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science On tHe cUtting edge

The Scripps Research Institute News

Solving The 175-Year- able to visualize biological complexes

Old Medical Mystery Of smaller than the diffraction limits
of light, and second, recent insights
Anesthesia’s Effects about the nature of cell membranes,
and the complex organization and
Billiard-Like Break Shot To Cell-Membrane function of the rich variety of lipid
Structures Triggers Brain’s Loss Of complexes that comprise them.

“They had been looking in a
Consciousness From Anesthesia, Scientists whole sea of lipids, and the signal got
Find washed out, they just didn’t see it, in
large part for a lack of technology,”
Surgery would be inconceivable without general Hansen says. dSTORM image of cell membrane exposed to chloraform
anesthesia, so it may come as a surprise that despite its From Order To Disorder
175-year history of medical use, doctors and scientists have Using Nobel Prize-winning microscopic technology, helps set a threshold, but is not the only pathway controlling
been unable to explain how anesthetics temporarily render specifically a microscope called dSTORM, short for anesthetic sensitivity,” they write.
patients unconscious. “direct stochastical optical reconstruction microscopy,” a Hansen and Lerner say the discoveries raise a host
A new study from Scripps Research published Thursday post-doctoral researcher in the Hansen lab bathed cells in of tantalizing new possibilities that may explain other
evening in the Proceedings of the National Academies chloroform and watched something like the opening break mysteries of the brain, including the molecular events that
of Sciences (PNAS) solves this longstanding medical shot of a game of billiards. Exposing the cells to chloroform lead us to fall asleep.
mystery. Using modern nanoscale microscopic techniques, strongly increased the diameter and area of cell membrane Lerner’s original 1997 hypothesis of the role of “lipid
plus clever experiments in living cells and fruit flies, the lipid clusters called GM1, Hansen explains. matrices” in signaling arose from his inquiries into the
scientists show how clusters of lipids in the cell membrane What he was looking at was a shift in the GM1 cluster’s biochemistry of sleep, and his discovery of a soporific lipid
serve as a missing go-between in a two-part mechanism. organization, a shift from a tightly packed ball to a disrupted he called oleamide. Hansen and Lerner’s collaboration in
Temporary exposure to anesthesia causes the lipid clusters mess, Hansen says. As it grew disordered, GM1 spilled its this arena continues.
to move from an ordered state, to a disordered one, and then contents, among them, an enzyme called phospholipase D2 “We think this is fundamental and foundational, but
back again, leading to a multitude of subsequent effects that (PLD2). there is a lot more work that needs to be done, and it needs
ultimately cause changes in consciousness. Tagging PLD2 with a fluorescent chemical, Hansen was to be done by a lot of people,” Hansen says.
The discovery by able to watch via the dSTORM microscope as PLD2 moved Lerner agrees.
chemist Richard Lerner, like a billiard ball away from its GM1 home and over to “People will begin to study this for everything you can
M.D., and molecular a different, less-preferred lipid cluster called PIP2. This imagine: Sleep, consciousness, all those related disorders,”
biologist Scott Hansen, activated key molecules within PIP2 clusters, among them, he says. “Ether was a gift that helps us understand the
Ph.D., settles a century- TREK1 potassium ion channels and their lipid activator, problem of consciousness. It has shined a light on a
old scientific debate, one phosphatidic acid (PA). The activation of TREK1 basically heretofore unrecognized pathway that the brain has clearly
that still simmers today: freezes neurons’ ability to fire, and thus leads to loss of evolved to control higher-order functions.”
Do anesthetics act directly consciousness, Hansen says. The paper, “Studies on the mechanism of general
on cell-membrane gates “The TREK1 potassium channels release potassium, and anesthesia,” appears May 29, in PNAS. In addition to
called ion channels, or that hyper-polarizes the nerve – it makes it more difficult Lerner and Hansen, the authors are Mahmud Arif Pavel, E.
do they somehow act on to fire – and just shuts it down,” Hansen says. Nicholas Petersen and Hao Wang, all of Scripps Research.
the membrane to signal Lerner insisted they validate the findings in a The work was supported by a Director’s New Innovator
cell changes in a new and living animal model. The common fruit fly, drosophila Award (DP2NS087943) and R01 (R01NS112534) from
unexpected way? It has Scott Hanson melanogaster, provided that data. Deleting PLD expression the National Institutes of Health, and a JPB Foundation
taken nearly five years of in the flies rendered them resistant to the effects of sedation. Grant, #1097. The Joseph B. Scheller and Rita P. Scheller
experiments, calls, debates and challenges to arrive at the In fact, they required double the exposure to the anesthetic Charitable Foundation have generously provided Petersen’s
conclusion that it’s a two-step process that begins in the to demonstrate the same response. graduate fellowship.
membrane, the duo says. The anesthetics perturb ordered “All flies eventually lost consciousness, suggesting PLD
lipid clusters within the cell membrane known as “lipid
rafts” to initiate the signal.
“We think there is little doubt that this novel pathway is
being used for other brain functions beyond consciousness,
enabling us to now chip away at additional mysteries of the
brain,” Lerner says.
Lerner, a member of the National Academy of Sciences,
is a former president of Scripps Research, and the founder
of Scripps Research’s Jupiter, Florida campus. Hansen is an
associate professor, in his first posting, at that same campus.
The Ether Dome
Ether’s ability to induce loss of consciousness was first
demonstrated on a tumor patient at Massachusetts General
Hospital in Boston in 1846, within a surgical theater that later
became known as “the Ether Dome.” So consequential was
the procedure that it was captured in a famous painting, First
Operation Under Ether, by Robert C. Hinckley. By 1899,
German pharmacologist Hans Horst Meyer, and then in 1901
British biologist Charles Ernest Overton, sagely concluded
that lipid solubility dictated the potency of such anesthetics.
Hansen recalls turning to a Google search while drafting
a grant submission to investigate further that historic
question, thinking he couldn’t be the only one convinced Get a second opinion on
of membrane lipid rafts’ role. To Hansen’s delight, he found
a figure from Lerner’s 1997 PNAS paper, “A hypothesis your financial health.
about the endogenous analogue of general anesthesia,” that
proposed just such a mechanism. Hansen had long looked
up to Lerner – literally. As a predoctoral student in San Schedule a complimentary, face-to-face
Diego, Hansen says he worked in a basement lab with a
window that looked directly out at Lerner’s parking space meeting with a Financial Advisor.
at Scripps Research.
“I contacted him, and I said, ‘You are never going to
believe this. Your 1997 figure was intuitively describing what Kevin Prazenica, AAMS® Terrence Burns, AAMS®, ChFC® Timothy Lynch
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Many other scientists, through a century of
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lacked several key elements, Hansen says: First, microscopes