Scientists have understood for many decades how the sensory receptors for vision and hearing are arranged within the eyes and ears and how light and sound wave information becomes mapped out within the brain. So it may come as a surprise that such is not the case for the odor, or smell (olfactory), receptors within the nose.
Science Daily had a recent report on research findings in Cell, stating,
Scientists have finally cracked one of the biggest mysteries in the senses, how smell is organized. By mapping millions of neurons in mice, researchers discovered that smell receptors in the nose aren’t random at all — they’re arranged in neat, overlapping stripes based on receptor type, forming a hidden structure scientists never knew existed. Even more striking, this layout mirrors how smell information is mapped in the brain, revealing a coordinated system from nose to neural circuits.
As I detailed here in my article on neural wiring:
The axon growth cone is the actively mobile, sensory navigation aid at the tip of the developing axon as it ekes out a path through the extracellular matrix (ECM). When it reaches its intended target (e.g. nerve, muscle or gland cell) it detects a specific biochemical “barcode” on the target cell’s membrane, along with matching molecular cues in the surrounding ECM. This combination of signals tells the growth cone that it has arrived at the right spot.
A Logical Question
How does a given olfactory sensory neuron (OSN) know which specific olfactory receptor (OR) to express and then send its axon to exactly the right place in the olfactory bulb where its smell information is processed before being interpreted by the brain?
Science Daily answers this question:
The researchers…identified retinoic acid, a molecule that regulates gene activity, as a key factor. A gradient of retinoic acid in the nose appears to guide neurons, helping each one activate the correct smell receptor depending on its position. When the researchers altered levels of this molecule (retinoic acid), the entire receptor map shifted upward or downward. They also showed that this map in the nose aligns with corresponding maps in the olfactory bulb of the brain. [Emphasis added.]
Retinoic Acid? You Mean the Teratogenic Medication for Acne?
How the body can safely use retinoic acid (RA), a teratogen that is known to disrupt embryonic development and cause permanent structural defects, for the gestational development and post-natal maintenance of olfaction, must invariably lead to questions — not only about mechanism, but also causation. Is it intelligent design or Darwinism?
Retinoic Acid the Morphogen — Who Knew?
Retinoic acid is a small molecule derived from vitamin A. As with other morphogens, its concentration within a developing tissue turns on or off particular transcription factors (TFs), producing distinct combinations. These combinations regulate gene expression that determines what cell types form, their spatial position, their proliferation and migration, and their expression of receptors, adhesion molecules, cytoskeletal components, and ECM proteins.
Beyond nasal development, preset RA gradients pattern the lungs, heart, gut, kidneys, eyes, and nervous system in the same way. Normally RA is produced inside the tissues, which keep it under control by using specific CYP26 enzymes to break it down locally. If the mother takes medication containing RA, the resulting embryonic exposure can exceed CYP26 capacity, increase local RA concentrations, disrupt the gradient, and force incorrect gene‑expression programs that cause structural malformations. That is why RA is classified as a teratogen.
Regarding how RA guides olfaction pattern development, the Cell article explains:
Here we show that the olfactory epithelium harbors an organized map in which each of the ~1,100 (mouse) receptors predictably occupies a unique and distinguishable distribution along the DV (dorsoventral = top to bottom) axis of the (nasal) epithelium. This pattern reflects a developmental program in which RA signaling transforms spatial position into transcriptional gradients across ~250 co-regulated genes. This coherent transcriptional axis — summarized as the DV score — allows us to demonstrate that precursors and OSNs harbor spatially specific transcriptional identities that restrict OR choice and coordinate the construction of spatial maps in the epithelium and bulb. Spatial variation also helps the OSNs to know both which OR they are to express and where in the brain they should send their axons. In addition to transcription factor genes that likely influence OR choice, the DV score includes known regulators of OSN axonal targeting as well as over thirty additional cell surface and cytoskeletal regulatory molecules that could facilitate axon guidance.
What this says is that the dorsoventral RA concentration gradient in the developing olfactory epithelium generates different TF combinations at different positions. Those combinations act through a coordinated set of ~250 genes. Their expression varies systematically along the DV axis. They inform each OSN — one of roughly 20 million in the mouse — which of the ~1,100 different OR genes it can express and which axon‑guidance receptors it will display.
The ability to generate combinations of TFs — which, through hundreds of downstream genes, make OSNs in the correct positions express the correct ORs and send their axons to the correct sites in the olfactory bulb — ultimately depends on the body obtaining vitamin A. Vitamin A is converted into a preset top-down RA gradient within the nasal tissue.
It all seems very neat and tidy. But the devil is in the details!
The Details
Vitamin A enters the digestive system as retinyl esters (REs) from animal sources (liver, fish liver oils, dairy fat, eggs, fortified foods). And it enters as carotenoids from plant sources (carrots, sweet potatoes, pumpkin, winter squash, mango, cantaloupe, apricot). In the intestinal lumen, lipase, carboxyl ester lipase, and retinyl‑ester hydrolases convert REs to retinol (ROL). Carotenoids are taken up into the intestinal cell, where β‑carotene monooxygenase 1, β‑carotene dioxygenase 2, and retinaldehyde reductase convert them into ROL.
To prepare ROL to be used in the body, intestinal cells use lecithin retinol acyltransferase (LRAT) to convert it back to REs and package them in chylomicrons, which are lipid particles that carry dietary triglycerides and fat‑soluble vitamins into the lymph and then the blood.
The intestinal cells release chylomicrons into the surrounding lymph vessels, and these travel into the blood through the thoracic duct. That is where all nutrient‑rich lymph from the GI system drains. As they circulate, lipoprotein lipase on the capillary endothelial cells binds apolipoprotein C‑II on the surface of chylomicrons. It removes their triglycerides, converting them into chylomicron remnants. These chylomicron remnants expose apolipoprotein E (apoE) on their surface. That allows liver cells (hepatocytes) with apoE receptors to bind and bring them into the cell by engulfing them through endocytosis.
The hepatocytes then use lysosomal retinyl‑ester hydrolases to convert REs back to ROL. ROL immediately binds to cellular retinol‑binding protein‑1 (CRBP1), which carries it within the cell. The hepatocytes have two options for the ROL–CRBP1 pool. They can release the ROL so it can enter nearby stellate cells, which bind it to their own CRBP1 and use LRAT to convert it back to REs for storage in lipid droplets. Or they can load ROL directly onto retinol‑binding protein‑4 (RBP4) and secrete it into the blood. There, transthyretin (TTR) binds to it to prevent ROL from being filtered out of the blood by the kidneys. It is this ROL-RBP4-TTR complex that circulates in the blood and delivers ROL to the tissues including the nasal epithelium.
Support cells in the nasal tissues use STRA6 (stimulated by retinoic acid 6) surface receptors to bind the circulating ROL–RBP4–TTR complex. That brings ROL into the cell where it is transferred to the intracellular carrier CRBP1. Inside the cell, ROL is either converted to REs for storage by LRAT or is converted to RA by aldehyde dehydrogenase 1 family member A2 (ALDH1A2). After that, RA diffuses out of the support cells. This RA‑producing process is counterbalanced in the nasal support cells by CYP26 enzymes. They break RA down into metabolites that can then be released from the body. The local balance between ALDH1A2 (RA synthesis) and CYP26 (RA degradation) in each region of the nasal tissue sets its RA concentration and thereby establishes the top‑down (DV) RA gradient.
Once inside the OSNs, cellular retinoic acid‑binding proteins (CRABPs) attach to RA and deliver it to the nucleus. Inside the nucleus are retinoic acid receptor (RAR) and retinoid X receptor (RXR). After RA enters the nucleus, it binds to RAR, and this RA‑bound RAR then binds tightly with RXR. This RA‑driven binding induces a conformational change in the RAR–RXR complex that ultimately activates transcription of RA‑responsive genes.
Voila!
A Biochemical Challenge
In his seminal book Darwin’s Black Box, Michael Behe quotes Charles Darwin:
If it could be demonstrated that any complex organ existed which could not possibly have been formed by numerous successive, slight modifications, my theory would absolutely break down.
Dr. Behe goes on to explain:
What type of biological system could not be formed by “numerous, successive, slight modifications” Well, for starters, a system that is irreducibly complex. By irreducibly complex I mean a single system composed of several well-matched, interacting parts that contribute to the basic function, wherein the removal of any one of the parts causes the system to effectively cease functioning. An irreducibly complex system cannot be produced directly (that is, by continuously improving the initial function, which continues to work by the same mechanism) by slight, successive modifications of a precursor system, because any precursor to an irreducibly complex system that is missing a part is by definition nonfunctional. An irreducibly complex biological system, if there is such a thing, would be a powerful challenge to Darwinian evolution. Since natural selection can only choose systems that are already working, then if a biological system cannot be produced gradually it would have to arise as an integrated unit, in one fell swoop, from natural selection to have anything to act on.
As noted above, the process the body uses to bring in vitamin A and produce the correct preset top-down RA gradient — so that “smell receptors in the nose…reveal a coordinated system from nose to neural circuits” — involves at least 21 different factors. Those include 11 enzymes, all of which have to be present in the right amounts and doing their jobs fast and well enough.
The origin of the preset RA top-down gradient needs to be explained. So does the origin of the “transcriptional gradients across ~250 co-regulated genes…in which each of the ~1,100 (mouse) receptors occupies a unique and distinguishable distribution along the DV axis of the epithelium.”
ID vs Darwinism
All this is irreducible complexity several orders of magnitude beyond what Darwin could have imagined. Otherwise he never would have written the statement that Behe cites. Is it possible that processes like mutation, gene duplication and divergence, co-option, co-evolution, domain shuffling and recombination, regulatory rewiring, selective pressure — along with all the other add-ons to try to save Darwinism — could have been responsible for the precision design logic that pervades olfaction?
The last paragraph of Dr. Behe’s book reads,
Now it’s the turn of the fundamental science of life, modern biochemistry, to disturb. The simplicity that was once expected to be the foundation of life has proven to be a phantom; instead, systems of horrendous, irreducible complexity inhabit the cell. The resulting realization that life was designed by an intelligence is a shock to us in the twentieth century who have gotten used to thinking of life as the result of simple natural laws. But other centuries have had their shocks, and there is no reason to suppose that we should escape them. Humanity has endured as the center of the heavens moved from the earth to beyond the sun, as the history of life expanded to encompass long-dead reptiles, as the eternal universe proved mortal. We will endure the opening of Darwin’s black box.
That’s wisdom to live by!