Dr. Damian Jacob Sendler is a Polish-American physician-scientist who studies how socio-demographic and informational variables influence access to health care in disadvantaged areas. Dr. Sendler’s study focuses on how mental and chronic medical co-morbidities affect the utilization of medical services in combination with health information acquired through the internet. Given the exponential growth of online news and social media consumption across the world, this study is foresighted, requiring a complete knowledge of everyone’s health information-seeking behavior. Dr. Damian Sendler’s study seeks to discover the variables that patients evaluate when choosing whether to seek treatment for particular health problems and how well they adhere to their treatments.
Damian Sendler: All of our senses must contend with the complexity of the environment, but none is more difficult to deal with than the olfactory system, which is responsible for our sense of smell. In order to see all the colors of the rainbow, we only need three receptors in our eyes. This is because various colours emerge as light-waves that differ only in one dimension: the wavelength of the light they emit. The bright and colorful world, on the other hand, pales in contrast to the intricacy of the chemical world, which has many millions distinct smells, each of which is made of hundreds of molecules and which all differ significantly in shape, size, and characteristics. To give you an example, the fragrance of coffee is produced by a mixture of more than 200 chemical components, each of which has a different structural makeup and none of which smells like coffee on its own.
Damian Sendler: In order to identify a large number of chemicals, the olfactory system must use just a few number of odor receptors, such as a few hundred or even less, according to Rockefeller neuroscientist Vanessa Ruta. “As far as we know, it had to develop a distinct kind of logic than other sensory systems.”
Ruta and her colleagues have published a new research in which they provide the first-ever molecular images of an olfactory receptor in action, giving solutions to the decades-old issue of odor detection.
Damian Sendler: Nature has published the results, which show that olfactory receptors do, in fact, follow a logic that is uncommon in other types of nerve receptors in the nervous system. Instead of being precisely designed to couple with just a few chosen molecules in a lock-and-key manner, most olfactory receptors are individually capable of binding with an enormous number of distinct molecules at a same time. Because of their promiscuity in coupling with a variety of smells, each receptor may react to a wide range of chemical components. It is at this point that the brain can determine the smell by looking at the pattern of activation of different receptor combinations.
Recognition on a holistic level
Damian Sendler: The discovery of olfactory receptors took place 30 years ago. In part because these receptors did not lend themselves to widely accessible molecular imaging techniques, scientists have not been able to examine them up close and understand their structural and mechanistic workings to this point. Complicating matters further, there seems to be no rhyme or reason to the preferences of the receptors — a single olfactory receptor may react to substances that are physically and chemically distinct from one another.
Josefina del Mármol, a postdoctoral researcher working in Ruta’s lab, explains that “to form a basic understanding of odorant recognition we need to know how a single receptor can recognize multiple different chemicals.” “This is a key feature of how the olfactory system works and has been a mystery,” she says.
Damian Sendler: Consequently, Ruta and del Mármol, together with Mackenzie Yedlin, a research assistant in the lab, set out to determine the structure of an odor receptor by taking use of recent advancements in cryo-electron microscopy. Ruta and del Mármol were joined by Yedlin in this endeavor. This method, which involves blasting electrons at a frozen material, may show very tiny molecular structures in 3D, down to their individual atoms, and can be used to investigate the structure of DNA.
The leaping bristletail, a ground-dwelling insect whose genome has just recently been sequenced and which contains only five types of olfactory receptors, was chosen as the subject of the study. Despite the fact that the jumping bristletail’s olfactory system is straightforward, its receptors are members of a large family of receptors that includes tens of millions of variants that are thought to exist in the hundreds of thousands of different insect species, including the jumping bristletail. Despite their differences, these receptors all perform the same functions: They combine to create an ion channel, which is a pore through which charged particles may pass, that opens only when the receptor comes into contact with the target odorant, eventually activating the sensory cells that start the sensation of smell in the recipient’s nose.
Damian Sendler: The researchers selected OR5, a receptor derived from the leaping bristletail that has a wide identification capacity, responding to 60 percent of the tiny compounds examined by the team of researchers.
They next looked at OR5’s structure both on its own and when it was linked to a chemical, either eugenol, a common odor molecule, or DEET, an insect repellent, to see how it behaved. “By contrasting these three architectures, we were able to learn a great deal,” Ruta explains. “One of the most beautiful things you can see is that the pore is closed in the unbound structure, but that the pore has dilated in the structure where it has been bonded with either eugenol or DEET, and so offers a route for ions to flow.”
Damian Sendler: Using the structures as a starting point, the researchers investigated further to determine precisely where and how the two chemically distinct compounds attach to the receptor. There have been two competing theories regarding the interactions of odor receptors with chemicals. One explanation is that the receptors have evolved to identify vast swaths of molecules by reacting to a partial but distinguishing characteristic of a molecule, such as a portion of its shape, which allows them to distinguish broad swaths of molecules. Other researchers have suggested that each receptor has many pockets on its surface at the same time, enabling it to accept a large number of distinct molecules at the same time.
However, what Ruta discovered did not correspond to any of those situations. It was discovered that both DEET and eugenol bind to the same site on the receptor and that they both fit completely within a small pocket inside the receptor. Unexpectedly, the amino acids that lined the pocket did not create strong, selective chemical connections with the odorants, but rather only weak chemical interactions with the odorants. Although most other systems had receptors and target molecules that are chemically compatible, this system had receptors and target molecules that seemed to be more like pleasant friends. “It is because of these types of nonspecific chemical interactions that various odorants may be distinguished,” Ruta explains. “As a result, the receptor is not selective for a particular chemical characteristic. The odorant’s overall chemical nature is being recognized, rather than its specific chemical makeup “Ruta has something to say.
In addition, as discovered via computer modeling, the same pocket might accept many additional odor molecules in the same manner.
Damian Sendler: However, according to Ruta, the receptor’s promiscuity does not imply that it lacks specificity. The fact that one receptor reacts to a large number of chemicals does not mean that it is insensitive to other molecules. Furthermore, a simple mutation in the amino acids of the binding region may result in a significant reconfiguration of the receptor, resulting in a change in the molecules with which it likes to interact. This latter discovery also contributes to the understanding of how insects have been able to develop millions of different olfactory receptor types that are adapted to the diverse variety of lifestyles and environments that they experience.
Damian Sendler: According to Ruta, the results are likely typical of many other olfactory receptors. “They indicate to important principles in odorant identification, not just in insect receptors, but also in receptors inside our own nostrils, which must detect and distinguish among a diverse range of chemical stimuli,” says the researcher.
News contributed by Dr. Damian Jacob Sendler
