Healing or Self-Damage:
Immunoreceptors' "Split Personality"
Sometimes described as a "liquid brain," the immune system
is continually poised at the edge of disaster, required to aggressively
attack invading pathogens without damaging its own body. The challenge
of understanding the complexity of signaling entailed in such a delicately
balanced system has been taken up by Laboratory researchers, who are
developing a mathematical model of immunoreceptors, a large and diverse
group of proteins that decode regulatory signals.
As recently reported in Molecular Immunology, a team led
by Byron Goldstein of T-10 (Theoretical Biology and Biophysics), and
including Michael Blinov,
Jim Faeder, Bill Hlavacek, Antonio Redondo, and Carla Wofsy, is studying
the Fc epsilon receptor. This receptor is a mast-cell membrane protein
that normally functions in inflammation to help remove pathogenic organisms
but which, when regulation goes awry, serves as a signaling intermediary
in allergic reactions. The receptor binds the IgE class of antibodies
and is activated when foreign substances (antigens) bind to those antibodies.
Receptor activation initiates a cascade of biochemical changes that culminates
in the secretion of histamine and other inflammatory biochemicals. In
allergic reactions, the inflammatory process becomes excessive, leading
to discomfort (as in hay fever) or even to death by asphyxiation (as
in extreme insect-sting reactions).
By creating and studying a mathematical model of this
signaling cascade, the investigators hope to understand the behavior
of the signaling system
as a whole. In the process, they should also be able to glean more insight
into the complex subcellular networks that regulate this form of receptor-mediated
signaling. As emphasized by Faeder, "Signaling has been thought
of as a linear chain of events, but it's not like that at all."
The investigators hope to expand the model to include
additional components of the signaling cascade. Another goal is to find
reduced models that
encompass only the key biochemical interactions in this cascade to make
it easier for experimentalists to identify critical points for potential
drug treatments. Currently available drugs like antihistamines and ibuprofen
tend to intervene after the fact, that is, after this signaling cascade
has run its course, and therefore relieve symptoms rather than address
"A detailed mathematical model of a signaling cascade for an immune
system receptor has never been done before," adds Goldstein. "What's
amazing is that as complicated as the system is, our model works. It's
consistent with a wide array of experimental observations." This,
of course, is potentially good news for allergy sufferers, since researchers
may some day be able to use the findings of this model to design more
efficacious medications that intervene in the allergic process at an
earlier stage.—Kevin N. Roark and Vin LoPresti
Improving Meteor Impact Predictions
An array of infrasound detectors used by the Laboratory to "listen" for
clandestine nuclear tests has played a key role in helping
scientists more accurately determine how often Earth is hammered by giant
like the one that flattened 1,900 square miles of forest in Tunguska,
Siberia, in 1908. Previously, scientists believed that very large meteors
like the Tunguska one entered Earth's atmosphere every 200 to 300
years. Now, Lab researcher Douglas ReVelle and his colleagues have
collected evidence that such catastrophic meteor strikes occur less frequently—about
every 1,000 years. Their findings were published in the November 21 issue
ReVelle teamed up with researchers from Sandia National
Laboratories, the University of Western Ontario, ET Space Systems, and
the U.S. Space
Command to look at both infrasound and light signatures from mid-size
meteors that entered Earth's atmosphere over the last eight years.
When such meteors—ranging from 3 to 30 feet in diameter—plunge
into the atmosphere, they explode, creating a brilliant flash of light
and a blast equivalent to many kilotons of TNT.
Because their arrival is heralded by a fireball and a
burst of shock-induced sound waves below the range of human hearing,
the meteors are easily
detected by satellites that look for flashes from incoming missiles
or nuclear blasts and by the Lab's infrasound arrays, which are
tuned to detect ultralow-frequency and very small amplitude waves.
amplitudes are only one-millionth those of normal sea-level atmospheric
pressure readings. The satellite and infrasound systems were designed
to detect clandestine nuclear weapons tests and other military activities.
ReVelle and his colleagues, however, discovered that by combining the
optical and infrasonic data, they could also more precisely calculate
the size and energy of large incoming meteors.
The team examined optical data for 300 meteors that "exploded" in
Earth's atmosphere between 1994 and 2002. From those data, they
evaluated the meteors' total optical energy and converted that
energy into an equivalent impact energy. As part of their conversion
work, they calibrated the optical data with independent source-energy
estimates for a dozen well-observed, large meteors. Most of these estimates
came from data from the Los Alamos infrasound arrays. Funded by the
Department of Energy, the Earth and Environmental Sciences Division
infrasound arrays across the western United States that routinely monitor
and locate global atmospheric explosions.
From the satellite and infrasound analyses, ReVelle produced
a graph that relates the number of meteors colliding with Earth in a
their impact energy and corresponding size. Over twelve magnitudes
of energy, a single distribution fits the data from mid-size meteors
giants like the one that leveled the Tunguska forest.
"What is exciting about this work for me is that without the data
from Los Alamos' infrasound arrays, this probably would not have been
possible," said ReVelle. "Infrasound provided the key to
unraveling the source energy of 75 percent of these collision events."
addition to providing impact estimates for large meteors, the team's
work also holds promise for accurately distinguishing between meteoric
fireballs and other atmospheric phenomena, such as volcanic eruptions,
accidental explosions, and incoming missiles. Combining satellite and
infrasound data offers a means of definitively identifying such events,
a capability that could prove critical during times of heightened regional
or global tension.—James Rickman
mast cell with IgE antibodies bound to the Fc receptors on its
surface; when a foreign substance binds to those antibodies, the Fc-receptor
cascade is triggered and inflammatory biochemicals such as histamine
are secreted. When the secretions become excessive, the foreign substance
is termed an "allergen."
Two infrasound microphones under white heat shields (about
2 feet tall). The black "wires" in the foreground are porous
hoses that reduce wind noise for the microphones.