|
|
September 29, 2005
Notes From the Field
...an insider’s view of this month’s fifth annual Packard Center symposium
Outside, in Baltimore's Inner Harbor, the last of hurricane Ophelia has left the city in a tropical fug. Tourists amble, pushing strollers or themselves, eyeing the few shady spots. Inside, however, in a cool conference hall of the small hotel overtaken by Packard scientists, the contrast couldn't be sharper: Several hundred eyes focus in the dim light on a central screen where, one after the other, grant recipients step up with their laptops to offer their year's work.
It's a United Nations in here: Irish, French, English, Italian, Japanese, Korean, Chinese, Australian and Belgian accents please the ears as talks begin. Professors, heads of institutes and eager postdocs in suits, khakis or jeans, the seasoned and the newly-converted to ALS work—the scientists are an articulate, savvy bunch united simply by passion.
To a person, they hate ALS and what it does to patients and their families. They figuratively shake their heads, disgusted that a real therapy has so long eluded medical science. Driven by altruism, intellectual curiosity and competitiveness — an effective mix — each longs to make the disease yield its secrets, to show where the body's earliest vulnerabilities lie, to find flaws that they can mend, at first with a band-aid and then with something effective enough to call a cure.
As the Center's writer, I've sat at five of these symposia, alternately transfixed by the discoveries and made brain-dead by the sheer volume that’s reported. Each of the two-day sessions has had a different feel. The first seemed tentative, the scientists wary of sharing their work with potential competitors before publication; the second one was tinged with euphoria as it began to dawn that the Packard approach could work. Each year you walk away optimistic because progress is clear — even the ideas that don’t pan out help move things ahead.
But this year has been the best. Really. This year, it's become clear that this place where I work has created a scientific community beyond what's typical for people who share a field. Perhaps because of the monthly investigators' meetings, the group of 31 researchers and their postdocs now know each others' work well — Oh, she's the copper chaperone woman or He's one of the axonal transport guys — and familiarity has bred an interest in, and even an affection for, one another’s projects.
Each symposium, the scientists set up more collaborations. They share animal models and antibodies like neighbors swapping power tools. There's a trust that wasn't obvious at the beginning. Also, defensiveness while work’s getting critiqued is in short supply — a trait the best in any field seem to share. “This is a crack group,” I'm thinking.
Best of all, this year, even my layperson’s brain can tell the strides made are considerable. You can see pieces starting to fall in place. The approach is working.
Here’s a sample of this year’s findings:
- Jeffrey Johnson has found a way to activate a cell master switch that turns on all sorts of protective pathways when that cell suffers insults. By increasing the availability of an agent that activates the switch, he’s had good results in ALS animal models.
- Looking at a key gene in the programmed “way of no return,” — apoptosis — that dying motor neurons take, Ron Oppenheim had believed that removing the gene in an ALS mouse model might save the animal’s motor neurons and, thus overcome the disease effects.
What he found, however, was that, though blocking apoptosis let motor neurons survive, their muscle connections still broke down. Eventually, the animals still succumbed though it took longer. The take-home message, Oppenheim says, is that upsetting the neuromuscular junction likely plays a major part in ALS, at least in the SOD1 models of the disease.
- Similar to the way scientists are exploring vaccines for patients with Alzheimer’s disease, Jean-Pierre Julien has made a good case for developing a vaccination to help familial ALS patients with the SOD1 mutation. His preliminary vaccines in ALS model animals are encouraging, he says.
- Richard Ransohoff has homed in on what looks like neurons’ very useful ability to rein in microglia, the nervous system’s resident immune cells. Overactive microglia injure nearby neurons and do so, apparently, in ALS. Ransohoff has shown that damping them down, via this route, affects the survival of ALS animal models.
- Rick Huganir is showing how the body produces, recycles and retires molecular receptors to glutamate at neuron endings. Because, in ALS, excess glutamate can damage those endings and the rest of the neuron, Huganir suspects that whisking the receptors away or reducing their number temporarily might be a nerve-protecting strategy. He’s developed a model culture system that could let him test ways to do that.
- Neurotrophins are molecules with a major role in development, survival and death of nervous system cells. In studying neurotrophins this year, Moses Chao and Marco Domeniconi focused on the longer “parent” molecules that the body pares down to form them. But these longer, immature neurotrophins are toxic to nerves, the researchers found. They also learned that the balance of immature and mature neurotrophins in a nerve cell is key to whether it flourishes or dies and that, in ALS models, the balance tips toward the toxic immature molecules.
- Yimin Zou has made real progress in understanding cues the body uses to encourage growth of motor neurons in the proper direction, through the spinal cord to target muscles. He’s identified specific molecules that inhibit that process in adult spinal cords, following injury. Understanding how to overcome that may be important, he says, in repairing ALS damage.
- ALS clinical trials traditionally explore therapies that would help both sporadic and familial ALS patients. But in doing so, says Jonathan Glass, we may — just by the way the study is designed — already have overlooked agents that could specifically helpthe familial form. He’s in the process of setting up clinical trials narrowed to those with familial SOD1 mutations.
- Nicholas Maragakis and Mahendra Rao are exploring the possibility that vulnerability to ALS is increased when fewer transporter molecules are available to clear toxic glutamate out of nervous system synapses. They’ve shown that animal models of ALS with fewer genes to make the transporters have higher spinal cord injury and a reduced lifespan.
- Ahmet Höke has uncovered a key molecule the body naturally uses in its efforts to protect injured nerve cells from deteriorating. Studies in spinal cord cultures show that treating cells with the agent protects them from an ALS-mimicking neuro-poison. The agent also encourages proper nerve growth. Both abilities would be more than helpful in repairing ALS damage.
- Using sophisticated molecular techniques, Hongjun Song has isolated and cultured stem cells from human spinal cord and brain (the hippocampus) as well as from the same areas in healthy mice and ALS mouse models. With direction, the stem cells can morph into mature motor neuronsand glia. Not only will Song’s techniques make large numbers of cells available for potential therapeutic studies, but knowing the cells’ signature electrical properties and biochemistry should let scientists create “designer” cells tailored to test various ideas on what causes ALS and how it kills cells.
- In his quest to find the place where ALS first appears in the nervous system, Don Cleveland has added microglia to his systematic search. He’s shown that purging a fair number of microglial cells of their mutant SOD1 dramatically extends life --- a strong sign the cells have a real role in the disease.
Some of our studies are just too close to publication to let us “spill the beans,” so be sure to check the Fall and Winter issues of ALS Alert for news on Packard stem cell studies and work that’s approaching clinical trials.
>>more Recent
News
|
|
|
|
| Recent news from the Robert Packard Center
for ALS Research: |
| In ALS, It’s Not the Number of Ailing Astrocytes That Counts - June 12, 2008 |
| Leaky Blood Vessels Add To ALS Damage, Could Offer New Repair Site - June 10, 2008 |
| William H. Adams Foundation Pumps New Energy, Funds into Search for ALS Cure - May 6, 2008 |
| Tell-Tale Protein Clumping in ALS is Less Complex Than Expected - April 10, 2008 |
ALS Mouse Study Highlights Astrocytes' Strong Potential as Therapy Target - February 7, 2008 |
| Exciting New Human ALS Trial: Lithium and Riluzole - February 7, 2008 |
| ALS Treatment: A Matter of Cleaning House? - December 19, 2007 |
New Study Brings What Goes Wrong in Inherited ALS into Focus - September 18, 2007 |
| New ALS Protein Could Be a Keystone - August 9, 2007 |
| Muscles More Than Passive Victims in ALS, Study Suggests - June 29, 2007 |
| Saer and O’Neill Named Packard Center Board Co-Chairs - June 28, 2007 |
Self-Attack? Self-Repair? First Real Look at Gene Activity in ALS Models Sparks Thirst for Answers - May 3, 2007 |
| Model of Accelerated Familial ALS Sheds Light on Disease Process - April 6, 2007 |
| Early News From First Large Search for Sporadic ALS Genes - February 20, 2007 |
| Human Stem Cell Transplants Mature Into Neurons and Make Contacts in Rat Spinal Cord - February 14, 2007 |
|
