Smell your way to a cure

In our daily lives, we come across millions of sensory stimuli that we don’t have to actively think about to interpret. But since when did our reactions to these stimuli become so automatic or instinctive? What makes one person despise the smell of cheese but one person love the smell? These questions, and many like them, will hopefully be fully answered in the future, but as a starting point, Dr. Timothy Bozza has researched an extensive amount, especially in regards to the function and significance of the TAAR receptors in the olfactory system. His research has examined two main potential functions: 1. TAARs being used as high affinity amine receptors (maybe even the most sensitive of the olfactory receptors for detecting amines) 2. TAARs potentially working with the very circuits that drive innate behaviors such as with the aversive behavior mice have towards PEA.

First, to figure out if the TAARs are the receptors with the highest affinity towards amines, Dr. bozza and his research team used TAAR cluster deletion through in vivo transallelic recombination to create a deletion allele that would in turn get rid of the TAAR cluster. Through this deletion method, the team would be able to determine a potential function of the TAARs based on what functions were lesser in function after the deletion. And the results did not disappoint. As hypothesized, Dr. Bozza was able to see that after the deletion of the TAAR cluster, the high sensitivity amine responses were gone because the glomeruli were not active. However, because the research team was unable to view the all parts of the glomeruli, concrete conclusions were unable to be made about this hypothesis.

Thus, Dr. Bozza and his research team developed an experimental method that could generate more concrete conclusions for the first hypothesis. They used an odor detection device to ask the mice if they smelled the odor or not. With the elimination of the TAAR cluster, they saw a 50 fold decrease in the sensitivity towards phenylethylamine and while with the wild type as the concentration of the odor increased, the performance also increased, the experimental group with the deleted TAARs needed an even higher concentration to match the performance of the wild type. Isopentylamine was also examined and showed similar results in that the mice with the deleted TAARs were less sensitive towards the isopentylamine. Thus, from this study, Dr. Bozza and his research team was able to confirm that TAARs are key to determining the detection thresholds for amines.

Following, Dr. Bozza also looked at how the deletion of a single TAAR would affect the detection threshold. The team deleted TAAR4 and from this they saw a decrease in the response to phenylethylamine in the dorsal bulb which is similar to the result they saw in the aforementioned experiment. Thus, from this study, they were able to conclude that for a single receptor can indeed have a significant impact on the detection of a single odor like in the case of PEA.

Next, Dr. Bozza and his team designed studies to test out the second hypothesis which relates TAARs to circuits that drive innate behaviors. Here, the focused on PEA which is a TAAR4 ligand that is present in carnivore/predator urine. They chose PEA specifically because mice have an innate aversive response to PEA. A place preference assay where in one chamber, there was odor and in one there was water, was done where the preference index was evaluated. From the deletion of the TAAR cluster, PEA was no longer aversive and this result was seen in IPA, NMP, CAD, and the natural stimulus Puma as well. Thus, the study revealed that the deletion of all TAARs stops the aversion towards amines.

Furthermore, Dr. Bozza and his team also examined the effects of deleting just the TAAR4 and from this study, they were able to conclude that the deletion of TAAR4 causes the abolishing of aversion for specific amines such as PEA and predator urines. For the other amines, the aversion remained for the most part. Therefore, looking at the grand scheme, the team was able to infer that the deletion of a single TAAR gene could influence different odor guided behaviors. From just these the studies conducted by Dr. Bozza, it is clear that the olfactory system has a great influence on much of our body responses and behaviors, thus, to expand a bit from this idea, we can examine an interesting find on the influence of olfactory receptors on a potential treatment option for patients suffering from Leukemia.

In research study conducted by Professor Hanns Hatt from the Ruhr-Universität Bochum, it was demonstrated that olfactory receptors were not only present in the nose but also in “white blood cells in humans” (Olfactory receptors in the blood). The research team were able to specify which olfactory receptor was involved with the white blood cells and it turned out to be the OR2AT4 receptor. This receptor was found to be activated by Sandalore which is not a natural but an odorant synthetically developed with a sandalwood odor. Through the activation of the O42AT4 receptor, researchers found that it caused a halt to the growth of leukemia cell growth as well as the death of the leukemia cells as well. Thus, because of this shrinking value in leukemia cell growth, the researchers were able to see an increased in the red blood cell count, a positive for patients affected with Leukemia.

For the specifics on the signaling pathways regarding the OR2AT4 receptor, we can look at the model relationship of the nose and its olfactory cells. Through the activation of the OR2AT5 receptor by Sandalore, the calcium ion concentration in the human blood cells will increase which will then activate signaling pathways. These signaling pathways will cause the phosphorylation of specific enzymes, specifically the MAP kinases and the process moves on from there with regulation. (Olfactory receptors in the blood)So far, there have been seven olfactory receptors in the blood cells that have been found, Professor Hatt and the research team are continuously working to untangle the mystery behind the relationship between the olfactory receptors and the cell, for example, currently, they are looking at another receptor that is activated by isononyl alcohol. Thus, while the exact details on the potential for the OR2AT4 receptor to help with treatment of Leukemia have not been all worked out, the fact that there is this potential for a much-needed treatment option is a sign we are headed in the right direction. 

Works Cited

 Figure 3: Sandalore Increases the Intracellular Ca2+ in the White Blood Cells of AML Patients. Digital image. Nature.com. Nature Publishing Group, 25 Jan. 2016. Web. 4 Mar. 2016. <http://www.nature.com/articles/cddiscovery201570/figures/3>.

Pacifico et al., An Olfactory Subsystem that Mediates High-Sensitivity Detection of Volatile Amines, Cell Reports (2012), http://dx.doi.org/10.1016/j.celrep.2012.06.006

"Olfactory Receptors in the Blood." EurekAlert! American Association for the Advancement of Science, 1 Feb. 2016. Web. 05 Mar. 2016. < http://www.eurekalert.org/pub_releases/2016-02/rb-ori020116.php>.