation in the tubulin specific chaperone gene. This gene appears to be involved in the stability of microtubules, important proteins enriched in motor neuron axons and important for axonal transport. The role of axonal transport abnormalities in ALS and other motor neuron diseases have become an area of intense investigation as different mutations in the transport machinery have now been linked to motor neuron diseases.
Dr. Francisco Andrade is currently approaching the question of selective vulnerability by looking at two different motor pools, the ocular motor neurons, which become affected much later in the disease, and the spinal motor neurons. Dr. Kurt Fishbeck commented on the enormous value of such a study and suggested approaches to the study design and analysis of data. It would be tremendously powerful to identify genes that are up regulated or protective in the occulor motor neurons, explaining why they are only affected in some patients at late stages in the disease.
Dr. Thomas Moeller spoke of the role of microglia in ALS and gave an excellent overview of exactly what microglia are and how they become activated. There is a growing amount of literature on ALS implicating microglia and inflammation in the disease. It is important to have investigators like Dr. Moeller who have a key understanding of the basic biology of these cells to work in the ALS field.
In addition, Drs. Jian Liu and Eric Beattie described their current studies looking at mitochondrial damage and glutamate, respectively.
The second day focused on gene therapy. Dr. Brian Kaspar started the session with the recent exciting data showing a dramatic increase in lifespan of the mutant SOD1 mice after administration of insulin derived growth factor 1 (IGF-1) by viral delivery. Efforts are underway to move this into the clinic as quickly as possible. Both Dr. Kaspar and Dr. David Shaeffer talked in detail about viral vector design.
One of the important challenges in using this delivery approach is to ensure that the gene product, IGF-1, reaches the motor neuron where it is hidden from other cells. After a muscle injection, the vector containing the gene product is taken up by the axon and transported to the cell body. Viral vectors are extremely variable in their ability to be transported up the axon. Dr. Shaeffer’s group is focusing on how to improve these delivery systems.
Dr. Sam Wang spoke of his efforts to use gene therapy technology to label motor neurons and develop live tracking systems which could be valuable for observing therapeutic effects. Dr. Christine Haenggeli described her preliminary studies in Jeffrey Rothstein’s laboratory and in collaboration with Dr. Brian Kaspar to deliver glial glutamate transporter to neurons and astrocytes.
Dr. Kurt Fishbeck, who has participated in all of these workshops, facilitated the wrap-up session seeking input from the group. The investigators commented that the forum was a great one for open and frank discussion, hearing about a large range of topics in the field and most importantly getting feedback and suggestions on their own studies.
All the investigators agreed that it was an exciting time to be in ALS research with the results of the gene therapy studies being particularly positive and with so many new tools and ideas being generated. Some expressed concerns about the great deal of focus on the SOD1 mouse models. The value of discovering new genes linked to classical ALS was underscored in the group discussions.
