We perceive the world around us through colors, sounds, geometric patterns, and smells. Although various theories and models have been proposed to explain how the senses are processed in the brain as sight, sound, and smell, we are still in the infancy stage of understanding these magnificent senses that God has gifted to animals and humans.

There are two types of photoreceptors in our eyes, which are in the form of rods and cones. These receptors are equipped with the ability to perceive certain wavelengths of vibrations in the outside world as light and color. They are sensitive to colors and to differences between black and white. The hundreds of color tones perceived by the cone cells reveal themselves by combinations of different wavelengths of red, green, and blue light.

Hearing receptors located in the inner ear are stimulated according to the frequency and volume of sounds, similar to the logic of vibrating strings of different lengths in an instrument and are perceived as sound in the brain. In the olfactory sense, there are about 400 different receptors.

Before the sense of smell occurs in the brain, an extremely complex decoding system operates within millions of odor molecules. It is not yet known how the signals from these receptor cells are brought together to trigger a particular sense of smell. If the codes of smell can be decoded, it may be possible to understand how animals find mates, offspring and food, and how molecular regulation is involved in understanding emotions, stress, appetite, and mood.

One of the biggest problems in understanding odor is that there is not always a relationship between the chemical structure of a molecule and the smell that is sensed. Two chemicals with very similar structures can smell very different, or two very different chemical structures can be perceived as almost the same odor. Often, fragrances are not a single substance, but a mixture of tens or hundreds of aromatic (odor-producing) molecules. For example, the smell of coffee or fermented cheese consists of a mixture of dozens of different proteins, fats, vitamins, and carbohydrates.

In this complex structure, the question is how a certain molecule gets in contact with other molecules to produce a common odor pattern. When you look at the tastes of three or four different types of pears or apples, the smell is different, as is the flavor of each one. When we isolate each of the minerals, organic and inorganic compounds in the structure of the apple, the smell they will produce individually is very different from the smell they will produce together. The fact that each of the apple types exhibits a different smell is related to the amounts and combinations of substances it has, but we do not know much about how this happens.

It is more or less understood how the two types of receptor cells in the human eye respond to light and the chemical processes involved in their operation. But it's unclear how signals from 400 different kinds of olfactory receptors come together to trigger a particular sense of smell. Also, because working with the proteins in the membranes of these receptors is a difficult task, what these membrane proteins look like and how they work is based on guesswork. However, thanks to the developments in the field of computers and artificial intelligence in data analysis, we can hope that there will be more progress soon in decoding odors and the fine architecture of biological structures.

In a study published in Nature, thousands of scents were introduced to a panel of people and to an AI system. “Using the structure of these molecules alone, the AI algorithm did well at predicting the smell of compounds compared with the average group assessments …, and it performed better than the typical individual sniffer.” One thing that can be deduced here could be that smelling is a subjective experience. Artificial intelligence, on the other hand, is man-made and does not have a soul, and is also deprived of the experiences that people encounter throughout their lives. Thus, it has been successful in dividing odors into groups more accurately in the predictions it makes by looking only at the codes of the molecular structures uploaded to the computer [1].

An arcane password

There are millions of olfactory neurons in the nose. They are created as the biological hardware used for sensing smells, and each typically carries only one type of olfactory receptor. The group of genes encoding them was discovered in the early 1990s, a discovery that was awarded with the Nobel Prize [2]. Each of these receptor types can recognize one or more odors, and each odor can also be recognized by multiple receptors. Therefore, it has been calculated that millions of neurons connected to 400 different types of olfactory receptors will respond to approximately one trillion chemical odor substances with the combination they will make together. Aashish Manglik, a biochemist at the University of California, San Francisco, argues that this system is incredibly perfect and flexible, and that this is the only way to understand the incredibly diverse chemistry of nature.

An important step in decoding odors will be to understand what these olfactory receptors look like and how they recognize chemicals. However, according to Manglik, these proteins, which are located in the membranes of the recipient cell, are very difficult to decipher, because it has not yet been possible to produce and isolate enough proteins to be analyzed.

Some of the scientists who study the subject of smell on insects have figured out the structure of the receptors that insects use to smell [3]. However, although the olfactory receptors in insects appear to be completely different from those in mammals, it is estimated that the working logic is the same [4].

Recently, two more receptor cells in the olfactory system of mice were deconstructed, and it was found that both of these receptor types detect clearly bad odors, such as the smell of fish or rot, which are the main components of common body odors in many animals [5, 6].

One research team succeeded in imaging for the first time in an electron microscope how a protein in a human odor receptor binds to an odorant molecule. It was seen how propionate, the cause of a pungent cheese smell, enters and binds to a pocket on the receptor, then changes the shape of the receptor and transmits information. Still, the exact nature of this occurrence is not understood [7].

Although the researchers are very excited, they are also aware that solving just one of the hundreds of receptors that detect odor substances will not yet say much.

They later saw that two separate compounds, both of which smelled of menthol, bound to the receptor at different places. They think that different odors probably bind to a single receptor in different places, triggering different events. This helps explain the level of complexity in scent codes. It can explain why two different chemicals can have similar odors, or why chemically similar compounds can smell so different. For example, the two types of carvone compound have the same structure as the mirror image of each other, but while one of them is perceived as the smell of mint, the other smells as cumin or dill. The mystery of this is hidden in these olfactory receptors. Efforts to unravel this mystery continue; our findings so far can be compared to a few drops of water from the ocean of God’s infinite knowledge. Meanwhile, with the help of techniques such as machine learning and artificial intelligence, odor molecules that bind to 20% of the olfactory receptors in humans have been identified. During the studies, they scanned millions of compounds to figure out which molecules would bind to the two receptors and found that one of these receptors was tuned to the smell of orange blossom and the other to the smell of honey [8].

Nose-brain connection

When a molecule of an odor attaches to the receptor cell and is processed, the resulting molecular information goes to a brain region called the olfactory bulb, which is located behind the bridge of the nose, and from there to the olfactory cortex in the brain. This olfactory cortex is much more mysterious. Research focuses on understanding how the information from the receptors is organized in the brain and by what principles and patterns the perception of smell emerges. If the mystery of this is solved, it may be possible to generate a similar pattern in the brain to detect a certain smell as if there is a substance even though there is no smell.

It seems that many new paths of discovery will be opened in the future of our world. Perhaps we will be able to understand how animals react to certain odors and find their direction. We may develop new techniques for eliminating harmful insects, diagnose diseases such as tuberculosis, cancer, and diabetes through smell, and discover how the coronavirus destroys smell receptors and suppresses the sense of smell. We might also produce devices that detect explosives and drugs, as well as electronic noses capable of identifying substances in contaminated wastewater. It is even possible that smartphones will one day be enhanced to detect and transmit smells, just as they currently process images and recognize voices. In relation to these developments, aromatherapy is another potential field that could advance significantly if we can identify which areas of the brain are activated by specific scents and how this knowledge can be applied to treat diseases.

Some faith traditions attribute the unpleasant odors associated with certain psychological disorders to metaphysical beings, such as demons. As we deepen our understanding of the olfactory system, we may uncover some of the underlying causes of these psychological conditions. The wisdom behind practices like drawing water into the nose during ablution in certain forms of worship may also become clearer, as scientific research continues to reveal more about the connection between the nose and the brain.

References

1. Smith, K. (2024): The most mysterious sense: Cracking the odour code. Nature, Volume 633, 5 September.
2. Buck, L. & Axel, R. (1991): A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell 65, 175–187.
3. Butterwick, J. A. et al. (2018): Cryo-EM structure of the insect olfactory receptor Orco. Nature 560, 447–452.
4. del Mármol, J., Yedlin, M. A. & Ruta, V. (2021): The structural basis of odorant recognition in insect olfactory receptors. Nature 597, 126–131.
5. Guo, L. et al. (2023): Structural basis of amine odorant perception by a mammal olfactory receptor. Nature 618, 193–200.
6. Gusach, A., et al. (2023): Molecular recognition of an aversive odorant by the murine trace amine-associated receptor TAAR7f. Preprint at bioRxiv https://doi.org/10.1101/2023.07.07.547762
7. Billesbølle, C. B., et al. (2023): Structural basis of odorant recognition by a human odorant receptor. Nature 615, 742–749.
8. Jabeen, A., de March, C. A., Matsunami, H., & Ranganathan, S. (2021): Machine learning assisted approach for finding novel high activity agonists of human ectopic olfactory receptors. Int. J. Mol. Sci. 22, 11546.