Tuesday, July 26, 2022

Avery Gilbert and the Terpene Revolution

He's calling the terpene revolution "the nucleus of the brand new field of cannabis psychophysics" (First Nerve, Feb 2021) and I can't argue because he is the first, and when you're the first, you get to name things.

Here's a quick run-down of Avery Gilbert's work circa terpenes since 2018. (Note that he was the first person to get federal approval for olfactory research on pot.)

Consumer perceptions of strain differences in Cannabis aroma, Feb 2018

The smell of marijuana (Cannabis sativa L.) is of interest to users, growers, plant breeders, law enforcement and, increasingly, to state-licensed retail businesses. The numerous varieties and strains of Cannabis produce strikingly different scents but to date there have been few, if any, attempts to quantify these olfactory profiles directly. Using standard sensory evaluation techniques with untrained consumers we have validated a preliminary olfactory lexicon for dried cannabis flower, and characterized the aroma profile of eleven strains sold in the legal recreational market in Colorado. We show that consumers perceive differences among strains, that the strains form distinct clusters based on odor similarity, and that strain aroma profiles are linked to perceptions of potency, price, and smoking interest.

Use of rating scales versus check-all-that-apply ballots in quantifying strain-specific Cannabis aroma, March 2019

Previous research using a check-all-that-apply (CATA) method to describe the strain-specific aroma of dried Cannabis flower revealed two major clusters, one characterized as woody, earthy, herbal and the other as citrus, lemon, sweet, and pungent. In this study, participants rated 10 strains (including seven strains not previously tested) using numeric rating scales and a slightly smaller set of odor descriptors. The results confirm the two major scent clusters, and indicate a possible intermediate cluster differentiated by a skunk note. We observed systematic variation in the use of descriptors and rating scales: evaluators who used more odor descriptors tended to assign higher scale ratings. Nevertheless, the CATA and rating scale methods yielded similar results.

Human olfactory detection of packaged cannabis, March 2020

Olfactory detection of cannabis aroma by police officers can be the basis for warrantless searches of motor vehicles in many jurisdictions in the United States. The odor source in these cases is often dried cannabis flower contained in various casual wrappings as well as in more elaborate packaging. Here we investigate whether packaging format alters the detectability of the cannabis. Two cannabis strains and five packaging formats were evaluated. Untrained observers were presented with two containers and asked to identify, based only on smell, the container that held a sample of packaged cannabis (the other container held identical, but empty, packaging material). The results showed that open and casually packaged cannabis was identified with high accuracy, while material packaged in doubly vacuum-sealed plastic was correctly identified at rates no different from chance. The results may help address issues involving the detectability of cannabis aroma in law enforcement and other scenarios.

Tuesday, July 19, 2022

Neural Waves Ahoy

We're getting a lot of amazing brain data from epilepsy science these days (like the first evidence of brain death under EEG). 

Because epilepsy patients undergo an entire week of EEG monitoring prior to treatment (so the doctors can "get familiar with" their brainwaves), other scientists ask to bother them with experiments that have nothing to do with epilepsy. Like olfaction experiments. So the patients volunteer to have the data from their brainwave monitoring used by researchers while they squirt smell molecules at their face. 

Olfactory processing in three distinct neural waves
Feb 2022, phys.org

Now we ask whether different oscillations represent distinct features of an odor, or if different odors are represented by different oscillations," Zelano said

They're talking about neural oscillations. 

Neurons in visual and auditory systems usually operate at a background hum of excitability, but when the brain is trying to see or hear something, these neurons are activated in sync.

But the olfactory cortex is hard to study because it's literally in the center of the brain (and that's because it is like the seed from which our big ass brain grew out of). Brainwaves can be detected non-invasively, so that's great. 

The low-frequency oscillations, termed theta waves, begin immediately after a volunteer sniffed and ended immediately afterwards. Theta waves were followed by two more sets of waves, beta (about 12-30 Hz) and gamma waves (above 30 Hz).

This raises the possibility of a two-step process, where the low-frequency waves "prime" the olfactory cortex and the high-frequency waves are responsible for olfactory processing.

"Low-frequency waves are used for communications between brain regions and high frequency oscillation is more involved in local computations, but it's very exciting to find a low-frequency oscillation motivating a high-frequency oscillation," said Guangyu Zhou, Ph.D., research assistant professor of Neurology and a co-corresponding author of the study.

Oh but this part is even better:

Further, the strength of the high-frequency waves was associated with volunteers' ability to correctly identify odors.

"This implies the higher-frequency oscillations are required to actually distinguish the odor one is smelling," Qiaohan Yang, MS, student in the Northwestern Interdepartmental Neuroscience Program (NUIN) and lead author of the study.

via Northwestern University's Comprehensive Epilepsy Center: Qiaohan Yang et al, Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity, PLOS Biology (2022). DOI: 10.1371/journal.pbio.3001509

Post Script, On Epilepsy:
Who knew that treating epilepsy would lead to such novel discoveries? Why is C. elegans or D. melonigaster so important for specific things, or how is the naming of the limbic system itself a kind of word-monster that grew out of our heavy reliance on rats during the concurrent explosion of olfactory science in the Behavioral era, and rats have a brain that is dominated by olfaction, and it basically controls the movements of their body, hence their limbs, and so the olfactory system was called the limbic system. Why rats? Why fruitflies? Why epilepsy? 

Life may actually flash before your eyes on death
Feb 2022, BBC News

First-ever recording of a dying brain discovered by accident. 

"This was actually totally by chance, we did not plan to do this experiment or record these signals."

This is also one of the reasons why it is important to care for every human equally, regardless of what happened to them. You're born without an immune system? We're keeping you alive as long as we can. Paraplegic? We're giving you wifi for your body

You have epilepsy? We're going to slap some electrodes to your head and monitor your brainwaves for a really, really long time, and figure out how to help you. Unless you have a heart attack in the headset, in which case we'll watch what happens, and use your accident to further the advancement of science. 

via Department of Neurosurgery, Henan Provincial People’s Hospital, Division of Neurosurgery, Vancouver General Hospital: Vicente Raul et al. Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain. Frontiers in Aging Neuroscience 14 2022. DOI: 10.3389/fnagi.2022.813531.

Why C. elegans? They have only 302 neurons, that's why.

Tuesday, July 12, 2022

What Have We Become

It appears that we could be evolving to better tolerate each other's body odor by having our noses become less sensitive to that smell over time. And the guy in the picture above has been "evolved" to withstand a car crash.

Humans and other primates have evolved less sensitive noses
Feb 2022, phys.org

The purpose of this study was to see if the genetics for smell remain constant across people from different backgrounds other than the Caucasians typically studied. 

The results showed that yes, they do, but also something unexpected.

"People with the ancestral versions of the scent receptors tend to rate the corresponding odor as more intense." And in opposition, the "newer" versions of those receptors lead to people having less intense odor detection capacity. And this suggests that we are evolving to be less sensitive to odors. 

In order to test their hypothesis, they used odors that were already known to be variable in the ways people perceive them. For example, some smells are very intense to some people but barely perceptible to others. Some of this is because of genetic variations in the way the receptor works. 

An interesting aside in the discussion -- "OR51B2 variation drives differences in the perception of human body odor component 3-methyl-2-hexenoic acid (3M2H) ... which could be a target for future studies interested in malodor blocking, or discovering the mechanisms underlying social communication from body odor."

Back to the big part of this study, which is the unexpected part (always the favorite part of any scientific endeavor). They measured the "age" of these genes, and found that the "newer" genes were less sensitive to intensity, and refer to this as "Degeneration of olfactory receptor gene repertoires in primates."

Image credit: Graham is designed to survive a car crash, Victoria’s Transport Accident Commission, 2016. Designed by Melbourne sculptor Patricia Piccinini, Royal Melbourne hospital trauma surgeon Christian Kenfield, and crash investigator at Monash University’s accident research centre David Logan.

Large genetic databases can be used to understand OR function, a proxy for general protein function.

In the discovery study, we may have the benefit of measuring olfactory phenotypes in a large, homogenous cohort (Fig 1) where genome-wide genotyping had already been conducted, giving us the statistical power of a large population without the time or expense. In this study, the novel signals do not have much population differences in MAF or effect size (Table 1 and Figs 3 and 4), suggesting that the large sample size rather than its genetic similarity might be the more important reason behind the findings. Given the increasing number of open databases of sequencing data, this method is becoming a more reasonable possibility for easily testing genotype/phenotype associations.

Olfaction is an excellent use of this new resource because of the ease of understanding the functional output of genetic variation in the protein. 
The human olfactory system has both robust assays to test the behavioral output of these proteins (psychophysics/rating odors) [5,6,10] and an established method for directly testing protein function in cells (heterologous cell-based assay) [42,43]. Genetic variation provides a strong tool for exploring olfactory coding and sheds light on how complex systems integrate information from variable sensors.

via Chinese Academy of Sciences Key Laboratory of Computational Biology at Shanghai Institute of Nutrition and Health, Monell Chemical Senses Center, Department of Neuroscience at University of Pennsylvania, and Sanghani Center for Artificial Intelligence and Data Analytics at Virginia Tech:  Li B, Kamarck ML, Peng Q, Lim F-L, Keller A, Smeets MAM, et al. (2022) From musk to body odor: Decoding olfaction through genetic variation. PLoS Genet 18(1): e1009564. doi.org/10.1371/journal.pgen.1009564

Some interesting facts about the variation of olfactory perception among populations, most of which was already known, but now confirmed for a more diverse population that includes Han Chinese:
  • Galaxide, a Musk molecule: Individuals can have specific anosmias to one or some, but not all musks, suggesting that there is not a single common coding mechanism.
  • Trans-3-methyl-2-hexenoic acid (3M2H), a Body Odor molecule: Almost 25% of the population has a specific anosmia to 3M2H [23–26], but this anosmia has not been connected to any olfactory receptor.
  • Aldehydes: Self-reported Asian populations rate aldehydes as more intense than Caucasian populations, but no specific genetic variants or receptors have been implicated. 

These are the receptors studied and their effects:
  • OR4D6 M263T and S151T ^ Galaxolide intensity
  • OR51B2 L134F ^ 3M2H intensity
  • OR5A1 D183N ^ β-ionone pleasantness (for the validation cohort and the meta-analysis, but not the discovery cohort)
  • OR7D4 R88W and T133M ^ Androstenone intensity and pleasantness (in the discovery cohort, for the validation cohort, only pleasantness)
  • OR2J3 T113A ^ Cis-3-hexen-1-ol intensity
  • OR1A1 =/= Caproic acid (although rs17762735 was associated with intensity in the validation study, the effect was in the opposite direction from the literature; there were no associations for 
  • pleasantness)
  • Aldehyde - There were no associations with aldehyde intensity or pleasantness 

On Body Odor:
3-methyl-2-hexenoic acid (3M2H) is also referred to as caproic acid, and as having a "hircine" odor, both of which refer to goats, because it smells like goats. Which means you smell like goats when you're hot and nervous and not wearing deodorant (although less likely if you're of Asian descent for whom one gene changes the production of body odor). Body odor in general is often characterized by thiolalcohols, which have sulfur molecules in them, although this one in particular doesn't have any sulfur in it. 

Related Post:
Social Deodorization

Tuesday, July 5, 2022

Fruit Flies Forever

Human sense of smell resembles that of insects
Oct 2021, phys.org

Good, because we would really like to use insect antennae to better understand human olfaction. They're easier to do experiments on, because their system is more simple than ours in many ways. Also good because the fruit fly is where so much smell science comes from.

They modeled the brain of a cotton bollworm so they could inspect its operations, and found they're a pretty good match for humans (minus the phermomones, of course). This is good for helping us understand the inner-workings of a robust neural network, or should we call it the prototypical, the primordial neural network: 

"We find striking similarities in the structure and function of the olfactory system across different organisms," says Xi Chu, a researcher in NTNU's Department of Psychology and senior author of the new publication. The similarities are probably related to the fact that the olfactory system is evolutionarily the oldest of all sensory systems. ... "It's worth noting that the primary olfactory center in the mammalian brain is located only one synapse away from the outside world," says Dr. Chu. "This means that the incoming information goes directly into the primary olfactory cortex, unlike all other sensory signals, which travel through a different brain structure before dispersing to their respective cortical areas. -Steinar Brandslet, medicalxpress

via Norwegian University of Science and Technology's Chemosensory Lab: Jonas Hansen Kymre et al, Distinct protocerebral neuropils associated with attractive and aversive female-produced odorants in the male moth brain, eLife (2021). DOI: 10.7554/eLife.65683

Image credit: Antenna of a male moth by Dr. Igor Siwanowicz at the Howard Hughes Medical Institute in Virginia for the 2015 Nikon Small World Photomicrography Competition [link]

Post Script:
Mapping the olfactory system in fruit flies
Feb 2022, phys.org

They describe the fly's olfactory system as having "the ability to make quick assessments of odors in an unusual way that circumvents synaptic communication, which is metabolically expensive."

They have created a map of receptors based on variations in the functionality of the molecules, but with one extra step -- the activation-inhibition dynamic at the neuron level.

This is a feature of the olfactory system that has been researched a lot lately (see this post for example). It also sounds like the model for neuromorphic processor systems, where the advanced processing via a dedicated cortex is eschewed for a complexity-based, emergent phenomenon at the neuron level.

via University of California - San Diego: Shiuan-Tze Wu et al, Valence opponency in peripheral olfactory processing, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2120134119