I love when I see smell research on Hacker News -- and hopefully I can provide a bit of context about this paper.
This finding recently made a big splash at AChemS 2021 (the annual meeting for the Association for Chemoreception Sciences). And it actually is a really big deal. A protein structure is extremely information rich, telling you where all of the atoms of a given protein are (ish). Before this finding, there were NO structures of any olfactory receptor, and historically the publication of the first structure of a given biomolecule has been a watershed moment for that field (insulin, ribosome, many other examples).
What's more, they used the structural information to rationally engineer their olfactory receptor, expanding the binding pocket and changing how the receptor responds to different odorants. That was pretty much impossible to do before this. So, this is a pretty huge finding, and will definitely encourage more structural work on olfactory receptors in the future.
If I had to poke a hole in this finding, it would be that insect olfactory receptors are substantially different from mammalian olfactory receptors. But in my opinion, it seems that the buzz about this paper is definitely justified. Very cool!
This paper is the first structure of any odorant receptor-ligand interaction. There's currently no equivalent structure for mammalian odorant receptors to validate the docking theory, but it's likely correct.
Question: does this put an end to Luca Turin's vibration theory?
I realize that this has long been considered crackpottery, and there has never been a reasonable sense of a mechanism for it. But it did seem to offer at least a stab at a couple of questions that didn't have good answers in the ordinary lock-and-key model of olfaction, such as why sulfur-containing molecules all smell "sulfury" if they all unlock different locks.
As far as I can tell the idea sorta just died out. A lot of work was done trying to make odor molecules with different isotopes, with intriguing but inconclusive results.
Still, I've been kinda curious to see if the theory was finally over and done.
This is truly a landmark study. This is the first structure of any odorant receptor. It is, however, one from an insect, so the structure is not homologous to mammalian olfactory receptors, which are a large family of G-protein-coupled receptors.
Forgive my ignorance, but I am wondering if this is all that different. GPCRs typically downstream towards ion channels, right? So even if insect physiology relies on ligand gated ion channels, is the end result the same, just more metabolically expensive in mammals?
Not really. GPCRs amplify signals at each step via their second messenger cascade. These channels form homotetramers whose structure differs greatly from the canonical seven transmembrane domain structure of GPCRs. So this study is important since there were no studies indicating how odorants bind and activate odorant receptors. However, it is unlikely that the mechanisms in insects odorant receptors will directly apply to those of mammalian odorant receptors. In contrast, mammalian odor receptors will work much more like those of other class A GPCRs like the β-adrenergic receptor, of which there are numerous structures interacting with ligands and in various configurations, and which was the basis of the work that won the nobel prize in 2012.
I wish we knew more on how covid messed them up and how to fix. Ever since I had covid my smell sensitivity is very low. I get really weird smells and tastes from food that sometimes make me sick.
If I understand correctly[1] covid messes with supporting cells and not the sensory neurons themselves and there is hope that this means that particular side effect should be temporary.
Unfortunately a new study (not yet peer reviewed) has just come out where they compared the brains of people before and after having covid, and they found "significant losses of grey matter surrounding the olfactory and gustatory system in those that had been infected with severe acute respiratory syndrome coronavirus." So there may actually be neurons involved in smell/taste loss, which isn't great news for the likelihood of these sensations coming back 100%. https://www.news-medical.net/news/20210618/Alarming-COVID-st...
The strange thing for me is that I lost the ability to taste citrus (I can still taste the acidity, but not what makes it good) but gained a heightened sensitivity to other things... I can taste the preservatives in bagged salads and it sucks.
Based on https://news.ycombinator.com/item?id=27570892 seeming reasonable to me, I’m inclined to believe the less sensationalized version of the paper than the breathless headlines that ran.
Probably we are looking at the neurological effects of functional smell loss. On average, this will result in a loss of cell mass in olfactory processing regions. There is no reason to believe this is permanent or something to be alarmed about. The brain is plastic, and it changes in response to use. Not being able to smell well will result in a reduction of resources put towards smell processing. Getting and recovering from covid is depressing (loss of smell is horrible and used to induce depression in mice), and that might explain the general brain-wide trend that's the cause of the breathless headlines.
Probably the olfactory loss continues to some degree for a long time. There may be some nerve damage even if the cells that are targeted by the virus aren't nerves. These then will take a long time to heal. Smells and memories of them seem fixed, but at least in mice, appear to be a flexible entity, with successive exposure to a particular smell causing different patterns of brain activity at every new exposure (https://www.theatlantic.com/science/archive/2021/06/the-brai...) "representational drift" is the key word. This particular system is highly regenerative. It can be damaged easily, and it can recover easily. Not to say that anyone should have to get COVID19.
Fascinating. The implicated gene family matches the subjective experience of the olfactory system damage. Specifically, it seems that while the smells are all "there" (presumably corresponding to intact olfactory neurons), odors associated with complex and toxic sources (e.g. various kinds of smoke) can overwhelm the olfactory system, resulting in a kind of noisy image. A hypothesis the support cells that should be helping to process the odorant molecules are reduced in number and/or efficiency after infection. Some people have more robust UDP glucuronosyltransferase gene copies, helping them to overcome this more easily. This might explain why nasal washes can help some.
You probably get into this in the preprint. I'll have a read before I prognosticate further!
It would be interesting to look at the gene family in the HPRC.
Very interesting! I remember this being an odd gap when I took an introduction to neuroscience course many years ago. Visual perception was well understood, auditory was fairly complete (although I remember there being some mystery around sound frequencies that are to fast to be encoded), and then smell was "We have some idea but its complex and not like the others. Some theories may involve quantum mechanics".
Reasonable, given the title, but as someone who had no idea how smell receptors work, I thought it was neat.
The nut:
> [T]he limited repertoire of receptors on its olfactory sensory neurons must somehow recognize a vast number of compounds. So an individual receptor has to be able to respond to many diverse, seemingly unrelated odor molecules.
> That versatility is at odds with the traditional lock-and-key model governing how selective chemical interactions tend to work. [....]
> Now, new work has taken a crucial and much anticipated step forward in elucidating the beginning stages of the olfactory process. In a preprint posted online earlier this year, a team of researchers at Rockefeller University in New York provided the first molecular view of an olfactory receptor as it bound to an odor molecule.
This finding recently made a big splash at AChemS 2021 (the annual meeting for the Association for Chemoreception Sciences). And it actually is a really big deal. A protein structure is extremely information rich, telling you where all of the atoms of a given protein are (ish). Before this finding, there were NO structures of any olfactory receptor, and historically the publication of the first structure of a given biomolecule has been a watershed moment for that field (insulin, ribosome, many other examples).
What's more, they used the structural information to rationally engineer their olfactory receptor, expanding the binding pocket and changing how the receptor responds to different odorants. That was pretty much impossible to do before this. So, this is a pretty huge finding, and will definitely encourage more structural work on olfactory receptors in the future.
If I had to poke a hole in this finding, it would be that insect olfactory receptors are substantially different from mammalian olfactory receptors. But in my opinion, it seems that the buzz about this paper is definitely justified. Very cool!