Staring into the crystal-clear plastic boxes inside the University
of Maine's zebrafish research facility, it can be difficult to focus
on the movements of an individual fish. Both its stripes and its size
make it hard to distinguish from its brethren in a population that is
now more than 40,000 strong. The fish, on the other hand, seem to be
very good at tracking the movements of an individual human, darting
away in a flurry of fins and sinew at the slightest agitation.
At first glance, it seems as if the frightened fish simply bullet
through the water, like tiny torpedoes propelled by some hidden,
turbocharged motor. But closer observation reveals the true power
behind their movements: a fluttering undulation of the body and tail,
dependent, of course, on muscle.
With every flip of its fins, tiny bundles of skeletal muscle extend
and contract in precisely coordinated synchrony, leveraging their
movements against the fish's miniature frame.
UMaine researcher Clarissa Henry has always been fascinated by the
dynamic processes that shape the complex machinery of movement, and
has pioneered a unique new system for studying how muscles and tendons
develop inside the zebrafish. With a $1.28 million grant from the
National Institutes of Health's National Institute of Child Health and
Human Development, Henry is shining a microscope-mounted light into
the darkest corners of developmental biology, revealing new truths
about embryonic processes that may lead to better treatment methods
for conditions ranging from muscular dystrophy to tendinitis.
Henry's current research, aimed at developing a better
understanding of tendon formation and attachment in the embryo, is the
next step in her pioneering efforts to describe the complexities of
early development in vertebrates using zebrafish. Her previous
research, funded by the Muscular Dystrophy Association, looked at how
embryonic muscle cells transform from relatively stubby globs of
cytoplasm into the long, multinucleated fibers of skeletal muscle in
fully developed fry.
Skeletal muscles — from the orbicularis oculi to the gluteus
maximus — are primarily responsible for movement in vertebrates, and
abnormalities that arise during their formation can have dire
consequences. For example, muscular dystrophy, one of the most common
genetic diseases in humans, is characterized by a loss in muscular
function that can manifest in many ways.
"One of the critical questions related to the treatment of muscular
dystrophy is: How do humans make muscle during embryonic development?"
says Henry. "We were able to make a significant step forward in this
area because we were able to use an in vivo model. Prior to our work,
no one was able to look into a live vertebrate embryo to see how
muscle cells form at high resolution. We were able to do that with the
zebrafish, thanks to the MDA."
The strength of the preliminary data was one of the reasons NIH
reviewers expressed such strong support for Henry's latest project,
pointing to her well-established methodology and the work's potential
benefits in the treatment of human disease. In addition to her obvious
enthusiasm for the research, Henry has a technological advantage as
well, utilizing cutting-edge equipment like a Zeiss ApoTome
fluorescence microscope to peer inside the living embryo.
Like their plastic tanks, the developing eggs of the zebrafish are
largely transparent, allowing researchers to observe and record
changes in the cells as they happen, which is difficult or impossible
in other vertebrate research models, such as mice or chickens. The
zebrafish model has advantages over cell culture techniques as well,
revealing important nuances in growth and development that can only be
seen when cells form under the influence and constraints of a living
organism.
With the help of the tiny zebrafish, Henry's early work uncovered
"a phenomenal amount of data" regarding muscle cell development,
laying the foundation for further research related to tendon
attachment and other processes. The new research path has already led
Henry and her team to some important discoveries.
"Tendons are incredibly important structures, but exceedingly
little is known about tendon development. It is very understudied, but
it has implications in the treatment of a variety of tendon
afflictions, from tendinitis to disorders caused by antibiotics or
cancer treatments," Henry says. "Traditionally, tendons have been
thought of as uniform, with the same protein structure throughout. We
have found that that is decidedly not the case. Tendon structure is
spatially and temporally dynamic. We're very excited about looking
further at how the type and location of tendon proteins change over
time."
Henry and her UMaine colleagues continue to show that the zebrafish
model has significant advantages over other research systems. Perhaps
best of all, recent studies have shown that many of the processes that
occur during zebrafish development are very similar to the
developmental changes that occur in mammals, including humans.
"There's a lot of basic science in this area that we just don't
understand," says Henry. "We don't know how these structures grow, how
they increase in mass or how the attachment between the tendon and the
skeleton is maintained. There's a real opportunity here to do
pioneering work."
While zebrafish development will remain the primary focus of her
research, an opportunity to interact with some of the country's
leading stem cell researchers will soon have Henry working with a
slightly larger fish: the dogfish shark. Henry is the recipient of one
of a handful of New Investigator Awards from Mount Desert Island
Biological Laboratory (MDIBL). The honor will allow Henry to work with
MDIBL scientists for several weeks, examining muscle growth and
development in the dogfish.
Dogfish developed their unique physiology long before bony fish
like the zebrafish evolved. Henry hopes that comparisons between
dogfish and zebrafish embryonic development offer insights into the
evolution of muscle development and function.
"This award allows my lab to delve into questions that we would be
unable to ask without the valuable intellectual and practical
resources at MDIBL," Henry says.
Hoping to make the most effective use of her discoveries, Henry is
currently working with UMaine's administration to develop new
opportunities for collaboration with specialists in human genetics and
other fields.
"Having a system like this, where we can see the fine details of
cell behavior as it forms structures like muscle, facilitates a much
more complete understanding of the processes at work. If we're going
to talk about developing treatments for diseases, we need a very
thorough understanding of what's going on," says Henry.
"Part of what is so exciting about this work is that we are not
just using the zebrafish model to recapitulate what has been done in
other systems, we're using the zebrafish to ask questions that aren't
easily answered in other systems to complement what's known."
by David Munson
July-August, 2007
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