An Alzheimer's Bet Based on Biology

Alzheimer's research has been accused of being hijacked by a misleading hypothesis that only survives to enrich drug companies.  The amyloid hypothesis has been extensively critiqued, including by this essay on the blog Astral Codex Ten that looked at problems with the original paper that started (by some accounts) 30 years of misguided research.  

In response to a call for counter-arguments, David Schneider-Joseph, presented a compelling argument in favor of the amyloid hypothesis.  He even went so far as to propose a bet; that a drug targeting amyloid would achieve at least a 75% slowdown in Alzheimer's in the next 12 years.

I wouldn’t take David’s proposed bet, because I’m sure some company will find a way to gerrymander clinical endpoints to get to 75% “slowdown”.  Probably with a drug that has horrible side effects and costs north of $100,000/year.  

I would bet on the following:  the leading* therapy in 12 years will not be one whose sole intended mechanism involves amyloid production or clearance, e.g. monoclonal antibodies, small molecules, or gene editing that work directly on amyloid.  

    * “Leading” means some combination of efficacious and most widely used.

This is the important sense in which the amyloid hypothesis is wrong: it may be “correct” in some narrow biochemical sense, but it is a dead end.

In a way this is an easy bet on the status quo continuing indefinitely, because the current drugs used to treat Alzheimer's do not target amyloid.  However, I’m also bullish on emerging therapies such as creatine, lithium, calcium channels, and mitochondrial therapies including far infrared, ketones, and other ways to generally affect metabolism and autophagy/mitophagy.  Some of these might be shown to improve clearance of amyloid, but the amyloid hypothesis is not necessary or very helpful in the development of these “general" therapies.  

My prediction is based on a general model of how biology works.  Simple infectious and traumatic medical conditions seem most amenable to targeted therapies, while general conditions like mental illness, cancer, and Alzheimer’s are so complicated and depend on so many general health processes that targeted therapies tend to miss the mark.  

Ideally, we would pursue both lines of treatment, but our pharma system is biased toward patentable targeted treatments to the exclusion of all else.  The “Amyloid Mafia” is shorthand for this trend in Alzheimer’s research.  

However, even given the funding disparity between amyloid research and other treatments, non-amyloid treatments are arguably already more efficacious.  As a good Bayesian, I predict this will continue, and so this seems like a safe bet to me!

Blood oxygen concentration during Wim Hof breathing

 Here is some interesting data:  Blood oxygen concentration and heart rate during three cycles of Wim Hof hyperventilation and breath holding.

Total elapsed time 14 minutes.  3rd breath hold I went two minutes and bottomed out the blood O2 meter!

Method: 

Followed "Guided Wim Hof Method Breathing" video on Youtube.  

Used Wellue O2 Ring Blood Oxygen Monitor to measure blood oxygen. I tested several wrist spO2 monitors and this finger spO2 monitor is much faster and more accurate. 

Atherosclerosis

Pathogenesis of atherosclerosis. (a) In the first stage, low density lipoprotein-cholesterol (LDL) is deposited in the endothelium and undergoes oxidative modification, resulting in oxidized LDL (oxLDL). OxLDL stimulates endothelial cells to express adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), P-Selectin) and various chemokines (e.g., Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin 8 (IL-8)). This leads to a recruitment of monocytes, which transmigrate into the intima and differentiate to pro-atherogenic macrophages; (b) Macrophages harvest residual oxLDL via their scavenger receptors and add to the endothelial activation and, subsequently, leukocyte recruitment with the secretion of Tumor Necrosis Factor α (TNF-α) and IL-6; (c) The increasing plaque volume promotes neovascularization. Proliferating smooth muscle cells (SMCs) stabilize the nascent fibrous plaque. With deposition of fibrin and activated platelets on the dysfunctional endothelium that expresses tissue factor (TF) and von Willebrand factor (vWF), a pro-thrombotic milieu is formed; (d) Foam cells can undergo apoptosis and release cell-debris and lipids, which will result in the formation of a necrotic core. In addition, proteases secreted from foam cells can destabilize the plaque. This can lead to plaque rupture, in which case extracellular matrix molecules (e.g., collagens, elastin, TF, vWF) catalyze thrombotic events.
(PMC full text: Int J Mol Sci. 2015 May; 16(5): 9749–9769. Published online 2015 )

Future of blood testing?

Data is power, and these four potentially-revolutionary blood- or breath-testing companies could help generate next-generation medical insights:

University of Southampton, Sharp Labs Europe is developing a mobile lab-on-a-chip 5-10 years

Integrated Diagnostics has a "sniffer" test to look for lung cancer. http://www.indidx.com/articles

V-chip to test 50 different blood chemical markers with microfluidics is still in development. 5-10 years

Theranos lab testing is already cheap and easy online, but they have recently been investigated by the FDA for failing to prove that their tests are accurate.

Traditional Chinese Medicine - 5 Phases Theory

Graphic from pulse-academy.org.

Graphic from pulse-academy.org.
For more archetypal correspondences, see http://www.adducation.info/lifestyle/five-elements/

The Traditional Chinese Medicine (TCM) approach to health is based on categories (types, archetypes) and balance. The first thing to note is that stereotypes actually help individualize nutrition and health by putting human differences front and center. One size doesn't fit all when we acknowledge the obvious truth that humans can be more different than similar. Recognizing these differences and similaries is aided by categories. (see danger below).

Secondly, nutrition and health are pretty complicated. Even the simple dictum to "Eat whole foods, mostly plants."(Michael Pollan) hides a huge amount of confusion and contradiction about what is healthy and how to cook it.  Books like "The Perfect Health Diet" are a great place to start and I won't argue with their research showing the optimum ratio of the various macronutrients and amount of micronutrients to consume.  But which spices to eat, what recipes to make, how much exercise to get, and when to wake up in the morning are not covered.  A more intuitive approach is needed to comprehend the human condition.

Third, the importance of balancing constitutions and forces is absent from much of modern nutrition, which acts as if a simple summation of inputs is enough to insure health. Perhaps the most important insight of TCM-based approaches and Hippocratic humours is that health is the sum of harmonious balancing interactions (i.e. homeostasis, for the scientists). There are too many forces and nutrients to consider to balance every input and output analytically. A wholistic approach is needed.

However, one danger of the archetypal approach is the tendency toward simplification and identification. For example, saying that "I am a water-type", or "I am a phlegmatic". Many people resist such limiting classification, rightly so, and with good reason. The trick to using archetypes is to lean on them gently, maintain perspective, and flexibility.  No one is X.  They are themselves, a real, infinitely-complex human system.  But many of us manifest observable types, and recognizing those types gives us the three advantages described above.

 Another danger, perhaps part of the danger listed above, is the hermetic tendency to see all people, phenomena, etc within one system of thought.  No system can be complete. TCM cannot answer all questions, and it is unbalanced to rely on it obsessively. Another closely related danger is the esoteric tendency to compile endlessly complicated tables, enumerations, calculations, and the like, in order to fit all people and phenomena into a system. This is the inevitable result of the hermetic temptation to apply one categorical system to all phenomena.

 Pavlov encountered this when he tried to explain his dogs' behavior using Hippocratic types. He was forced to expand, and then expand again, endlessly redoubling the complexity of the system to attempt to fit a (probably infinite) range of idiosyncratic variation within a comprehensive system. Somewhat the same tendency can be seen in the 16 Type Indicators of Myers Briggs testing, which was an outgrowth of Pavlov's work. The system could easily be expanded to 32, or 64, or.. types, in order to continue to incorporate more degrees of variation. But the cost to understanding and ease of use is progressive.

 As any system becomes more baroquely complicated, it begins to lose the explanatory power of simplicity. In any analytical system, there must be a balance between conceptual simplicity and accuracy.

Traditional Chinese Medicine

"The logic underlying Chinese medical theory - a logic that assumes that a part can be understood only in its relation to the whole -- can also be called synthetic or dialectical.

The character for Yin originally meant the shady side of a slope.  It is associated with such qualities as cold, rest, responsiveness, passivity, darkness, interior, downward, inward, decrease, satiation, tranquility, and quiescence.  It is the end, completion, and realized fruition.

The original meaning of Yang was the sunny side of a slope.  The term implies brightness, heat, stimulation, movement, activity, excitement, vigor, exterior, upward, outward, and increase.  It is arousal, beginning, and dynamic potential.  

All things have Yin and Yang aspects....and any Yin or Yang aspect can be further divided into Yin and Yang.  

Yin and Yang mutually create, control, and transform one another.  Although Yin and Yang can be distinguished, they cannot be separated.   Yin and Yang are always subtly supporting, repairing, and transforming into one another.  This constant transformation is the source of all change.  Organic transformation can occur harmoniously in the normal course of events or sudden ruptures can occur. If Yin and Yang are unbalanced for prolonged periods of time or in an extreme manner, the resulting transformation can be drastic.  

Lao Tzu says:  

In order to expand, it is necessary to first contract.  In order to stregthen, it is necessary to first weaken.  In order to create, it is necessary to first destroy.  In order to give, it is necessary to first take.

In Chinese thought, events and phenomena unfold through a kind of spontaneous cooperation, an inner dynamic in the nature of things.  The key word is Pattern - people and things behave in particular ways not necessarily because of prior actions or impulses, but because their position in the cyclical universe and their endowment with intrinsic natures. 

The Chinese assume that the universe is continuously changing.  The cosmos itself is an integral whole, a web of interrelated things and events.  The desire for knowledge is the desire to understand the interrelationships or patterns within that web, and to become attuned to the unfolding dynamic.

A traditional Chinese landscape painting captures the essence of nature in balance and in flux.  The paiting is like the Taoist symbol, containing Yin and Yang in their proper proportions but constantly interacting and transforming into each other.  

The scene depicts a vast range of elements, from the towering mountain to the little trickling stream.  Nature is shown as a balance of the yielding Yin (foliage, water) and the unyielding Yang (rock, trees).  There are the dynamic (water, people) and the quiescent (mountains, houses); the slow (trees) and the fast (mist); the dark and the light; the solid and the liquid.  All things contain both Yin and Yang.  The water, for instance, is both yielding (Yin) and dynamic (Yang).

The picture is a totality, and each detail takes on meaning only as it participates in the whole.  The mountain is immense by virtue of its smaller foothills; the people are small by virtue of the vastness of nature.  All things are imbued with interactive qualities and dynamics in their relationships to the things around them.

The painting depicts a time and place that through their correspondence with the cosmos become timeless and placeless.  It rediscovers the elemental and continuous course of the cosmic pulsation through the figurative representation of a landscape...The tension created by the correlation between the lines and the washes, the visible and the invisible, fullness and emptiness, endows the landscape with a power to suggest more than the merely visible and open it to the life of the spirit. " 

(from p. 7-17 The Web That Has No Weaver by Ted Kaptchuk)

What if "Integrative Medicine" and "Alternative Therapies" Are Full of .... ?

What if the most valuable thing to come out of the vast torrents of nutrition bloggers and comments on those blogs and alternative medicine conferences, etc, is this chart of dookie? That's what the authors of the Science Based Medicine blog seem to think.

At least this chart presents an actual, observable, measurable observation of the world!

Contrast this chart with the endlessly proposed and promulgated (without testing) navel-gazing "syndromes" that could be any disease or no disease at all.  While I don't necessarily think alternative medical treatments are completely bogus, I have noticed that most alternative therapy information is heavy on the factoids, but very light on actual testable theories or metrics.

But maybe.... instead of criticizing scientifically-untested therapies, we should make an effort to test them!  When it comes to health the line between objective science and subjective experience blurs and I'm never sure which source of information to trust.  Maybe, in the end, after all the scientific and unscientific hypotheses, we just have to follow our gut-instincts!

If you do, this Bristol Stool Chart may be a helpful metric!

Microbiome and Disease: Experimentation, Gulf War Syndrome, and Mycoplasma

Humans are host to a large number of bacteria which may influence health and disease. Whether or not any given microorganism, such as E coli, becomes pathogenic is not understood. What is becoming increasingly clear is that, in addition to exogenous influences such as diet and exercise, endogenous factors such as bacteria (and genetics!) are crucial determinants of human health. Carl Zimmer, science writer, has proclaimed: "I, for one, welcome our microbial overlords!" after reviewing recent research establishing that certain bacteria can lead to obesity. His famous New York Times fecal transplant article is here.

In the absence of scientific certainty, groups of concerned citizens have begun moving forward, experimenting with antibiotics and probiotics to try to nudge the population dynamics of their microbiome toward healthier states. This emerging field, combined with the failure of the medical community to communicate and collaborate with patients who are sick and aren't being helped by currently available diagnosis or treatment has created fertile ground for web-based DIY experimentation. The community of Chronic Fatigue Syndrome sufferers in particular have latched onto research examining possible links between a tiny gram-negative bacterium called Mycoplasma fermentans and Gulf War Syndrome. The bacteria, which can apparently be a member of normal human microbial flora, is implicated in the vague symptoms of GWS, and by extension, CFS. A definitive book on GWS found little evidence to suggest such a link, but the initiator the research, Dr. Nicholson, has forged ahead nonetheless, starting a nonprofit research lab to investigate and link between Mycoplasma fermentans and health problems.

It is unfortunate that so much of the information available online is anecdotal. If these types of alternative medical practices could keep better data it may be possible to scientifically evaluate them. However, in the absence of peer-reviewed double blind trials, it appears many people are simply grasping for any treatment that offers hope, no matter how unsupported. Indeed, the scientific jury is still out, and this developing field may see fringe transformed into mainstream.

Research into M. fermentans is certainly controversial, but continuing: see, for example:

Kawahito et al. Mycoplasma fermentans glycolipid-antigen as a pathogen of rheumatoid arthritis. Biochemical and Biophysical Research Communications. 2008;369(2):561-566.

Medical Decision-Making

When a doctor diagnoses a patient, who makes the decision about treatment? Perhaps the patient defers to the knowledge and authority of the doctor: "you're the doctor, you decide." Although the structure of power dynamics between the doctor and patient can bias decision-making, the final decision usually comes down to money, which is decided by the insurance company. So how does a large insurance company decide what procedure to pay for?

Others have pointed out that this is a system of misaligned incentives can lead to situations where, for example, insurance companies would be much more worried about over-prescribing rather than under-prescribing treatment. So how do insurance companies do this in practice? By conducting a scientific review of all published literature on a given treatment, and then evaluating it. For example, Aetna's Clinical Policy Bulletins lay down the law of what is, and isn't accepted medical diagnosis and treatment.

"Brawling Over Mammography"

An interesting debate about the problem of false-positives in medical testing. Obviously, everyone wants to be tested "just in case", but a sensible policy would favor plausibility testing; everyone is not equally likely to have every disease. This article from the February 19, 2010 issue of Science, details the situation surrounding the release of a report by the U.S. Preventive Services Task Force that ran afoul of political accusations of "medical rationing". For women age 40-49 years with no other risk factors, the odds that a positive mammogram is actually due to cancer, rather than a false-positive test, is only about 2%. In other words, for every one breast cancer detection, 50 women are told that they have tested positive on their mammogram.

Doctoring is a Doomed Profession

Although medical doctors have quite a large amount of power in our economy, I believe that their bargaining power is being diminished by technological innovations and managerial restructuring. Robin Hanson's idea of negative health care would significantly raise the prestige of massage and personal training at the cost of doctors.

Jason I. Altman predicts: "By 2030 all surgical anesthesia will be administered and monitored by computers, with no need for professional medical supervision beyond the surgeon." Even sooner than that we are likely to see outsourcing of surgery, as robots controlled from the next room are replaced by robots controlled from India.

Its only a matter of time until large, centrally-controlled and ineffecient hospitals are replaced by "the Trader Joes of healthcare", a business model that goes straight from the drug companies to the client, and "cuts out the middleman" who in this case is none other than the good Doctor.

DNA screening is the wave of the future. Ever seen GATTACA? You can currently buy limited DNA tests that will soon be cheaper than a doctor's visit to tell you everything from whether your kids are likely to have Crutzfield-Jacobson disease to what your life expectancy is based on genetic markers for cardiac disease.