When Windows operating system starts to run funny, system administrators refer to it as “Windows Rot”. It is not unusual for businesses to routinely reinstall Windows programs every six months to avoid windows rot. Somehow, somewhere, the programming drops something. We are learning that genetic reprogramming is also a bad thing.
Interestingly, central pain was one of the very first conditions where genetic reprogramming was postulated to be the cause for a medical condition. In CP, output of Nerve Growth Factor in the surrounding glial cells which surround neurons in a ratio of 5:1 had the unfortunate ability to reprogram genes in the neuron to begin to manufacture pain exciters, leading to undesirable proteins, especially the Nav 1.3 ion channel. Nav 1.8 is the normal adult sodium channel in pain neurons. Nav 1.3 is a FETAl ion channel, presumably there to make the skin of the fetus uncomfortable with too much touch of the uterine wall, thereby preventing limb deformities from undesirable positions and posture. The genes producing Nav 1.3 turn on and off during embryonic life in an orchestrated drama designed to balance comfort with occasional discomfort, lest the baby become too habituated to a bad posture. Adults never have Nav 1.3. Our pain is handled by Nav 1.8. However, in central pain, the genetic programming changes. CP patients develop “Nav rot”. (NaV stands for Voltage gated Sodium channel, or which there are at least twenty).
The dorsal root ganglia are positioned just outside the cord and represent the home of the cell bodies of the neurons who send axons out to the body to pick up sensation. From the DRG, sensory signal goes directly into the dorsal horn of the spinal cord, hitting layers which were first numbered by Rexed. Layer I contains very fine fibers (specialized C fibers) which supply large portions of the body, up to one half the body by a single cell. Layer II, or the substantia gelatinosa, represents the termination of C fibers coming in from the peripherae, which then hypersensitize the other larger A pain fibers to pain.
Immunfluorescence studies by Bryan Hains at Yale, (sponsored in part by Christopher Reeve’s Foundation, with Wise Young participating) showed no Nav 1.3 channels in normal dorsal root ganglia, whereas animals with central pain were absolutely peppered with spots showing the presence of these undesirable channels. Ion channels which allow sodium to pass into the cell increase the firing rate of the neuron. Since pain is frequency modulated, which is to say only the frequency of firing and NOT the amplitude of firing determines how much pain signal is sent up to the thalamus.
In some fashion, central pain was causing genes which produce the protein building blocks of Nav 1.3 channels to be manufactured, increasing the firing rate of pain neurons, and leading to hypersensitization.
Now, a second condition seems to be the result of genetic reprogramming. T cells are immune cells which identify foreign proteins and help in the development of an immune response. The immunity is fairly specific. However, it has now been discovered that considerable genetic reprogramming occurs even with trauma.
In a study linked to the Proceedings of the National Academy of Sciences, surprising numbers of changes in the genes regulating T cells were found after severe trauma.
According to Carol L. Miller-Graziano, Ph.D., professor of Surgery and of Microbiology & Immunology at the University of Rochester Medical Center:
“Results showed that the expression of nearly 5,700 genes related to T cell function is changed in cases of massive trauma, as are 2800 genes related to the function of macrophages, partnering immune cells necessary to T cell activation. Trauma had the most profound effect on just 338 of the genes, an at least two-fold change in their expression, the process by which the information they store is converted into proteins that carry out bodily functions. Post-traumatic genetic changes had two major effects on T cells: a marked increase in regulatory protein pathways that diminished their function, and a decrease in signals that turn them on, researchers said.”
Trauma care has been stymied with no improvement in death rate over the past ten years. Doctors had wondered why some victims of trauma recover and others develop what is called “total body organ failure”. Now it would appear that T cells have turned on the person’s own body.
Something like this is almost certainly happening in central pain, although this is the first study to suggest that hundreds of genes may well be altered, rather than just a few. We hope researchers will turn their attention to central pain and inform us which genes have gone wrong. This will illuminate which genes are directly linked to pain.
The future is all good for genetic research. We just hope the government has enough commitment to make grants available to help those with pain states.