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Nose for Design: Irreducible Complexity, Goal-Directed Hierarchical Organization, Combinatorial Coding

Olfactory rosette.jpg

One of the dramatic moments in Living Waters: Intelligent Design in the Oceans of the Earth begins with a trip into the nostril of a salmon. Illustra's animators take us on a journey through that tiny opening to view a beautiful structure, the olfactory rosette (pictured above), where millions of specialized cells called olfactory sensory neurons (OSNs) sport cilia, like antennae, equipped with olfactory receptors (ORs). Each OR responds to a specific odor molecule according to its shape and charge distribution. A correct hand-and-glove fit triggers electrical impulses that travel down "wires" (long axons of the neurons) to the olfactory bulb. This structure is a signal processing center that gathers and sorts the information coming from millions of OSNs before transmitting it to the brain.

The animation is simplified to meet the needs of general audiences, but olfaction is anything but simple. The sense of smell was the last of the five major senses to be understood. Got ID? It's all here: irreducible complexity, goal-directed hierarchical organization, and combinatorial coding. Another layer of olfactory design was just revealed in a new paper in Current Biology by 15 neuroscientists primarily from the University of Pennsylvania's Perelman Medical School.

The paper describes rodent olfaction, but since the nomenclature is similar in fish and mammals, we can apply the principles to vertebrates in general (fish, naturally, sense odors in water; most mammals detect air-borne odor molecules). The gist of the paper is that the cilia are arranged in patterns that maximize sensitivity to odors. This implies that evolution could not just add more of the same cells to the olfactory epithelium (the tissue that supports the OSNs). Instead, the OSNs, and their cilia, and their receptors, have to be arranged according to a higher order of design:

Cilia with receptor.jpeg

Moreover, this pattern is "intrinsically programmed," the researchers say.

In many sensory organs, specialized receptors are strategically arranged to enhance detection sensitivity and acuity. It is unclear whether the olfactory system utilizes a similar organizational scheme to facilitate odor detection. Curiously, olfactory sensory neurons (OSNs) in the mouse nose are differentially stimulated depending on the cell location. We therefore asked whether OSNs in different locations evolve unique structural and/or functional features to optimize odor detection and discrimination. Using immunohistochemistry, computational fluid dynamics modeling, and patch clamp recording, we discovered that OSNs situated in highly stimulated regions have much longer cilia and are more sensitive to odorants than those in weakly stimulated regions. Surprisingly, reduction in neuronal excitability or ablation of the olfactory G protein in OSNs does not alter the cilia length pattern, indicating that neither spontaneous nor odor-evoked activity is required for its establishment. Furthermore, the pattern is evident at birth, maintained into adulthood, and restored following pharmacologically induced degeneration of the olfactory epithelium, suggesting that it is intrinsically programmed. Intriguingly, type III adenylyl cyclase (ACIII), a key protein in olfactory signal transduction and ubiquitous marker for primary cilia, exhibits location-dependent gene expression levels, and genetic ablation of ACIII dramatically alters the cilia pattern. These findings reveal an intrinsically programmed configuration in the nose to ensure high sensitivity to odors.

The design principle is similar in vision, where cone receptors are concentrated at the center of the visual field, and in touch, where touch receptors are concentrated at the fingertips. So in a way, it's not surprising that olfaction obeys this principle, too. But it should be surprising that a blind process like evolution would keep hitting on the optimum principle for sensitivity and acuity in very different senses. Mutations for the arrangement of rods and cones in the eyes, for instance, would likely have no effect on the arrangement of OSNs in the nose. Natural selection would have to arrive at each pattern independently.

The design in olfaction gets more wonderful the deeper we look. The paper describes the olfactory receptors (ORs), which Illustra animated as simple ports on the cilia. The film didn't have time to describe how activation of an OR begins a cascade of responses, including gene expression with feedback, cycling of enzymes, and transmission of electrical signals down the nerve axon by means of ion channels rapidly opening and closing in turn like a chain of dominos -- only these dominos reset themselves. Remember the image of the olfactory bulb? Those bumps on the exterior, called glomeruli, are the initial collection points for nerves responding to a particular odor.

The mouse main olfactory epithelium contains several million olfactory sensory neurons (OSNs), each of which expresses one G protein-coupled odorant receptor (OR) type from a repertoire of ?1,200. A few thousand OSNs expressing the same OR are scattered within one broad zone, while their axons coalesce typically onto two discrete glomeruli (one medial and one lateral) in each olfactory bulb. Odor detection begins when odorants are absorbed into the mucus layer covering the epithelium and bind to ORs on the cilia of OSNs. Odorant binding leads to increased intraciliary cyclic AMP (cAMP) levels via sequential activation of olfactory G protein (Golf) and type III adenylyl cyclase (ACIII). Subsequent opening of a cyclic nucleotide-gated channel and a Ca2+-activated Cl? channel depolarizes OSNs, which fire action potentials and transmit odor information to the brain.

You don't have to remember the jargon to get the gist of how complex this is. Once again, the precise placement of the glomeruli (Latin for "ball-shaped mass") on the olfactory bulb is critical to function:

Olfactory bulb.jpeg

The olfactory bulb is able to tell whether a specific odor signal is coming from a particular glomerulus on the front, back, top, bottom or side. The timing and signal strength of each signal is also factored into the equation.

In a quasi-"magical" algorithm that would be the envy of any programmer, all this information gets compressed and expanded again via a chain of combinatorial codes. In other words, the incoming information from 1,200 odorant receptor types -- producing millions of signals -- gets scrunched into a smaller number of odor codes depending on the location, timing, and strength of each input. Think of a giant switchboard with blinking colored lights. If a particular pattern emerges, the switchboard operator knows, "OK, that's cheese," or "that's a hormone." This coded information is once again expanded into a repertoire of thousands of odor signals the brain can recognize.

That may sound complicated, but even this description is simplified. The authors of the Current Biology paper have added another layer to the complexity, explaining that the cilia in the olfactory epithelium (the entry point for smelling) are specifically arranged (front-to-back, top-to-bottom, and side-to-side) for maximum sensitivity. Additionally, the cilia are optimally placed according to the physicochemical properties of each odorant: for example, hydrophilic molecules that are more easily absorbed reach the tissue first, and hydrophobic molecules reach the back. The length of each cilium is also fine-tuned for its location and odorant type. It's as if somebody who understood electronics wired this up:

The most dramatic difference in cilia length is found along the medial aspect of the dorsal zone; i.e., a single medial glomerulus receives inputs from OSNs that are heterogeneous in their cilia lengths (Figures 1, 2, and 3). Patch clamp analysis reveals that OSNs in the dorsal recess and anterior septum (with longer cilia) are more sensitive to odorants compared to cells in the posterior septum (with shorter cilia) (Figure 7). This can be explained by the fact that longer cilia have a larger surface area for contacting odors. Based on the cable theory, the length constant of olfactory cilia is estimated to be ?220 ?m when the membrane is not leaky (i.e., with negligible channel opening). This suggests that upon stimulation by faint odors, the electrical signals generated along a long cilium can travel far enough to the cell body and contribute to membrane depolarization. Due to spatial summation, cells with longer cilia would show a higher sensitivity and larger response to low concentrations of odors. Conceivably, placing OSNs with longer cilia in highly stimulated regions would increase their chance of encountering faint odors and boost the sensitivity of the system.

Compared to their long-cilia counterparts, short-cilia cells have a higher response threshold and are less likely to reach saturation, making them better suited for coding intensity differences at higher concentrations. Therefore, placing OSNs with shorter cilia in the posterior septum, which is only reached by strong odor stimuli, would ensure a broad dynamic range of the system. If these neurons were designed to carry redundant information, OSNs in the posterior septum should grow longer cilia to compensate for weaker stimulation. Our work reveals the opposite scenario, suggesting that the peripheral olfactory system is spatially organized to match cell sensitivity with the incoming stimuli, adding a new dimension to the sorption theory.

Did you catch that word "designed"? They found that the system is not designed for redundancy, but for sensitivity. Did you catch the word "coding"? Olfaction is a signal processing system based on combinatorial codes. It's no wonder that evolutionary theory is almost completely absent in the paper, except for a single, passing reference of dubious consequence in the first quotation. A more pertinent word is "optimize" -- it appears three times. We discussed earlier this month how optimization is an intelligent design science.

Look at all the design-rich words in this quotation:

These findings offer new insights into peripheral coding and processing of odor information and regulation of cilia morphology and function. Moreover, this work has broad implications for how sensory receptors optimize detection sensitivity in various physiological contexts.

At the risk of overpowering our readers with complexity, we can just summarize the main point: there are multiple, information-rich, hierarchical design principles at work in olfaction, brought about by millions of independent parts cooperating for function. So next time you enjoy the wonderful scent of coffee, a steak, or your favorite food, or when you watch Living Waters and learn about a salmon sensing odorants at parts per trillion to guide it to its native stream, enjoy a moment of good old-fashioned awe.

Images: Courtesy of Illustra Media.