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In microbe’s genome, a potential
target
A neuron’s hard day’s night
Et cetera
It’s a fly’s life (and a longer
one)
Hope for the sleep-deprived
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In microbe’s genome,
a potential target
Wigglesworthia exposes chink in the armor of deadly tsetse fly,
route for attacking sleeping sickness.
As genomes go, the sequence of the lowly bacterium Wigglesworthia
glossinidia doesn’t carry quite the clout of the human genome
or even that of the mouse. But tiny as the bug’s gene collection
may be—a mere 700,000 base pairs, compared to humans’ 3 million—it’s
not at all trivial. Details of Wigglesworthia’s genetic code,
deciphered by Yale’s Serap Aksoy, Ph.D., and co-workers and reported
in the November 2002 issue of Nature Genetics, could lead to new
approaches for dealing with a deadly disease that has been nearly impossible
to control.
Wigglesworthia causes no illness itself. But in a complex, interdependent
relationship that has evolved over the past 100 million years, the bacterium
has come to live only in the gut of the tsetse fly. And it’s the
blood-sucking tsetse fly that transmits a parasite responsible for sleeping
sickness, a disease that caused severe epidemics in the last century and
has been on the rise in southern Africa in recent years. An estimated
500,000 people currently have the disease, which is fatal without treatment
with highly toxic drugs. Animals, too, are affected, with some 3 million
head of livestock dying from the animal form of the disease every year.
Infection of livestock has severely limited development and cattle raising
in large parts of Africa.
“There are no vaccines and few effective drugs for treating sleeping
sickness,” said Aksoy, an associate professor in the Division of
Epidemiology of Microbial Diseases at the School of Public Health. “Vector
control has been the major strategy employed for controlling the disease,
and yet everything that’s being used for vector control is very
inefficient and environmentally unsound. So it’s very crucial that
we develop new approaches.”
That’s where Wigglesworthia could prove useful. Like many
organisms, tsetse flies need vitamins to reproduce, but blood—their
dietary mainstay—is notoriously low in vitamins. Previous research
suggested that Wigglesworthia somehow helps supplement the fly’s
diet, Aksoy said. “It was shown that if you eliminated the bacteria
by antibiotic treatment, you aborted the fly’s fertility, and that
supplementing with vitamins could restore fertility very slightly. That
suggested that Wigglesworthia might be supplying vitamins to the
fly, but no one really knew which vitamins or how extensive the requirement
was.”
By decoding the Wigglesworthia genome, Aksoy and co-workers learned
exactly which vitamins the bacterium produces for its host. They repeated
the earlier experiments, first using antibiotics to clear Wigglesworthia
from the flies and confirming that the flies became infertile, then supplementing
the flies with the very vitamins that Wigglesworthia produces.
This time, the flies’ fertility was fully restored.
The results suggest that finding ways to wipe out Wigglesworthia
in the field might drastically reduce tsetse fly populations, helping
to curb the spread of sleeping sickness.
“This opens a whole new avenue for us,” said Aksoy. “Before,
the avenues for controlling the disease were based on targeting the parasite
in the human or targeting its biology by interfering with insect functions,
but now we have another target that we can aim at to reduce fly populations.”
Another observation Aksoy’s team has made in the lab underscores
Wigglesworthia’s pivotal role. “We find that during
their development in the fly, the parasites aggregate in very large numbers
around the gut cells where Wigglesworthia live, suggesting that
the parasites might also be obtaining nutrients from these bacteria,”
said Aksoy. “Now we’re studying Wigglesworthia gene
expression in both parasite-infected tsetse flies and uninfected flies,
trying to understand what the bacteria might be provisioning to the developing
parasites.”
In addition to Wigglesworthia, the researchers are studying two
other bacteria that live in tsetse flies. The commensal Sodalis glossinidius
also lives in the gut, and its genome sequence is near completion, while
Wolbachia is found in the insect’s ovaries. “They’re
all very compartmentalized, and they seem not to get in the way of one
another in terms of tsetse biology, so we’re interested in how this
all fits together—how the insect is able to maintain homeostasis
or harmony, in association with all these bacteria.” In addition,
Aksoy’s team is engineering Sodalis and Wolbachia
to express foreign genes, in hopes of making tsetse flies resistant to
infection with the disease-causing parasites.
“We’re hoping,” said Aksoy, “that eventually all
of our studies with Wigglesworthia and the other bacteria will
lead to novel control strategies whereby we can render tsetse flies incapable
of parasite transmission.”
—Nancy Ross-Flanigan
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Measuring energy expended
by nerve cells, Yale team finds it’s all in a day’s work
For the first time, a team of Yale scientists has quantified the link
between the work neurons perform for sensory or cognitive tasks and the
energy they expend.
“These results could later contribute to more targeted treatments
for certain brain disorders, where brain imaging is involved,” said
Fahmeed Hyder, Ph.D., assistant professor of diagnostic radiology.
The team’s work could also change approaches to the use of data
from functional magnetic resonance imaging (fMRI). It has been common
practice for neuroscientists to take fMRI images from a baseline phase
and compare them to images obtained during the performance of the task.
The result is a difference map which shows where tasks have led to increased
brain activity.
“If all they look at are these differences from baseline, then they’re
ignoring an important fraction of the total work required for brain function
and perception,” Hyder said. “Not everyone starts at the same
baseline. Even in our animal experiments, which were done under very well-controlled
conditions, there are still slight variations in the baseline, and incremental
changes from baseline alone can’t accurately reflect the amount
of energy used. Only the total energy used can reflect the total activity
within a region.”
Hyder and his colleagues measured the firing of neurons in the brains
of rats as the neurons sent electrical signals from one region to another.
Then they varied the workload for neurons in a specific brain region.
By using fMRI to measure local energy use, they were able to estimate
the energy the neurons expend when the workloads are varied.
Hyder and colleagues published their findings in two papers in the Proceedings
of the National Academy of Sciences in September.
—John Curtis
Et Cetera
It’s a fly’s life (and a longer one)
Fewer calories may mean longer life, and Yale scientists working with
colleagues at the University of Connecticut may have found a way to mimic
a reduction in calories even when food intake remains constant.
In a study published in the journal Science in November, the scientists
reported that inhibiting the enzyme Rpd3 histone deacetylase extends the
life span of fruit flies. The enzyme may play a key role in regulating
hundreds of genes whose expression is linked to caloric intake. “If
you decrease the level of the enzyme without eating less, you still get
life span extension,” said Stewart A. Frankel, Ph.D., senior author
of the study and an associate research scientist in pediatrics. “The
trick is to find specific drugs to target this enzyme.”
—John Curtis
Hope for the sleep-deprived
Narcoleptics and those who are sleep-deprived may find comfort in a recent
study by Yale scientists. According to research published in the journal
Neuron in December, hypocretin neurons, a class of peptide neurotransmitters
that originate in the hypothalamus and whose absence causes narcolepsy,
have been found to interact with other cells and start a chain of events
that ultimately excites the hypocretin system. This knowledge may lead
to ways of harnessing this system to enhance arousal, and possibly improve
cognitive abilities at times of day when people become drowsy. “It’s
like turning on the ignition in a car, which in turn activates a number
of different automobile circuits,” said Anthony N. van den Pol,
Ph.D., professor of neurosurgery, whose team observed the activity of
GFP-tagged hypocretin neurons in the brains of transgenic mice. “These
studies may point us in a direction to help people who have to work long
hours or at unusual times of the night. Maybe there is a way to facilitate
their performance and cognitive state using the hypocretin system.”
—John Curtis
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