Touchy Feely: Touch and How It Is Linked to Other Senses

Our Senses: An Immersive Experience - Rob DeSalle 2018

Touchy Feely: Touch and How It Is Linked to Other Senses

“My own parents were touchy-feely.” —Ben Stiller, comedian

Touch is the final mechanosensory sense to consider, and it is implemented through the skin (often touted as the largest sense organ in the body). Unlike the other sense organs discussed so far, touch sensors are variable. Some have called the collection of touch receptors associated with the skin a “medley,” others a “menagerie.” Indeed, unless you’re inclined to remember obscure facts, the names of these organs are instantly forgettable. Nowhere as easy to remember as John, Paul, George, and Ringo, Meissner’s corpuscles, Merkel cell-neurite complexes, Ruffini endings, and Pacinian corpuscles are the four major somatosensory receptors embedded in the bottom layer, or dermis, of the skin (fig. 8.1). Two other receptor systems are also recognized that relate to nerve endings: anceolate endings and free-nerve endings.

Meissner’s corpuscles are specialized on light touch and sensing vibrations hitting the skin. These receptors are the kissing receptors or, more generally, the receptors that send information from the lips to the brain. They are also involved in sensing by touch in the fingers. Merkel cell-neurite complexes are found in the basal epidermis of the skin and in hair follicles. Because of their locations, they can sense low-level vibrations. Whereas Meissner’s corpuscles can detect vibrations with frequency of 10 to 50 hertz, Merkel nerve endings detect vibrations in the range of 5 to 15 hertz. As a result of having what is called a small receptive field, they are most effective in the fingertips, where fine detail is the major focus of touch. Ruffini endings react to skin stretch or distortion. They are slow-response receptors, and they basically tell our fingers where to be when touching. Pacinian corpuscles can distinguish rough and soft objects. They are quick acting and are most sensitive to vibration in the range of 250 hertz, much greater than Merkel or Meissner’s bodies. The reader might be asking, then why aren’t our brains afire with signals from wearing clothes? The answer is that Pacinian corpuscles react only to sudden stimulation. They quickly forget that they are touching cloth when you put on a shirt and patiently wait for the next sudden stimulation. Free-nerve endings are the tough guys of the mechanosensory group, because they take the touch stimulus and communicate with the brain only after a threshold is reached and that threshold is pain. Lanceolate endings are situated in hairs and follicles and detect movement of the hairs. They cannot detect the direction of the movement of the hairs but are rather good at sensing vibrations at even higher frequencies than the other sensors discussed above (200 Hz—1,000 Hz).


Figure 8.1. Types of cells that implement our sense of touch through the skin.

This menagerie of sensory cells, though different in basic structure, all have the same basic floor plan with respect to their connection to the brain. A review of the connections of these receptors from the brain and brain stem outward starts with the connection to the brain stem or the dorsal root ganglia along the spine. From there the cells extend axons called sensory afferents. These axons are the wiring that carries the electrical impulse that signals the brain that something is being touched. The axons then spread out into the endings described above. Information from these touch sensor cells is transmitted to several regions of the brain, depending on the kind of information. For instance, stimulation from the sensors that focus on vibrations is connected to a different region of the somatosensory cortex than sensors that are specialized for surface texture.

As an example of how a sensory receptor is connected to the somatosensory cortex, consider how the brain processes fine touch. When someone touches a small object with the fingertips, Meissner’s corpuscles will become distorted by the force of the touch. This will produce a reaction in the sensory cells that in turn produces an action potential. The electrical signal from the action potential travels through the axon of the sensory cell and connects to the spinal cord, where it then travels to the brain. When it reaches the brain, the action potential can take one of several routes to the sensory cortex. Once the signal reaches the sensory cortex, it is processed and linked to the amygdala and the hippocampus as a means to reinforce memory of the sensation. The routes of other action potentials generated by the various mechanosensory cells are similar.

According to David Linden and other neuroscientists, two major neural pathways in the brain are dedicated to touch. The first is the sensory pathway just described and in Chapter 2. Linden points out that this pathway is based in the somatosensory cortex of the brain, where the information from touch ends up. What happens next is that this cortex “figures out the facts, and it uses sequential stages of processing to gradually build up tactile images and perform the recognition of objects.” The other pathway is involved in the social and emotional context. The data from the touch and recognition of objects from touching are then interpreted to affect how we behave socially and emotionally in a kind of dual layer processing. And touch can hugely affect our emotional social behavior. In addition, human populations vary greatly when it comes to touch.

Just five years ago, it would have been safe to write that little was known about the human variability of touch. Researchers did know that some humans are exquisitely sensitive to touch. Some people who are on the autism spectrum express what is called touch aversion. They find touch quite unpleasant—not necessarily painful but just unpleasant. This phenomenon more than likely is not because they sense more intensely or are supertouchers but rather because the social aspects of touching are problematic. On the other end of human touch sensitivity, the sense of touch can be diminished in several ways. As with hearing and balance, humans tend slowly to lose the sense of touch with age. Health problems can also result in the loss of the sense of touch. Vitamin B12 deficiency, diabetes, and stroke can result in the loss of touch in certain parts of the body. Inherited syndromes also involve the loss of touch. Riley-Day syndrome, for example, affects sensory nerve cells and produces many symptoms, one of which is decreased sensitivity to touch and other stimuli. It is what is called an autosomal recessive syndrome, meaning first that it is on one of the autosomes in the genome and second that one needs to have two copies of the gene that causes the disorder. This syndrome is found in higher than usual frequencies in people with Ashkenazi Jewish ancestry. Usually a person with the syndrome has inherited abnormal copies of genes from parents who were carriers. These carrier parents are heterozygous (have one normal copy and one abnormal copy) for the gene for the syndrome and don’t express the syndrome themselves. The gene that is mutated to cause the syndrome is known, and it is called IKBKAP. This gene makes a protein important in transcription of other genes into messenger RNA. The connection to the disorder is not at all obvious.

Other genetic syndromes exist such as Charcot-Marie-Tooth disorder (CMT). This syndrome is also an autosomal recessive genetic trait. The symptoms are loss of the sense of touch (and loss of ability to sense pain) in extremities of the body such as the hands, feet, and legs. People with the disorder have been known to contract nasty lesions on their extremities as a result of being unable to feel pain there. The disorder also affects balance, not because of problems with the vestibular system but because people who are affected can’t judge where their feet and legs are.

James Lupski, a professor and medical doctor, has lived with CMT disorder for more than forty years. Many genetic lesions are thought to be involved in CMT, but Lupski’s case was difficult to pin down with the techniques available in 2010. So, he and a team of scientists decided to sequence his genome and the genomes of his family members. By generating the three billion bases of his genome, they hoped to pin down the genetic basis of Lupski’s particular kind of CMT. Members of his family don’t have the syndrome, and so by cross-referencing the DNA sequence of his family members with his DNA, the team could find the gene responsible for CMT syndrome. In a feat much like finding a needle in haystack, Lupski and colleagues were able to determine that the culprit was a gene called SH3TC2.

Here’s how they did it. Remember that each strand of DNA is a long, linear molecule made up of four nucleotide bases (G, A, T, and C) that composes our genes. How the Gs, As, Ts, and Cs are arranged tells our cells to make certain proteins, such as a protein involved in nerve cell structure. Also remember that the genetic code states that different amino acids in a protein are coded for in DNA by triplets of nucleotides. In an illustration of a gene sequence from part of the SH3TC2 gene (fig. 8.2), I separate the sequence at every third base because the DNA triplets code for amino acids in proteins.

The next illustration is the part of the protein for which the DNA codes (fig. 8.3). The letters below the DNA sequence are abbreviations for the twenty amino acids in proteins, and the numbers above the DNA sequence are the positions in the protein numbered from the beginning of the protein. Lupski and colleagues scanned his genome for places where he differed from the reference human sequence (a sequence from someone without CMT) and identified them. These positions are called single nucleotide polymorphisms (SNPs). The researchers had to sift through 3,420,306 SNPs. They rapidly excluded 2,255,103 of the SNPs because they did not lie in regions of known genes. Now they had 1,165,204 SNPs to sort through. So next, they eliminated regions that were in genes but did not code for amino acids (regions like introns). This reduced the number to 18,406 SNPs to search through—better, but still not a trivial job!


Figure 8.2. Partial sequence of the SH3TC2 gene.


Figure 8.3. DNA and protein sequences of the region of the SH3TC2 gene where mutations will cause Charcot-Marie-Tooth disorder.

As a result of the way the genetic code works, they could eliminate even more SNPs. The genetic code is redundant—for some amino acids, multiple triplets of DNA will code for that amino acid. For instance, CCA, CCG, CCT, and CCC all code for the amino acid proline. If there is a SNP in the third position of the codons that code for proline, it will not code for a different amino acid. No change, no foul, no harm. Such changes are called silent because they don’t result in a change in the amino acid their codon codes for. This elimination got the team down to 9,069 SNPs that cause amino acid changes in proteins in Lupski’s genome. Next, they used the vast knowledge human geneticists have accumulated over the past century in the Human Gene Mutation Database. This allowed the genomics team to match Lupski’s SNPs with positions in known Mendelian inherited diseases and got them down to 54 SNPs in coding regions of genes known to be involved in genetic disorders. Finally, they obtained a list of genes known to be involved in neural disorders, and—lo and behold—by cross listing these, they discovered two SNPs in the neural gene SH3TC2. In fact, they could pin down the exact SNP that was involved in the disorder, and it resides in the 169th codon in the sequence (fig. 8.4).

The change in the DNA sequence in Lupski’s genome in these sequences is a C→T (on the coding strand the mutation is G→A), and it causes an amino acid shift from histidine (H) to tyrosine (Y). The precise function of SH3TC2 is still unknown, but it is more than likely involved in myelination, or the coating of nerve cells. Myelination acts much like plastic insulation on wires. Without proper myelination, the nerve cells that transmit touch sensations to the brain eventually lose the action potential signal on the way to the brain, and depleted information about touch gets to the brain. This mutation and form of CMT is unique and demonstrated the power of genomics in understanding a neuropathy of the senses in a single individual.


Figure 8.4. DNA and protein sequences showing the location of James Lupski’s mutant SH3TC2 gene (bottom).

Genetics has been used in other ways to pin down the genes involved in the sense of hearing, but until recently no such studies have been conducted on the sense of touch. For instance, there are more than sixty known heritable hearing syndromes, based on genetic studies, but only a handful of touch syndromes, of which CMT is one. Geneticists use all kinds of tricks to map genes and to look for correlations of genes with phenotypes such as those important for understanding the sense of touch. The common lab model systems have been chosen over the years because they can be manipulated genetically. One of the niceties of these model organisms such as the fruit fly (Drosophila melanogaster) and the nematode worm (Caenorhabditis elegans) is that they can be bred rapidly and in a controlled manner. Human geneticists do not have this luxury when they ply their trade. The ethical problems with doing human crosses is so obvious that we need not even go there. So, human geneticists use tricks, as in the case of Lupski, where a pedigree is well known for the disorder.

Another technique is to use twin studies. This tried-and-true approach in genetics is important because of the way that traits are inherited. Twin studies exploit the fact that there are two kinds of twins from a genetic perspective. Some twins are monozygotic and arise from a single egg that gets fertilized and then literally splits to make two clones of itself; the two developing embryos are genetically identical, and hence the twins are called identical twins. Other twins arise as a result of two eggs being fertilized at the same time by two different sperm, and because two eggs are involved, they are called dizygotic or fraternal. Dizygotic twins are no more closely related to each other than two siblings born from different births of the same parents. Twins who participate in these kinds of studies are reared together, and that is part of the trick of twin studies. The rearing together ensures that the environments of the two individuals are as similar as possible. Further, identical twins have the same genomes, whereas fraternal twins do not. But when both kinds of twins are reared together, they experience the same environment. Whatever differences there are between them should be caused entirely by genetics, and so by measuring traits of both kinds of twins, researchers can determine the heritability of the traits. Geneticists use an approach that results in what is called the heritability (h2 or h-squared) of the trait. Heritability ranges from 0.0 to 1.0, and traits with heritability close to 1.0 are considered to be nearly completely genetic; those with heritability close to 0.0 are considered to have minimal genetic context.

A pioneering twin study was done in 2012 in Germany using more than three hundred subjects. Of these about two hundred were twins—sixty-six pairs identical and thirty-four fraternal. Researchers obtained heritability measures for two touch mechanosensory traits (fine touch and sensing vibration). In addition, they measured hearing and temperature sensing traits. The researchers were able to show clearly that mechanosensory touch traits have a genetic component. A surprising finding was a strong correlation between touch and hearing traits. By examining test subjects who were severely deaf, they showed that some deaf subjects had terrible tactile acuity, strengthening their contention that good hearing means good touch.

These researchers then turned to known syndromes associated with hearing impairment. One such system they could examine is Usher syndrome because of the concentration in Europe of people with this hearing impairment syndrome. There are three major types of Usher syndrome—USH1, USH2, and USH3—with the severity of the syndrome higher in USH1 and the lowest in USH3. The clinical manifestation is early onset deafness and later-onset retinitis pigmentosa, causing vision problems. Using the same touch tests that they applied to the twins, the researchers examined people who had USH2 (the intermediate type). The subjects had all been genotyped for a specific mutation in a gene called usherin (also called USH2A) that is known to be involved in the syndrome and codes for a protein known to be involved in the workings of the inner ear. Some subjects had known USH2A mutations, and other participants did not. A surprisingly clear-cut result ensued. Those participants with the known USH2A mutations also showed poor tactile acuity, and those with genetic changes not in the USH2A gene were pretty good at touch. This study identified that the USH2A mutation has a common impact on both hearing and touch.

The researchers also studied touch in blind people to determine whether blindness was correlated with tactile acuity. The results demonstrated clearly that there was no correlation. In fact, visually impaired people often have higher tactile acuity than others, suggesting a plasticity in the tactile sense. What we lose in one sense, we can sometimes overcome because of the plasticity of others.