ELECTRON-SPIN CLUE TO HOW GENERAL ANESTHESIA WORKS
August 19, 2014
So, what’s the point?
You don’t need to be a brain surgeon (or even an anesthetist) to work out that anesthesia plays a crucial role in modern medicine. Local anesthesia are used toreduce or remove sensation in a particular area so that a medical procedure can be done without causing the patient pain.
General anesthesia, on the other hand, does much more: it is actually an induced coma, intended to not only render a patient unconscious and unfeeling, but also relaxation of the muscles and the automatic reactions of the body (such as heart rate, breathing, sweating etc.).
But precisely how GAs work is a bit of a mystery, and the fact hat such a wide range of chemicals from xenon gas(which is just single atoms) to 3-hydroxypregnane-11,20-dione (a complex neurosteroid of 56 atoms) can induce the same type of response in organisms is very strange.
The authors of the paper call it ‘baffling’, and that ‘the range of compounds capable of acting as GAs makes no pharmacological sense’ (which is obviously comforting if you’re just about to go under the knife).
Solving this mystery will not just bring closure (and sanity) to a niche group of GA specialists, a better understanding of how it works could help improve the effectiveness and safety of current anesthetics as well as identifying new ones.
What did they do?
The researchers ran tests on fruit flies (Drosophila, a scientific favourite!) placed in a cold tube (kept at 6oC by nitrogen gas) so they wouldn’t move. Some of the flies were genetically mutated to be resistant to anesthetics (6 different mutants were tested).
All of the flies produce a group of pigment proteins calledmelanins (which are also responsible for skin colour in humans). Melanins contain lots of unpaired electrons which can be excited into a higher-energy spin-state by magnetic fields.
Unpaired electrons in the higher-energy spin states will sometimes spontaneously drop back to the lower-energy state, emitting radio-frequency (RF) signals as they do so. By subjecting the flies to a magnetic field, the unpaired electrons in the flies will be excited and will emit RF signals which can be measured.
This is a similar principle to MRi scanners, which excite the protons in hydrogen atoms (rather than electrons) and compare the different radio frequency signals emitted from various parts of the body in order to tell apart different types of tissue.
In this case, the scientists wanted to see if general anesthetics affected the electron spin properties of proteins in the flies. If it did, then it could explain how different types of GAs could all have similar biochemical effects, despite being different from one-another chemically.
They subjected different sets of flies (normal and anesthetic-resistant) to four different types of gaseous GA while measuring how their electron spin properties changed over time.
Did they prove anything?
They found that, of the four GAs tested on the wild-type (non-mutant) flies, N2O (laughing gas) had no effect on the electron spin, xenon had a small effect, SF6 had a significant effect and chloroform had an irreversible effect (electron spin did not return back to normal within the timescale of the experiment).
Weirdly, N2O did affect two of the mutants, while another two were unaffected by chloroform. The fact that the wild-type and different mutants exhibit significant changes in their electron spins in response to the same anesthetic suggests that the anesthetics do have some sort of effect on the movement of electrons in some biochemical processes.
The scientists suggest that GAs could change the shapes of highest-occupied molecular orbitals (HOMOs) in proteins. HOMOs are basically shapes that estimate the regions on the molecule where you are most likely to find the electrons which can participate in chemical reactions.
Obviously if these shapes change, the ability of the protein to react or otherwise interact with other proteins will also be altered.
To test this, the team ran computer simulations on a variety of known anesthetics, claiming that all of them changed the shape of HOMOs in the generic proteins and extend the HOMOs into the anesthetic molecule itself, while two non-anesthetic gases did not.
So, what does it mean?
This is a really interesting theory, but one which appears quite a long way from being proven.
This research only covers one type of organism and only tests four anesthetics, all of which are relatively small molecules. The researchers suggest that future tests on mice (which can be given liquid anesthetics rather than gas), yeasts and nematode worms.
Another issue is that in some of the flies, no real difference in electron-spin was detected even though the anesthetics are believed to have worked. It could well be that in these cases the anesthetics affected proteins which didn’t have many unpaired electrons (so didn’t register a significant electron excitation), but this would need to be proven.
Understanding precisely which proteins are involved in anesthetic resistance would help, but unfortunately, while one mutant was known to have a defective ion channel (a protein which helps certain charged-particles to enter/leave a cell), the genes which conveyed anesthetic-resistance to the other 5 mutants were unknown.
But their computer simulations do reveal a possible action of how a wide range of anesthetics could elicit similar responses in biochemicals, but obviously this model was for a generic protein. Until actual proteins which are acted on by the anesthetics can be identified this will remain a mystery.
Original article in PNAS Aug 2014
All images are open-source/Creative Commons licence.Credit: CDSG (First); Astrochemist (Second); L Turin et al. (Third); L Turin et al. annotated by TSiC (Fourth); A Karwath (Fifth)