Forsyth Scientists Discover Early Key To Regeneration
Science may be one step closer to understanding how a limb can be
grown or a spinal cord can be repaired. Scientists at The Forsyth
Institute have discovered that some cells have to die for regeneration
to occur. This research may provide insight into mechanisms necessary
for therapeutic regeneration in humans, potentially addressing tissues
that are lost, damaged or non- functional as a result of genetic
syndromes, birth defects, cancer, degenerative diseases, accidents,
aging and organ failure. Through studies of the frog (Xenopus) tadpole,
the Forsyth team examined the cellular underpinnings of regeneration.
The Xenopus tadpole is an ideal model for studying regeneration because
it is able to re-grow a fully functioning tail and all of its
components, including muscle, vasculature, skin, and spinal cord. The
Forsyth scientists studied the role that apoptosis, a process of
programmed cell death in multi-cellular organisms, plays in
regeneration. The research team, led by Michael Levin, Ph.D., Director
of the Forsyth Center for Regenerative and Developmental Biology, found
that apoptosis has a novel role in development and a critical role in
regeneration. According to Dr. Levin, "Simply put, some cells have to
die for regeneration to happen."
The findings will be published in the January 1, 2007 issue of
Developmental Biology (v301i1). "We were surprised to see that some
cells need to be removed for regeneration to proceed," said Ai-Sun
Tseng, Ph.D. the paper's first author. "It is exciting to think that
someday this process could be managed to allow medically therapeutic
regeneration."
Summary of Study
In the context of efforts to understand biophysical controls of
regenerative processes, The Forsyth Center for Regenerative and
Developmental Biology investigated the dynamics of cell number control
in the regenerating tail bud. Previous research in the field has shown
that one mechanism by which cell number is controlled is by programmed
cell death, which has been shown to be involved in sculpting of growing
tissue in a number of developmental systems including heart, limb and
craniofacial patterning. This study shows that despite the massive
tissue proliferation required to build the tail, an early apoptotic
event is required for regeneration. Normal regeneration of the tail
includes a small focus of apoptotic cells; when apoptosis is inhibited
during the first 24 hours, regeneration cannot proceed and the growth
of nerve axons becomes abnormal. Later inhibition of apoptosis has no
effect, suggesting that the programmed death of a specific cellular
component is a very early step in the regeneration program. One
possible model is that tissues normally contain a population of cells
whose purpose is to prevent massive growth in the region surrounding
them. Future work by the Levin group will identify the cells that must
die, in order to try to understand the signals that cells utilize for
growth control.
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Michael Levin, PhD. is an Associate Member of the Staff in The Forsyth
Institute Department of Cytokine Biology and the Director of the
Forsyth Center for Regenerative and Developmental Biology. Through
experimental approaches and mathematical modeling, Dr. Levin and his
team examine the processes governing large-scale pattern formation and
biological information storage during animal embryogenesis. The lab's
investigations are directed toward understanding the mechanisms of
signaling between cells and tissues that allows a living system to
reliably generate and maintain a complex morphology. The Levin team
studies these processes in the context of embryonic development and
regeneration, with a particular focus on the biophysics of cell
behavior.
The Forsyth Institute is the world's leading independent organization
dedicated to scientific research and education in oral, craniofacial
and related biomedical sciences.
Contact: Jennifer Kelly
Forsyth Institute
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Key To Treating Neurological Damage Is Harnessing The Brain's Plasticity
With an aging population susceptible to stroke, Parkinson's disease
and other neurological conditions, and military personnel returning
from Iraq and Afghanistan with serious limb injuries, the need for
strategies that treat complex neurological impairments has never been
greater.
One tack being pursued by neuroscientists and
engineers is the development of "smart" neural prostheses. These
devices are intended to restore function, through electrical
stimulation, to damaged motor neural circuits - the long, slender
fibers that conduct neurochemical messages between nerve cells in the
brain and spinal cord.
It is the rapid-fire transmission of messages between nerve cells that
prompts the body's movements, leading the hand to whisk away a fly, the
leg to stretch, the head to turn. And it is disruption of these
messages that leads to impairment, including paralysis, staggered gaits
and other forms of motor dysfunction.
Simple forms of neural prostheses -- some external, some implantable --
have been developed over the last four decades to treat loss of
hearing, bladder control and respiration. And recent advances have led
to the development of some "smart" neural prostheses, which engage
higher levels of brain function.
However, significant challenges remain in developing ever-more precise
implanted neural interfaces that operate at the cellular level and that
will provide even greater precision and fidelity in restoring function.
Harnessing the brain's "plasticity"
To truly harness the capacity of neural prostheses to treat complex
damage of the nervous system, the devices must be designed to exploit
the brain's "plasticity," or capacity for change, says Michael
Merzenich, PhD, UCSF Francis A. Sooy Professor of Otolaryngology and a
member of the Keck Center for Integrative Neuroscience at UCSF.
Merzenich's pioneering studies over three decades have revealed the
capacity of the brain to rewire itself in response to new conditions,
even during adulthood and aging. And in developing the first neural
prosthesis - the cochlear implant, in the early 1980s -- and software
programs for language and learning disabilities in the mid 1990s - he
has demonstrated that the brain has the capacity to actively engage in
a remediation, or retraining, process.
"The brain is amazingly adaptive," says Merzenich. "Our early studies
developing the cochlear implant showed that the brain can take crude
electrical inputs and interpret them and create new constructs," he
says.
"But our studies showed that the brain wants to receive this
information in certain forms. Information delivered from the interface
of a device has to be adequate for the brain to extract enough
information to reestablish control."
As neural prosthetics involve extracting neurological information from
the higher levels of the brain, and transmitting it back to a critical
nerve center in an unfamiliar form, he says, they should engage the
brain in this process.
"The success with any complicated prosthetic device relates as much to
how the brain adjusts to it, accepts it and controls its use as it does
to the device itself. If we can figure out how to engage the brain to
do its part it can make a merely adequate neural prosthetic device work
marvelously."
Merzenich presented a talk, "The role of plasticity in the nervous
system in neural prosthetics," at the AAAS symposium "Smart
prosthetics: Interfaces to the nervous system help restore
independence" Friday, Feb. 16, 2007).
Neural prostheses can be "smart" in various ways, says Merzenich. They
can: be smart in and of themselves, by operating "intelligently" adapt
to the brain tissue environment in which they are introduced be
designed to grow in their utility as the brain is trained to take
advantage of them
In all cases, he says, devices should be organized to engage the brain
in ways that "enable plasticity and promote plasticity," such as by:
delivering plasticity-enabling chemicals providing a body/brain/device
interface that maximizes the potential for plastic adaptation applying
stimuli in forms that effectively induce plastic change enabling the
implementation of an intensive training program that makes the most out
of the device
Alternative forms of plasticity-based training
Notably, Merzenich's own current research focuses not on developing
neural prosthetics, but rather on developing intensive plasticity-based
mental and physical training programs. His targets are schizophrenia,
bipolar disorder, functional losses in normal aging, mild cognitive
impairment, Alzheimer's disease, acquired movement disorders, autism,
and learning, language and reading impairments in children.
"We are trying to see how far we can drive the brain in corrective directions by intensive training without a device," he says.
In these cases, the neural circuits at play are those that receive
sensory inputs - smell, touch, taste, sound and sight - support memory
and cognition, and orchestrate behaviors.
Merzenich's ongoing studies involving the use of software to accelerate
the speed at which children with language and learning disabilities
process sound suggest he's on track. (His patented findings led to his
founding in 1996, with Paula Tallal of Rutgers University, Scientific
Learning, a therapeutic software company in Oakland, California.)
And numerous clinical trials targeting the other neurological
conditions are producing encouraging results. A clinical trial for
schizophrenia, underway at UCSF and Yale, aims to drive misdirected
neural circuitry in a normal direction, though cognitive therapy,
perceptual training, movement control, response control.
The results of this trial (supported by a second therapeutic software
company that he has co-founded, Posit Science, in San Francisco) are
"outstanding," he says, far better than those produced by the standard
medication for the disease, but at this early stage in the development
of the strategy the regimen requires a burdensome 100 hours of work.
Other clinical trials under way at UCSF involve normal and infirm aging
populations, including mild cognitive impairment and Alzheimer's
patients.
The studies on autism are the least developed, he says. "We've trained
thousands of autistics with our child training programs, but our
training tools and their effective applications are still very limited.
We know that we can provide much better help for these individuals."
Merzenich is not currently collaborating with neural stem cell
scientists, but he talks with them, and thinks about their work. With
the establishment of new neurons in the brain, he says, "brain
plasticity will have to be a substantial and necessary part of
recovery."
"These are interesting stories," he reflects. "They do not involve
trying to substitute, compensate or work around a problem. In each
case, the work involves trying to correct the processing in the
machinery with the machinery being substantially intact."
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UCSF is a leading university that advances health worldwide by
conducting advanced biomedical research, educating graduate students in
the life sciences and health professions, and providing complex patient
care.
FOR MORE INFORMATION:
Merzenich laboratory
UCSF Magazine, Dec. 2004, "Grasping Autism"
UCSF Magazine, 2003, "Faculty Entrepreneur"
Contact: Jennifer O'Brien
University of California - San Francisco
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Moderate Alcohol Helps You Survive Brain Injury
A Canadian study has surprised scientists by suggesting that brain
injured patients with low to moderate blood alcohol have a better
survival chance than those with zero or high blood alcohol.
The study is published in the Archives of Surgery and was led by Dr Homer Tien, trauma surgeon at the Sunnybrook Health Science Centre in Toronto.
Dr Tien and his team looked at 16 years of trauma registry data from
1988 to 2003 describing patients admitted with traumatic brain injury
(TBI) due to blunt head trauma, resulting from a road accident for
example. They analysed the results of 1158 patients according to their
blood alcohol level: None (0 milligrams per decilitre, 0mg/dL), low to
moderate (under 230mg/dL), and high (230mg/dL and above).
The researchers performed statistical tests to work out the survival
rates of the three groups. The results suggest that severely brain
injured patients with high blood alcohol are more likely to die from
their injuries than those with zero blood alcohol.
However, those with low to moderate blood alcohol stand a significantly
better chance of survival than those with no alcohol in their blood.
The researchers are not sure how to explain the results. They suggest
it could be because the initial brain trauma can develop into a
secondary brain injury which is hard to manage when blood alcohol is
high. Patients with high blood alcohol are less likely to respond to
rescucitation.
Perhaps low blood alcohol (as opposed to none) actively reduces
secondary brain injury, which together with the increased likelihood of
successful rescitation means survival is more likely. Further research
is needed, but the early indications are that alcohol may have a part
to play in helping patients recover from severe brain injury.
Dr Tien and his team describe the results as a "paradox" and are careful to point out that:
"the study only describes the effect of alcohol on the brain after
injury occurs and I’d like to stress that alcohol remains the leading
cause of preventable trauma deaths and dramatically increases the
likelihood of injury and fatal injury.”
Up to 50 per cent of people admitted to hospital with trauma were drunk at the time they got injured.
"Association Between Alcohol and Mortality in Patients With Severe Traumatic Head Injury."
Homer C. N. Tien, MD, FRCSC; Lorraine N. Tremblay, MD, PhD; Sandro B.
Rizoli, MD, PhD; Jacob Gelberg, BSc; Talat Chughtai, MD; Peter
Tikuisis, PhD; Pang Shek, PhD; Frederick D. Brenneman, MD.
Arch Surg. 2006;141:1185-1191.
Click here for Abstract.
Written by: Catharine Paddock
Writer: Medical News Today
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New Supercomputer Brings Unique Opportunities For Swedish Brain Research
Approximately 127 million people in Europe are suffering from some
kind of brain disease or injury. With the long term goal to improve
diagnostics and find new therapies in their sights, the Stockholm Brain
Institute (SBI) and IBM have embarked on a partnership that gives
Swedish brain researchers access to a unique supercomputer. The
computer system Blue Gene is the first of its kind in the Nordic region
and will be installed in the Parallel Computer Centre at the Royal
Institute of Technology. The joint project, which will cost an
estimated SKr 20 million, was presented today at a press conference in
Stockholm.
"The combination of such enormous computer capacity and a
high-resolution PET camera is unique in the world," says Hans
Forssberg, Vice President of Karolinska Institutet and representative
of the SBI. "Add to this the proximity to patients and clinical
practice and we get entirely new opportunities for brain research from
both a Swedish and international perspective."
The SBI was set up by Karolinska Institutet, the Royal Institute of
Technology and Stockholm University to promote cutting-edge research
into the cognitive functions of the brain, such as memory and learning
or emotions, action and perception. Such research is attacked from
three angles: development and ageing, gender differences, and brain
diseases (Alzheimer's, schizophrenia or ADHD). Important tools for
scientists working on these areas include high-performance
computational resources for simulation and image analysis.
The SBI was also established to team up with industry to drive the
development of innovation projects concerning medicines, advanced
computer technology, memory research, medical image processing, and the
rehabilitation of people with brain injuries.
"The purpose of Blue Gene will be to give scientists extreme
computational power to help them develop a deeper understanding of
brain function so that they can improve the diagnosis and treatment of
diseases of the nerve system and the brain," says Ajay Royyuru, head of
the Computational Biology Centre at IBM Research. "Blue Gene has
established itself as the world's leading supercomputer architecture,
and suits the needs of the SBI down to the ground."
"We're also creating two new research posts one at IBM Research outside
New York and one at the SBI in Stockholm," he continues. "These
researchers will be developing new algorithms and methods for making
better use of Blue Gene's capacity."
Also involved in the Blue Gene project are Astra Zeneca and the OECD's
International Neuroinformatics Coordination Facility (INCF).
KAROLINSKA INSTITUTET
SE-171 77 Stockholm
http://info.ki.se/index_se.html
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