A Brief History of Stress Theory



Nearly sixty years have now elapsed since Watson and Crick announced their momentous discovery of the DNA mechanism in 1953. From our distant perspective, it is difficult to comprehend the excitement that pervaded the worlds of medicine and biology in that exhilarating era.  The achievement was unprecedented, and many thought that the very secret of life was at hand.  Stress theory was born only a year later, in the midst of this intense excitement, when Dr. Hans Selye postulated the presence of a single physiologic mechanism (aka “stress mechanism”) that repairs and maintains the vertebrate body. His visionary insight was that combinations of stressful forces and stressful stimuli activate this mechanism, so that its fluctuating activity explains all manifestations of stress, disease, and physiology. Dr. Selye believed that this would provide the basis for a Universal Theory of Medicine that would explain the relationships between and among diseases and physiology, and thereby revolutionize medicine. It would enable practitioners to focus their treatments on the actual cause of disease rather than judge them in terms of their effects on symptoms. This would enable medical treatments to be far more predictable and effective. The idea was so simple and powerful that many expected that the discovery of the stress mechanism would be the next great advance in biology. Thus for some 30 years after its inception, stress theory inspired a massive international research effort to find the stress mechanism that explains how stress theory works. The intense research during that era produced many important advances, including photosynthesis, the Krebs Cycle, the immune system, the Hypothalamic-Pituitary-Adrenal (HPA) Axis, and the coagulation cascade. Clinical anesthesia research produced a solid body of information that showed how the addition of analgesia to anesthesia improves surgical outcome. Selye’s visionary ideas established a science and introduced the concepts of stress, stressor, eustress, distress, and the general adaptation syndrome. More recently, the terms allostasis and allostatic load have supplanted Selye’s classical terms.

The search for the stress mechanism consumed the careers of hundreds of researchers, sacrificed thousands of test animals, and cost the equivalent of billions of dollars, but it failed to find even a clue to the existence of the mysterious stress mechanism. Worse yet, though the animal experiments were well intended, they were often necessarily harsh and cruel, and thus inspired a “backlash” of protests and regulations that have sullied the image of science and produced restrictive regulations that inhibit research efforts. The failure to find the stress mechanism was so frustrating that the effort was gradually abandoned and rejected.  Most experts now believe that no single mechanism could possibly explain the bewildering multitude of manifestations of stress, disease and physiology, and that such a mechanism would surely have been discovered by now if it actually existed. As a result, stress theory is now relegated to the status of the unicorn.  It has now been more than 30 years since stress theory was abandoned and rejected, so that most students and researchers have never heard of it. Meanwhile, attempts to explain adult physiology, pathology and allostasis in terms of DNA/RNA signaling (aka "Genomics") have become increasingly complex, speculative and tenuous, so that it becomes more obvious with each passing day that this concept has exceeded the limits of its utility. Seen in the context of scientific history, the stage is now set for the appearance of a more effective theory.

The previous generation of stress theorists and researchers thought long and hard about the characteristics of the stress mechanism in their efforts to find it. They knew that the DNA mechanism by itself couldn’t explain how genetic information is converted into embryological cell proliferation and differentiation. They therefore reasoned that there is a "companion mechanism" that works closely with the DNA mechanism to enable embryological development, and that this "stress mechanism" remains active throughout life to maintain and repair mature structures, while the DNA mechanism becomes quiescent once embryological development is complete. This offered the simplest explanation of observed facts. Indeed, despite intense research efforts for the past 60 years, little evidence of DNA activity has been found after embryological development is complete. This explains why genomics research grows more frustrating with each passing day. 

The old stress researchers encountered a major problem in their efforts to describe the stress mechanism: they were unable to imagine a single mechanism that could explain all aspects of physiology, pathology and stress as predicted by Dr. Selye. The best they could do was develop capillary gate theory and unified tissue repair theory.  Each of these concepts is powerful and provocative, but neither can explain all manifestations of physiology, pathology, and stress.

Capillary gate theory is based on the assumption that a sub-microscopic mechanism governs capillary blood flow. The idea is appealing, because capillary surface area is far greater than the combined total of larger vessels, and blood turbulence, pressure and flow is minimal at the capillary level, so that blood flow could be controlled more efficiently and effectively at the capillary level than in larger blood vessels. The capillary gate also explains capillary hemostasis, where capillary blood loss mysteriously ceases after approximately 10 minutes, even though capillaries lack muscular elements that could produce vasoconstriction. Moreover, the presently prevailing notion that muscular vasoconstriction explains hemodynamic physiology is a weak concept, because vascular muscle contraction is a brief and energy-intensive phenomenon that is soon followed by exhaustion and obligatory vasodilation.  It cannot explain sustained elevations of blood pressure and flow resistance that are observed in essential hypertension and other conditions. There is considerable evidence that the capillary gate mechanism exists, but nobody has ever been able to identify the mechanism, so that capillary gate theory remains untested and unproved.  Because of this, it is seldom discussed today.

 Unified Tissue Repair Theory is based on the observation that tissue repair occurs in a predictable sequence, beginning with clot formation, followed by inflammation that loosens cell connections, chemotaxis that draws repair cells into damaged tissues, fibrin infiltration that facilitates cell activities, cell proliferation and collagen production that produces granulation tissue that fills the wound, immune cell activation that removes debris and fights infection, angiogenesis that supplies perfusion to granulation tissues, and finally apoptosis that draws wound edges together.  This predictable sequence suggests the presence of a single control mechanism that governs tissue repair, but such a mechanism has yet to be identified, so the idea cannot be tested.

 Capillary gate theory provides a superior explanation of hemodynamic physiology, but it does not explain tissue repair.  Tissue repair theory explains tissue repair, but it does not explain hemodynamic physiology.  Because of this, the two theories have traditionally been regarded as competing or incompatible, and it has never been expected that both theories are correct, or that both might be incorporated into a single mechanism that explains both hemodynamic physiology and tissue repair.  However, it turns out that the “Stress Repair Mechanism” (SRM) incorporates semi-independent sub-components that are analogous to capillary gate theory and tissue repair theory, so that the SRM simultaneously explains hemodynamic physiology and tissue repair as well as the multiple effects of stress, pathology and physiology.  This is the great surprise of the SRM. The old stress theorists would no doubt be gratified to see that their old ideas were so close to reality, but they would have been amazed to see that both are incorporated into the same mechanism.  They would have been further astonished to see that the SRM is analogous to the old coagulation cascade concept that appeared during the heyday of stress research.  The SRM incorporates recent research evidence that shows how nervous activity affects coagulation enzymes, how thrombin energizes cell and enzyme activities, and how the SRM regulates thrombin throughout all tissues to energize and regulate tissue maintenance and repair. Thus stress theory is at long last poised for verification, acceptance and exploitation, because the long-anticipated SRM that explains its operation has been identified.

The old stress theorists and researchers were amazingly insightful, and they were a lot closer to success than they could ever have known.  They might be likened to Jules Verne trying to plan a trip to the moon before rockets were invented. There were critical gaps in the information available to them in their time.  Little was known about the vascular endothelium, the relationship of thrombin to tissue repair, and the function of Factor VIII and other blood enzymes. There was no Internet, and no email.  They were simply too far ahead of their time.

 “In science, the credit goes to the man who convinces the world, not to the man to whom the idea first occurred.” –Sir William Osler

“It is a popular delusion that the scientific enquirer is under an obligation not to go beyond generalization of observed facts...but anyone who is practically acquainted with scientific work is aware that those who refuse to go beyond the facts rarely get as far.” -----Thomas Henry Huxley





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