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What can scientific experimentation on
undeuterated and deuterated isotopomers inform us
about the validity of the vibration and shape theories
of olfaction mechanics?

Abstract
There remains between biophysicists a contentious argument over the nature of olfaction; whether itis by
vibration or by shape. Here, by looking at studies between undeuterated and deuterated isotopomers, it will be
determined that although it is impossible to definitively prove by experimental means the vibrational theory of
olfaction, that itis the more valid of the two and that with a system of assisted electron tunnelling as proposed by
Luca Turin in a 2005 Ted Talk olfaction can be gradually pieced together by the human mind.

Introduction U bthot 4 1%, Pye Peog

For the last 60 years, human understanding of olfaction has been plagued by an‘uncertainty of the precise
mechanics behind it ever since shape theory was first introduced (Amoore, 1963), theorising that olfaction was a
od
product of “substrate/enzyme-like ies, ape (OR) interactions” (Block et a/., 2015). This was in ~
direct contrast to the previously thought vibration theo y, that was a product of the discovery of Pauli’s exclusion
principle (Pauli, 1925) and of the wave nature of electrons and Schrédinger's equation (Schrédinger, 1926),
originally proposed to be due to the infrared vibrational frequency of Van der Waals forces (Malcolm Dyson,
1938). Over time, both theories have been developed and expanded but the core of each remains the same. In
principle, experimental testing should be able to shed some lighton the validity of these theories; in particular, but
not limited to, testing undeuterated and deuterated (replacing one or more protium hydrogen atoms with
deuterium) isotopomers (an isotopic isomer such that it has same isotopic composition but a different isotopic
location leading to same exact mass). These should have altered frequencies of their vibrational modes but with
the same ground state conformation (Wade, 1999). Therefore if the shape theory were to be correct, both
molecules would smell identical: ifnot.then the vibration theory would be right as the difference in smell could be
explained by the different vibrational modes given off due to the difference in mass between the undeuterated
and deuterated isotopomers. y

_—
Experimental Results 44,26
ds that trained subjects could tell apart the
In 2013, an experiment performed by Simon Gane et alii}determined
scents of deuterated and undeuterated musks (base perfume scents) (Gane et al. 2013). The experiment was
carried out with 99% deuterated musks as it would be cheaper, require less work and reduce the production of
waste products. They chose their musks based on a set of criteria; it should be a molecule of high purity and
contain no double bonds leaving them with cyclopentadecanone, cyclopentadecanolide, 1,4-dioxa
cyclohepta decane-5,17-dione and 1-(3,5,5,6,8,8 -hexamethyl-6,7-dihydronaphthalen -2-yl) ethenone.
As figure 1 (below) shows, there is a clear separation of retention time, at A showing the purity of
deuteration.
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Figure 1: Figure 1: GC (gas chromatographed) and MS (mass spectrum) spectra of deuterated cyclopentadecanone

Results were obtained by asking each candidate whether the two musks had the same or different
smells. Each trial consisted of 10 samples of a deuterated molecule and 10 of the same undeuterated
molecule shaken in a box and then given to the subject, afterwards the sample was replaced then
shaken again to ensure a 50% chance of the scents being the same or different molecules. In the
table below the results can be seen. Here results range from 75% to 100% correct as can be seen by
binomial probability if they were all to be the same, the chance of this occurring would be miniscule.
Even the most likely probability is 10.94%, clearly suggesting that human ORs use molecular
vibrations to smell, explaining how they can differentiate between deuterated and undeuterated
isotopomers.

Subject MG LT KF KM NH cc AM cs JB ve AD
number 9 12 6 17 12 9 12 11 12 9 10
correct
number 10 12 8 17 12 12 13 12 12 12 12
of trials
binomial p 0.0097 0.0002 0.1094 7.00E-06 0.0002 0.0537 0.0016 0.0029 0.0002 0.0537 0.0161

Tests were halted when the subject reported fatigue. The binomial probability of the successes having arisen by chance is indicated at the bottom of each column. See
text for details of method.
doi:10.137 1/journal.pone,0055780.t002

Figure 2: Results of human discrimination tests between GC-pure deuterated and undeuterated acetophenone.

Discussion

The use of some trained evaluators here adds accuracy to the experiment as the samples were
smelt double blind where both deuterated and undeuterated molecules are smelt in succession from
the same source but with a gap between, therefore trained evaluators are required since they have
practiced memorising smell and the comparison of a smell with another. The addition of human
evaluators does add an element of human error but as this is a test primarily aimed at human
olfaction this cannot be avoided. All subjects whether trained or(not took’ “a standard University of
Pennsylvania Smell Identification Test [UPSIT] test and a Sino-Nasal Outcome Test [SNOT-22]
questionnaire to exclude obvious nasal disease” and to exclude those with bad sense of smell.
Unique labels were written on samples but only visible under UV light to not affect the judgment of the
subjects. Finally, the use of 11 distinct subjects and 132 tests further aids the accuracy of this test.
Furthermore, the greatest efforts were taken to avoid impurities such as by starting with commercial
fragrances, already purified to a high extent. In addition, GC purification was designed to only let the
peaks of each test through the machine so an impurity would have to electrical mobility of which there
is no evidence in NMR spectra.

Another interesting observation was that all the undeuterated musks smelt similar being described
as “sweet”, “oily” or “animalic” while the deuterated musks were described as “burnt”, “roasted”, “nutty”
or “toasted”. Therefore there was a clear difference between deuterated and undeuterated musks;
however it is interesting to note that all deuterated musks smelt similar and all the undeuterated
musks smelt similar. The proposed explanation is that as all the musks have many C-H bonds more
than the usual 19 bond limit at which molecules are odourless, for instance cyclopentadecanone has
28, that there are simply very few ORs for musks so fewer combinations of OR interactions for musks
and more similar scents. This is supported by the fact that one of the researchers was anosmic to the
smells of all the musks which would suggest that their musk ORs were lacking or not functioning; if
there were many musk ORs it would be highly improbable that one person were to be anosmic to
musks but not anything else. Therefore researchers proposed this explanation of vibrational olfaction
in terms of musks: that the molecule is so large that only one or a very limited number of ORs are
activated, one of which has to detect vibrations in the 1380-1550 cm-1 (reciprocal wavelengths) in
which the wagging and scissor modes of C-H bonds in musks have been known to be since their
precursors, nitro musks, were found to be in this range (Baur, 1891) and finally that the molecule has
intense bands whose vibrational modes are in the same range either few nitro groups or many CH2
groups.

In response to this paper, a group of researchers performing similar experiments (Block et al.,
2015) in term determined that the ability of humans to distinguish undeuterated and deuterated
cyclopentadecanone is not due to different vibrational modes but to impurities or perireceptor events
(Biochemical interactions between odorants and elements of the nasal mucus that odorants must
pass through before reaching the OR neurons (Pelosi, 1996)). This paper also cites that in other
mammals, notably mice, can differentiate non-pheromonal chiral odorant antiomeric pairs (pairs of
molecules which are mirror images of each other but cannot be superimposed on top of each other)
which have identical chemical properties but different shapes, clearly proposing that mice smell by an
enzyme-substrate like interaction with ORs determined by shape not vibrational modes (Rubin and
Katz, 2001; Laska and Shepherd, 2007; Rizvanovic, Amundin and Laska, 2013).

100;

90;

80,
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70;

604

50
1500 1000 600
4000 3000 2000 om- '

Figure 3: Superimposed IR spectra d30 (red) and undeuterated muscone (black) showing that d30 is devoid of IR absorption
in the 1380-1550 cm-1 region suggested by Simon Gane’s team

They followed a similar method to the previous study, including similar control measures but
discovered that human test subjects could not distinguish undeuterated and deuterated
cyclopentadecanone musks as suggested by Simon Gane’s team. However in response letter (Turin
et al., 2015) from the same researchers of the first paper, they reply that after running a t-test on the
primary data of Block et alii’s paper, they found a different response between two undeuterated and
 deuterated isotopomers, suggesting that Block et alii’s test was either caried out wrong or fixed to
obtain beneficial results.

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Figure 4: Difference in undeuterated and deuterated results from Block et alii's test after a t-test

Conclusion

In conclusion, though Simon Gane et alii's paper promises results favourable of the vibrational
theory of olfaction, they leave much to be desired. The results are of only a very narrow range of
musks and no shorter chain molecules were tested that may yet have different olfaction mechanics.
However, the proponents of shape theory present an even weaker agreement, having failed to
present actual, true results with instead only 2 out of 4 results showing the same scent, the
mechanics of human olfaction appear to be impossible to prove through experimental evidence; but
by simplifying the problem and treating it in a more philosophical manner other answers can be
gleaned. In a Ted Talk from 2005, Luca Turin (TED, 2005) describes two molecules (below) with
identical structures but for the substitution of an OH for an HS changing the smell from an alcoholic
one to one of rotten eggs.

CH,

HS

Figure 5: Cis-3-hexene-1-thiol, smells like rotten eggs Figure 6: Cis-3-hexene-1-ol, smells alcoholic

Turin cites this as the fundamental disproof of shape theory. Furthermore Turin narrates how, with
a computer program, one can find molecules with a very similar vibrational mode to a known one and
make accurate predictions about the smell. This, he had used to work for big brand perfumery
companies to find cheaper and higher yield alternative fragrances to the ones fundamentally used in
the industry. From this he has developed a model of vibrational olfaction, based upon assisted
electron tunnelling where an electron gives energy to a molecule with the right vibrational mode
corresponding to the loss of energy needed for the electron to jump down a gap and trigger a neuron
in a specific OR. The vibrational modes required for different ORs are different whence why we can
distinguish different smells.

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Figure 7: Assisted electron tunnelling in ORs

References

Amoore, J.E. (1963) ‘Stereochemical theory of olfaction’, Nature, 198(4877). Available at:
https://doi.org/10.1038/198271a0.

Baur, A. (1891) ‘Studien tiber den kiinstlichen Moschus’, Berichte der deutschen chemischen
Gesellschaft, 24(2). Available at: https://doi.org/10.1002/cber.189102402106.

Block, E. et al, (2015) ‘Implausibility of the vibrational theory of olfaction’, Proceedings of the
National Academy of Sciences of the United States of America, 112(21). Available at:
https://doi.org/10.1073/pnas.1503054112.

Gane, S. et al. (2013) ‘Molecular Vibration-Sensing Component in Human Olfaction’, PLoS ONE, 8(1).
Available at: https://doi.org/10.1371/journal.pone.0055780.

Laska, M. and Shepherd, G.M. (2007) ‘Olfactory discrimination ability of CD-1 mice for a large array of
enantiomers’, Neuroscience, 144(1). Available at:
https://doi.org/10.1016/j.neuroscience.2006.08.063.

Malcolm Dyson, G. (1938) ‘The scientific basis of odour’, Journal of the Society of Chemical Industry,
57(28). Available at: https://doi.org/10.1002/jctb.5000572802.

Pauli, W. (1925) ‘Uber den Zusammenhang des Abschlusses der Elektronengruppen im Atom mit der
Komplexstruktur der Spektren’, Zeitschrift fir Physik, 31(1). Available at:
https://doi.org/10.1007/BFO2980631.
Pelosi, P. (1996) ‘Perireceptor events in olfaction’, Journ
of Neurobiology.
al Available at:
https://doi.org/10.1002/(SICI)1097-4695(199605)30:1<3::AID-NEU2>3.0.CO;2-A.

Rizvanovic, A., Amundin, M. and Laska, M. (2013) ‘Olfactory discrimination ability of asian elephants
(Elephas maximus) for structurally related odorants’, Chemical Senses, 38(2). Available at:
https://doi.org/10.1093/chemse/bjs097.

Rubin, B.D. and Katz, L.C. (2001) ‘Spatial coding of enantiomers in the rat olfactory bulb’, Nature
Neuroscience, 4(4). Available at: https://doi.org/10.1038/85997.

Schrédinger, E. (1926) ‘An undulatory theory of the mechanics of atoms and molecules’, Physical
Review, 28(6). Available at: https://doi.org/10.1103/PhysRev.28.1049.

Turin, L. et al. (2015) ‘Plausibility of the vibrational theory of olfaction’, Proceedings of the National
Academy of Sciences of the United States of America. Available at:
https://doi.org/10.1073/pnas.1508035112.

Wade, D. (1999) ‘Deuterium isotope effects on noncovalent interactions between molecules’,

Chemico-Biological Interactions. Available at: https://doi.org/10.1016/S0009-2797(98)00097-0.

TED, 2005. The science of scent. [Online]

Available at: https://www.ted.com/talks/luca turin the science of scent
[Accessed 14 April 2023].