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United Press International (United PressInternational
via COMTEX) - After two centuries of animal studies
aimed at unlocking the secrets of sleep, researchers
have identified two genes that apparently protect
fruit flies from dying from lack of rest.
Despite the sizeable gap between the 3-millimeter-long
fruit fly, Drosophila melanogaster, of their studies
and the intended human beneficiaries of the research,
the findings should awaken interest as the first
genetic "hook" for grasping the molecular mechanisms
of human slumber, the investigators said.
Further down the line, the stress-response gene
tests in the fruit fly which appears to experience
a state of human-like snoozing might lead to refined
approaches to sleep deprivation, jet lag and night
shift work, said the authors of the paper to be
published Thursday in the British journal Nature.
"So far, the similarities between sleep in the
fly and human sleep have been eerily similar. Thus,
they sleep about the same amount of time. Sleep
is abundant in young flies and declines with age.
They respond to stimulants like caffeine and hypnotics
such as anti-histamines the way that mammals do,"
lead author Paul Shaw of The Neurosciences Institute
in San Diego told United Press International.
"Some of the same genes that are expressed at higher
levels during waking than sleep in the rat are similarly
changed in the fly. Future investigations will ultimately
determine exactly how much the fly will contribute
to our understanding of human sleep," Shaw said.
Another researcher warned about jumping to premature
conclusions, however.
"Although this is interesting and important work,
it is a great leap of faith to draw so many generalizations
with human sleep," cautioned Jim Horne of the Sleep
Research Laboratory at Loughborough University in
Leicestershire, England. Horne is author of the
book "Why We Sleep," which explores the stress effects
of sleep loss on humans.
"Indeed, both rats and fruit flies die without
sleep, but this only happens if they are otherwise
stressed by the sleep deprivation procedure itself
which is clearly unnatural," Horne told UPI. "Humans
can be deprived of sleep without additional stress
they volunteer, understand what is happening and
can pull out any time and then there is little sign
of any stress response."
In the experiments, Shaw and his colleagues exposed
various mutant flies to differing amounts of light
and darkness and a range of levels of sleep deprivation.
The flies' fates some died "represent a first step
in identifying the molecular mechanisms that constitute
the sleep homeostat," the team concluded.
Biological scientist Paul Franken of Stanford University
in Palo Alto, Calif., whose mouse sleep findings
support Shaw's observations, called the study "probably
the most important contribution to the field of
sleep research this year."
The two-year investigation built upon previous
work that drew parallels down to the genetic level
between fruit fly and mammalian slumber. For both,
there is no life without sleep, the researchers
said.
"Until now, we've only known with any scientific
confidence that rats will die from sleep deprivation"
after 17 days, Shaw said in a telephone interview.
"Our study extends this observation beyond mammals."
The findings have been 200 years in the making,
he added, noting that the first animal sleep studies,
with cats and rats, were conducted in Russia in
the 1800s. In this latest research, the investigators
found:
- fruit flies start dying after 60 to 70 hours
of sleep deprivation, about the same amount of
time it takes them to starve, suggesting food
and sleep may be of equal biological importance;
- flies with a mutated gene called cyc, shown
to help control the internal clock that signals
when it is time to arise or go to bed, start dying
after only 12 napless hours;
- activating another gene called Hsp83 (for heat
sensitive protein), known to protect the body
against stress, before sleep deprivation prevents
the premature deaths;
- in flies with a mutated Hsp83 gene, 12 sleepless
hours prove terminal, even in the presence of
a normal cyc gene.
"It is too early to know exactly how these genes
function with respect to sleep," Shaw said. "This
is a very complicated pathway, and thus it may take
some time to unravel it."
Shaw explained what is clear is how significant
sleep is to survival.
"It is so important that it has survived throughout
evolution even though it is a costly behavior. While
animals sleep, they can't take care of their young,
forage for food or engage in any number of other
vital biological activities," he said.
"It is a really nicely done study with remarkably
clear results," Robert Stickgold, assistant professor
of psychiatry at the Harvard Medical School in Cambridge,
Mass., told UPI.
"The genes that control the fruit fly circadian
rest-activity cycle are clearly the same genes as
those that control the human wake-sleep cycle. So
the extent to which this so-called sleep in flies
can be taken as a model for human sleep remains
to be seen."
The two genes identified in the study play such
an important role in sleep function that when they
are disabled or discarded, the sleep-deprived flies
die five times faster, Shaw said. When the investigators
stressed the flies with heat, turned up to 96 to
98 degrees Fahrenheit, or low oxygen and food provisions
before keeping them awake, the tiny insects survived.
"For many years, most scientists have believed
that the sleep and clock mechanisms were independent,
although it was widely recognized that they could
influence one another," Shaw said. "Our data suggest
a much more intimate relationship."
Stickgold said, "The sleep homeostatic mechanism
is supposed to be but now obviously isn't completely
separate. (The study) appears to show that the rest-activity
cycle of the fly is critical for its survival, and
... mutations in a gene that control both the rest-activity
cycle in flies and the sleep cycle in humans plays
a critical role (in flies) in waking survival. How
this relates to humans, and what role the heat shock
protein Hsp83 is in this process remain to be determined."
He added, "At the moment, these findings almost
represent an anomaly, but it has the feel of one
of those anomalies that will lead to a whole set
of unexpected and exciting findings." Shaw believes
the research offers scientists a "hook" to examine
more advanced possibilities for sleep related behaviors
and afflictions that affect humans.
"For example, findings may suggest treatments
and behavior modifications that eliminate or minimize
the impacts of night shift work, sleep disorders,
jet lag, to name a few," he said.
"These 'clock' genes and their transcriptional
targets might be direct drug targets for sleep disorders
and to improve performance under sustained periods
of wakefulness," Franken told UPI.
For Franken, the study raises interest on a more
basic level. "Although many people die in accidents
related to lack of sleep, people don't die of sleep
loss per se at least in modern times," Franken said.
"My personal excitement is of a more fundamental
nature. The Holy Grail of sleep researchers is sleep
function."
Shaw's findings do not solve that mystery but point
to a well-studied pathway formerly not implicated
in sleep the regulation of sleep need. Identifying
the molecular structure of sleep need will be a
important step toward increasing understanding of
sleep's function.
Next, Shaw and teammates Ralph Greenspan and Donald
Robinson will try to pin down the mechanisms by
which the genes increase and/or protect against
the lethal effects of sleep deprivation.
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