The Selye Phenomenon: Scientists Behaving Badly

Hi, I'm Dr. Jeff Bland and I'm the president and founder of the Personalized Lifestyle Medicine Institute. And I'd like to raise what I think is probably a serious question with you for a moment. If you're at all interested in the evolution of medicine, of health care, how decisions are made, what evidence is required to make a decision, how does the standard of identity change over time? This is a big one I'm going to share with you, so hold tight, keep yourself strapped in and don't get too upset too quickly. Let me go through the topic. So I want to start with the most singularly most used in the English language that's applied to healthcare. And you know what that is? It's the word stress. And how did that word stress get in the lexicon of medicine and physiology when it was really born out of physics, stress and strain, mechanical issues. And yet somehow we associate it so strongly with, with physiology. And it's a common used term not just in the trade in the medical field, but across all sectors of our society, people are familiar with an understanding of what stress means in physiology. Well, as you know, the person who appropriated that term physics over into physiology in the late 30s, 1930s, was a physiologist working in the early days of endocrinology at McGill University in Montreal, Quebec, Canada, Dr. Hans Selye. And his science and history is legendary in the field. And it's interesting to note, isn't it, that this individual who coined a term and built a concept within physiology, the so called general adaptation syndrome, and gave rise to an understanding of stress related disorders that had never before been understood, never won a Nobel Prize in physiology and medicine. Why? Why? With a person that made that contribution. And that leads me into a topic that I hope you'll appreciate. How discoveries are made and how they gain stickiness and become part of the guild. And I want to use the term guild because sometimes this field of science and medicine is a guild. You got to be a member of the club. So when I think of Hans Selie and I go to the history, I'm led back into many books that have recorded his years of experience and contributions up through the 60s and the 1970s and the magnificent legacy he left us. But one of the books which really struck me in reading about his life and history was a book called the Stress Myth. The Stress Myth, Science and Humanities Press in 2000 after his death. So recounting in 287 pages what they consider to be the myth of his discovery that stress really is not A physiologically hardcore term that he never was fully cloistered by the scientific field in which he operated in. He didn't have the level of evidentiary support that was necessary to fully prove his hypothesis. And therefore we somehow should question the importance of Hans Selie and his contributions to medicine and physiology. There is always these doubting individuals, aren't there, in science and medicine. So how did that happen and why did it happen? Well, it's been purported that the reason that occurred and why Selie never got full respect for his contributions was that he never allowed himself to be a member of the Guild. He worked kind of outside the scientific and medical Guild. He did his work in his laboratory. He then had the audacity to write consumer books that were describing the physiology of stress in consumer language. And he took it around the science and medical community to the direct consumer. And that was like the kiss of death for him scientifically, that he never was validated then as a member of the Guild. His methods, although they stuck and they created huge change, he never got the accreditation that he deserved. How does this play out today? Let's move from stress to a companion issue and that is another neurologically related condition which are called neurodegenerative diseases. And let's move to a more recent discussion, not the book in 2000 written about Hans Selye and the supposed myth of stress, but let's move to pseudo medicine. The article discussing the rise of other ways of approaching neurodegenerative diseases, particularly Alzheimer's. And I'm struck when I read this editorial that appeared in the Journal of the American Medical association more recently. This is in the February 12 issue of 2019, the title of which is the Rise of Pseudo Medicine for Dementia and Brain Health, in which the investigator authors of this editorial, who are all faculty members at the University of California San Francisco School of Medicine in the neurology department, took umbrage and strong criticism of anyone who would take to the general public directly approaches that would be considered out of the box thinking related to the prevention and management of neurodegenerative disorders, including Alzheimer's. And in fact I would say that this particular article is, to use the word scathing would almost be an understatement. It's a very, very critical, and I won't even quote some of the verbiage because I don't want to give it credit, but suffice it to say that the conclusions they derive is that one needs to be very cautious of self reported cures and without hard science and proof of concept that we should not get people too excited about or raise their expectations that there are approaches that could be used for reduction in their incidence or severity of neurodegeneration that are outside the bounds of traditional medical neurological therapies. Now, with that in mind as a context, let me give you some other thoughts that might relate to this. So I'm now going to go to the New England Journal of Medicine. Most of us would say that that's a very highly respected, internationally regarded medical journal. And I'm going to now quote from the April 11, 2019 issue of this issue of the New England Journal of Medicine in. In which there were two papers back to back published concerning a test of a new drug for the potential treatment of Alzheimer's. So this is moving into phase two, phase three clinical trial work. These are beta secretase inhibiting drugs, which are known, by the way, at least in the animal studies and in some in vitro work, to lower amyloid deposition, assuming that these amyloid plaques, these neuropapillary plaques that are associated with amyloid plaque deposition are the causative agents for Alzheimer's disease. So if you could find a silver bullet or a gold or platinum bullet that went directly in and blocked amyloid production, beta amyloid, that you could then prevent and even treat Alzheimer's disease. And so there are many, many different companies in drug development that are focusing on different ways of blocking these pathways, these specific approaches towards what is considered the idiopathology of ALZH Alzheimer's. And so what the editorial that follows these two papers that are published in the New England Journal of Medicine talk about is the fact that neither of these studies showed clinical success. Not only did they not show clinical success, but the patients got worse on the drugs. Now, that's like the kiss of death, right? You spend a billion dollars developing a drug to treat a condition, only to find that the drug that you're using makes the condition worse. Now, why would that be? They go on to offer a potential explanation. Because in this editorial they show that there are many different ways that these injuries that are associated with hippocampal injury associated with Alzheimer's disease might occur. It's just not like a one route to Alzheimer's. There may be multiple ideological contributors, and therefore maybe just blocking one thing has an untoward effect on other things. It produces not a benefit, but a risk. And in fact, maybe we are using a different wrong model. Maybe our model should be looking at multiple hits across multiple things to create a symphonic orchestration of the dysfunction that we call Alzheimer's, rather than thinking there's a single cause for this single named disease because maybe it's a multimodal disease. So that's really the New England Journal of Medicine saying, isn't it too bad that this is just another of the multiple trials that have been done at great expense that have demonstrated failure in the treatment of Alzheimer's disease based upon this single hit target model of pharmacology. Hmm. Well, what do we do about that? Well, that leads to another paper in this interesting litany of recent papers. This is from the Journal of the American Medical Association. Now I'm in the April 2, 2019 issue and what in this issue was a very interesting paper entitled amyloid protein emission tomography, or PET scanning and changes in the clinical management of patients with cognitive impairment. Now this is a new technology that's been developed, radiological intervention that allows for the evaluation of different anatomical structures in the brain, one of which is looking at potential amyloid deposition in certain portions of the brain. And what they find is that looking at hippocampal volume and looking at amyloid, Amyloid deposition, that maybe you can start to actually understand early on features of the disorder that allow intervention much earlier than waiting until you get serious idiopathology that we call Alzheimer's. And in fact, in the last part of this paragraph of the summary, they say ultimately the hope in the management will include access to pathophysiologically appropriate disease modifying interventions, disease modifying, pathophysiologically focused, which may be complex in their mechanism of action, not just single hit. And in fact, if you look at the association of amyloid positron emission tomography with the progression of disease, you'll find maybe you could look at multiple factorial multimodal interventions and at a much earlier stage than just a single hit technology looking at late stage disease. Okay, interesting. Now where does that take us? How does that relate to Hans Selye? Where are we today? Well, I think if we're honest, we would say that the billions of dollars that have been spent by pharmaceutical companies to date to develop drugs to treat Alzheimer's based upon a single hit mentality with a single target has been uniformly unsuccessful. Not only unsuccessful, but even in some cases, as I just talked about, creating worse outcome than the patients that did nothing. So what's the alternative? And the alternative leads us into a Hanselier like argument that without all the evidence that we might want from a placebo randomized clinical control approach towards one agent against one disease, there is evidence accumulating that this multimodal disease called Alzheimer's may need a multimodal approach for its treatment. And where is this born? This born is born out of a number of individuals. But the champion of this, of course, is the author of the book the end of Alzheimer's, a well known neuroscientist who has published literally hundreds of papers, working at the Buck Institute at UCLA at Alzheimer's research, and also, interestingly enough, at the University of California San Francisco Medical School, the exact same medical school where the critics were talking about pseudomedicine and cognitive impairment. And what has this individual, Dr. Dale Bredesen, found? He's found that maybe a multimodal approach to a multimodal disorder called Alzheimer's would be the preferential way of approaching it. And you would need to personalize the approach based upon the functional implications it had on the patient. Now, when you get into multimodal approaches against a multimodal disease, it's going to be getting very complicated to do a single target intervention based upon a traditional randomized clinical control trial against a placebo. So you're going to have to have new evidence based information, some of which is going to be nested case history, some of which is going to be observational, some of which is going to be holding some variables constant and others that can be varied, going to be a variety of different data, meta analysis, animal work and mechanistic studies and so forth, all of which has to be accumulated together into a body of knowledge that someone can get their minds and hands around to understand how to personalize the program. And that is what Dr. Bredesen has done. And so in 2014, he authored what I consider to be a landmark and somewhat controversial paper entitled Reversal of Cognitive Decline, A Novel Therapeutic Program, which is a multimodal approach to towards a multimodal condition using lifestyle intervention, personalized therapy, based on over 30 different principles that might lead to risk based upon the types of data, the evidence that I was describing across a wide variety of studies, clinical intervention, trials of open source, observational work, animal work, mechanistic studies, well, that was followed up then in 2015 with another paper published by Dr. Bredesen entitled Metabolic Profiling Distinguishes Three Subtypes of Alzheimer's disease in which he was able to start differentiating different idiophenotypes that would then maybe be candidates for different types of multimodal personalized intervention. And again, reporting this and doing it in such a way as to bring both the science and evidence together for both discussion, knowing at worst, intervention would do no harm, because these are principally lifestyle intervention personalized therapies. And then more recently and most recently, a third paper in this sequence, which is actually a clinical nested series of case histories of individuals who had actually been approached by this personalized intervention, multimodal intervention, the Brednison Protocol, as it's often been labeled, and this is entitled Reversal of Cognitive Decline in Alzheimer's Disease. Actually showing a variety of case histories of positive outcome, some truly remarkable of people who are functionally so depreciated that they were unable to be involved with activities of daily living, which after intervention resumed daily living, sometimes even getting back to where they were driving their car, once again going back to work. Really remarkable case histories. Acknowledging that this is not a randomized clinical controlled trial, acknowledging that this is fraught with the uncertainty of nested case histories and cross platform studies in multiple clinical centers. But the most important thing is that the clinical proof of concept, which is outcome, seems to point in a direction that maybe this is where therapies ought to be found. Does this sound at all like Hans Selie and the development of the stress concept in which it was not yet clinically proven by randomized clinical controlled trials? He took it outside the guild and went to the direct public. He started talking about it and training people and trying to get them to really understand the importance of stress as a mitigator to many chronic diseases. This is a similar theme. And so I ask the question, how do we as a culture adopt new information and make it part of the standards of care and to really gain traction and get it in such a way that individuals will lose their fear that if they do something different from that of their colleagues, they're not going to be exorcised from the community. I think we do so by the strength of rational thinking. We do so through the innovation and leadership of a few. We do so when individuals are willing to put themselves in harm's way and bring their ideas out and have it tested by others and show whether it's valid. We do so by leadership, like Dr. Bredesen has demonstrated. So I think this is a very interesting model example of what I call the sellier phenomena as to how ideas ultimately gain traction against the convention of the guild that sometimes already has a vested interest they're trying to protect. Interesting thought.