A Touchy Subject

More often than not when learning science, we are taught to ignore the context underlying major discoveries. We are told to memorize details without seeing the big picture; however, the stories behind these great advances can be extremely compelling. To me anyways, one of the most intriguing trends in the stories underlying scientific exploration is that often times the most critical advances in understanding come not from rigorous experimentation (as so many of us are misled to believe), but from insights and revelations formed via intense observation of natural processes.

The greatest scientific minds throughout history are remembered for predictions rooted in realizations that had never occurred to anyone else before them. Based only on the movements of stars in the sky, Copernicus postulated the structure of our solar system. Newton hypothesized gravity by observing falling objects and Darwin created the Theory of Evolution by collecting specimens and fossils separated in form by time and geography. In the same manner, a great German anatomist once predicted the cellular basis for the sensation of touch.

http://en.wikipedia.org/wiki/Friedrich_Sigmund_Merkel

Friedrich Sigmund Merkel

In 1864, after bureaucracy put a stop to his adventurous dream to become a sailor in the German navy, a youthful Friedrich Sigmund Merkel began studying to be a physician. The son of intelligent and wealthy parents, Friedrich’s free thinking was encouraged in his pursuit of a scientific education. Early in his learning, however, he firmly assured his mother that out of all of the sciences, he would never become an anatomist; a statement completely invalidated by his lasting impact on the field he so adamantly rejected early on.

The ambitious scientist’s fascination by the invention of the microscope lead to many revelations. He published works on the iris musculature of the eye, papers about the connections of the chest muscles, and manuscripts outlining benefits of microscope use for anatomy. Then, in 1875, Merkel first observed and described “Tastzellen”, or touch cells. Merkels’ newly discovered cells would make an enormous impact on the physiology of touch, or mechanosensation, but his original term has been substituted for a new name. “Merkel Cells” forever commemorate the enormous impacts of the famous Anatomist.

In mammals, Merkel cells are dispersed throughout all of the skin. While, in the majority of the body, the cells surround the base of hair follicles; the areas that are highly sensitive to touch use Merkel cells concentrated in tiny lumps called touch domes. In both cases, these specialized skin cells form connections with sensory neurons projecting to the brain. While it is true that your skin is the largest body organ, containing over 30 billion cells, very few of them actually connect with the nervous system in any way. Most just form protective layers which will eventually be shed off of your body.

In a manner resembling other great scientific discoveries outlined above, having only the observation that his cells form synaptic connections with underlying neurons, our insightful Friedrich Merkel predicted that his tastzellen were likely responsible for the sensation of touch.

Modern science now defines several classes of mechanosensation including painful touch, heavy pressure, vibration, stretch, and more. Other cell types have been explored for roles in these sensations, and evidence has been built for the Merkel cell’s involvement in the discrimination of “light touch”. These cells likely give us the basis for discriminating between textures and finding small edges.

Hair Follicle and Touch Dome Merkel Cell Complexes Updated Merkel Cell Drawing

How can these skin-derived, or epithelial, cells send all this information to our brains? Non-neuron cells are known to play parts in the tongue for taste detection, and also in the inner ear in our ability to hear. The common feature of these signaling epithelial cells is their ability to quickly change their electrical charge, or depolarize, in the same way that our neurons do. However, unlike neurons, epithelial cells do not form complex signaling networks or project to the brain or spine. When the correct stimulus is present, these cells open channels in the surrounding membranes to allow charged ions to flood the cell. This rapid change is carried all the way to the site where the receptor cell meets a sensory neuron, at which point; the depolarization is carried along the length of the neuron towards the brain.

Now, a major question is begging to be asked. How do these receptor cells, in our case, Merkel cells, discriminate between different types of stimuli? Each receptor cell must have a specialized receptor molecule on its cell membrane, either acting as an ion channel itself or else with the ability to cause a separate ion channel to open. In many cases of sensory transduction, vision, taste, smell, these ion channels are well known. However, in most cases of touch mechanosensation, the identity of these critical players was not known. What we do know is that both isolated Merkel cells and the ones in living tissue display electrical current changes when slightly moved by a probe. This means that a molecule on the membrane of these cells must respond to mechanical force by allowing charged ions to enter the cell.

The Piezo family, a family of large membrane proteins, is one of the largest proposed ion channels with over 30 regions of the protein passing through the membrane (most have only 7 such regions). Over the last year, groups around the world have been investigating the role of one such Piezo protein family member, named Piezo2, as the ion channel involved in Merkel Cell touch sensation in mice.

Mice typically prefer textured ground conditions in their cages. When given a choice between a textured surface and smooth ground, mutant mice without working Piezo2 protein don’t show the same preference. By tagging one end of the protein with a fluorescent marker, they can use microscopes to observe Piezo2 expressed only at the tips of the neurons closest to the Merkel cells and in the Merkel cells themselves. Studies of electrical current changes, or electrophysiology, in Merkel cells and the sensory neurons demonstrate that the mutant mice cells do not respond to mechanical force as do the cells with working Piezo2.

The enormous body of evidence continues to build for Piezo2’s responsibility as the mechanically activated ion channel in mice. While studies in mice are not always indicative of answers for humans, our two species’ versions of the proteins are fairly similar. Future studies will determine whether or not the protein plays the same role in the human being, but if so, the identity of the channel responsible could have major impacts on the medicine of touch and pain. It is astounding to me that just now, 150 years after Friedrich Sigmund Merkel began his studies as a physiologist, we are finally beginning to understand the molecular basis for his most important prediction and the cells that bear his name.

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