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December 15, 2005
Notes From the Field
...an ALS writer’s view of this
year's Society for Neuroscience meetings
Just
before Thanksgiving, neuroscientists worldwide made the pilgrimage to Washington,
D.C., for the annual Society for Neuroscience meetings. The capitol’s
convention center resembled nothing so much as an ant colony, as more
than 34,000 participants went from lecture to lecture or stopped to catch
up with colleagues. The event is one of the planet’s largest conferences,
with some 17,000 presentations during five days of speeches, slide lectures
and poster sessions. Anything to do with the nervous system — its
development, neuro-diseases, behavior, neurochemistry, stem cell workings
and more — is a fair topic.
The meetings aren’t all work: in one exhibit hall, a bazaar of
scientific book and equipment sellers beckon, using free food or give-away
gizmos to entice postdoctoral students --- who provide the muscle behind
most laboratory work --- to listen to their pitches. (Little brain-shaped
refrigerator magnets were popular this year.) And in the evening, specialty
gatherings provide truly-needed contrast to each day’s intense
focus on science: the Hippocampus and Thalamus Socials draw folks in,
for example, as does the Serotonin Club dinner.
The science, however, is undeniably serious. Not only are the meetings
a quick way to learn what’s hot in ALS research and to see if people
know their stuff; they’re also useful for perspective. The huge
breadth of topics exposes neuroscientists to news from adjacent fields
that they wouldn’t
hear much about otherwise, ideas that may help bridge the gaps in understanding
how ALS works. Researchers can also pick up novel techniques or approaches
to problems. Just getting consensus on a lab finding can be important,
can shift its significance closer to truth.
Two last asides: the first is that nobody comes to these meetings for
the food. Convention-hall catering is pretty grim: rubber charburgers
and overpriced pizza which you may have to eat sitting on the floor.
When 34,000 decide it’s
time for lunch, tables are at a premium.
The second reflects a comment by the Dalai Lama, whose controversial
presence centered on his lecture the first evening, part of a series
of dialogues on neuroscience and society. “I like to imagine all
human activities, including science, as individual fingers of a palm,” he
said. “So long as each of these fingers is
connected with the palm of basic human empathy and altruism, they will
continue to serve the well-being of humanity.” That could summarize
the ALS research I regularly witness.
So here are some of the meeting’s more interesting ALS studies.
They’re from a cross-section of researchers, some Packard scientists,
some not:
- A new study using ALS model mice exposed the animals to a combination
of exercise and gene therapy with positive results. Researchers introduced
genes for insulin-like growth factor (IGF), which has been shown to
help protect animal models’ motor neurons, via a harmless virus.
At the same time, the mice, unlike controls, had long access to a running
wheel. The work, from a team led by Brian Kaspar at Ohio State University,
showed that the treated mice lived almost twice as long as those without
the approach. Because the study also looked at the effect of exercise
alone in the ALS mice, without added gene therapy, the scientists found
it, too, had a positive effect, though milder. Mice that exercised
from a younger age lived a month longer than controls; those who began
exercise later lived, on average, 11 days longer. The researchers suspect
some of exercise’s benefits may be due to an internal IGF-boosting
effect. (Fred Gage, a Packard scientific advisor,
was on the research team.)
- Work by Jean-Pierre Julien and a team of Canadian
and Japanese colleagues found that mutant SOD1 molecules — those
that bring about a familial form of ALS — often associate with
proteins called chromogranins, both in nerve cell cultures and in spinal
cords of ALS mice. While the purpose of chromogranins in nerve cells
isn’t clear, the
fact that they’re linked with the release of substances to the
outside of cells strongly suggests that chromogranins help mutant SOD1
find its way into a nerve cell’s surroundings. Moreover, Julien’s
group found that extracellular mutant SOD1 is toxic to motor neurons
in culture. Their results are in keeping with the new idea that ALS
doesn’t necessarily originate in motor neurons and that toxicity
can transfer from one cell to another. The team’s report will
appear in an upcoming issue of Nature Neuroscience. (Julien
is a Packard scientist.)
- Scientists are no
strangers to VEGF, a molecule that directs growth
of blood vessels. Blocking VEGF is the basis for new cancer therapies,
for example. But, more recently, researchers have come to realize that
VEGF also plays a major part in the developing nervous system and,
in adults, in the survival of neurons. Following earlier work that
strongly suggests certain mutations in VEGF increase the risk of ALS,
Belgian researcher Peter Carmeliet and his team have
new studies that could explain how. Not long ago, mice they engineered
with defective VEGF genes had a greatly reduced supply of the growth
factor and developed a motor neuron disease not unlike ALS.
More recently,
Carmeliet’s group bred their VEGF-poor mice
with animal models of ALS (a mutant SOD1 model) to see how one condition
might affect the other. The resulting offspring had a far-shorter lifespan
than the ALS models alone. Especially interesting was the fact that
before ALS symptoms first appeared in the animals, blood supply to
key areas of the body — including motor neurons — dropped
as nerves responsible for maintaining blood pressure failed. This added
stress on motor neurons, along with havoc wreaked by the disappearance
of VEGF’s normal protective effects, apparently made them more
susceptible to ALS damage. The finds suggest poor blood supply to motor
neurons may be part of the disease in some patients.
By contrast, ALS
mice engineered to carry extra copies of normal VEGF genes had greatly
improved motor neuron activity compared with typical ALS animals.
Because
gene engineering is a complex way to introduce more VEGF, especially
if there’s an eye to human therapy, Carmeliet is investigating
a brain-implanted delivery system in which the growth factor works
its way into the spinal cord. The approach significantly lengthened
ALS animals’ survival. (Peter Carmeliet is a Packard scientific
advisor. Wim Robberecht, on the team for a number
of the studies, is a Packard scientist.)
- Christopher Henderson,
of Columbia University, is
struck by similarities between a natural event that takes place in
developing nervous systems — namely,
a stage before birth when roughly half of motor neurons die off — and
what happens in neurodegenerative disease. Understanding what triggers
the natural death and what protects neurons that are spared, he says,
could help understand ALS and treat it.
Studies show that in both instances,
neurons survive when supported by a number of survival-encouraging
molecules called trophic factors. When Henderson artificially removed
certain of the factors, internal death programs quickly became active
and the cells died.
To understand what’s going on, Henderson
focused on a specific molecule called fas that takes center
stage when trophic factors are gone. There’s a great increase
in cell-surface receptors for fas in ailing cells. Henderson
expected to follow the usual sequence of events such cells go through:
the doomed cells release fas,
it binds to the now-plentiful receptors on cell membranes and trips
a well-known cascade of chemical reactions ending in death. And that
does happen, he found. But he also discovered that, by contrast, motor
neurons have a parallel, previously undiscovered death pathway.
Knowing
the importance of motor neurons in ALS, Henderson turned to mouse models — the
mutant SOD1 mice that mimic a familial form of the disease. He found
the animals tremendously sensitive to fas stimulation.
Their motor neurons died considerably faster than usual, he found,
probably because the parallel pathway was working overtime. Not only
has Henderson gone on to find a tie between the activation of this
pathway and the presence of mutant SOD1 protein, but he also has suggestions
this same pathway is turned on in the common, sporadic forms of ALS,
an exciting idea that opens doors to new, more fundamental targets
for therapy. (Henderson is a recent member of the Packard scientific
advisory committee.)
- In exploring just why the growth factor VEGF
apparently protects motor neurons, a Belgian team led by Packard scientist Wim
Robberecht has singled out a particular chemical
pathway marked by an enzyme called protein kinase B that’s a
key player in cell survival, cell growth and cell movement. Flaws in
the pathway have already been tied to diabetes and cancer.
Now Robberecht’s
team has shown, in ALS rat models, that protein kinase B disappears
early on in the disease process. They’ve also
showed that treating rats with VEGF significantly increases the enzyme.
More than a simple mapping out of a pathway, the work supports the potential
of this small chemical cascade as a target for therapy.
>>more Recent
News
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| Recent news from the Robert Packard Center
for ALS Research: |
| Packard Center Welcomes Its First Dedicated Science Director - July 30, 3008 |
| 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 |
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