Surgery would be inconceivable without general anaesthesia, so it may come as a surprise that despite its 175-year history of medical use, doctors and scientists have been unable to explain how anaesthetics temporarily render patients unconscious.
A new study from Scripps Research published recently in the Proceedings of the National Academies of Sciences (PNAS) solves this longstanding medical mystery. Using modern nanoscale microscopic techniques, plus clever experiments in living cells and fruit flies, the scientists show how clusters of lipids in the cell membrane serve as a missing go-between in a two-part mechanism. Temporary exposure to anaesthesia causes the lipid clusters to move from an ordered state, to a disordered one, and then back again, leading to a multitude of subsequent effects that ultimately cause changes in consciousness.
The discovery by chemist Richard Lerner, MD, and molecular biologist Scott Hansen, PhD, settles a century-old scientific debate, one that still simmers today: Do anaesthetics act directly on cell-membrane gates called ion channels, or do they somehow act on the membrane to signal cell changes in a new and unexpected way? It has taken nearly five years of experiments, calls, debates and challenges to arrive at the conclusion that it’s a two-step process that begins in the membrane, the duo say. The anaesthetics perturb ordered 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.
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 of membrane lipid rafts’ role. To Hansen’s delight, he found a figure from Lerner’s 1997 PNAS paper, “A hypothesis about the endogenous analogue of general anaesthesia,” that proposed just such a mechanism. Hansen had long looked up to Lerner – literally. As a predoctoral student in San Diego, Hansen says he worked in a basement lab with a window that looked directly out at Lerner’s parking space at Scripps Research.
“I contacted him, and I said, ‘You are never going to believe this. Your 1997 figure was intuitively describing what I am seeing in our data right now,'” Hansen recalls. “It was brilliant.”
For Lerner, it was an exciting moment as well.
“This is the granddaddy of medical mysteries,” Lerner says. “When I was in medical school at Stanford, this was the one problem I wanted to solve. Anaesthesia was of such practical importance I couldn’t believe we didn’t know how all of these anaesthetics could cause people to lose consciousness.”
Many other scientists, through a century of experimentation, had sought the same answers, but they lacked several key elements, Hansen says: First, microscopes able to visualise biological complexes smaller than the diffraction limits of light, and second, recent insights about the nature of cell membranes, and the complex organisation and function of the rich variety of lipid complexes that comprise them.
“They had been looking in a whole sea of lipids, and the signal got washed out, they just didn’t see it, in large part for a lack of technology,” Hansen says.
Using Nobel Prize-winning microscopic technology, specifically a microscope called dSTORM, short for “direct stochastical optical reconstruction microscopy,” a post-doctoral researcher in the Hansen lab bathed cells in chloroform and watched something like the opening break shot of a game of billiard