Michael Fossel Michael is President of Telocyte

July 20, 2016

Curing Disease: More Insight Instead of Mere Effort

 

Curing disease correlates with insight, not blind effort.

There is an eternal trade-off between insight and effort. If we think carefully, understand the problem, and plan, then effort is minimized. If (as too often happens) we think carelessly, misunderstand the problem, and rely on hope instead of planning, then effort is not only maximized, but is usually a complete waste. Lacking insight, we foolishly flush both money and effort down the drain. In the case of clinical trials for Alzheimer’s disease – and in fact, all age-related diseases – this is precisely the case.

The major problem is a naïve complaisance that we already understand aging pathology.

If there was a single concept that is key to all of aging, it is the notion that everything in our organs, in our tissues, and in our cells is dynamically and actively in flux, rather than being a set of organs, tissues, cells, and molecules that statically and passively deteriorate. Aging isn’t just entropy; aging is entropy with insufficient biological response. Senescent cells no longer keep up with entropy, while young cells manage entropy quite handily. At the tissue level, the best example might be bone. We don’t form just bone and then leave it to the mercy of entropy, rather we continually recycle bony tissue throughout our lives – although more-and-more slowly as our osteocytes lose telomere length. This is equally true at the molecular level, for example the collagen and elastin molecules in our skin. We don’t finish forming collagen and elastin in our youth and then leave it to the vagaries of entropy, rather we continually recycle collagen and elastin molecules throughout our lives, although more-and-more slowly as our skin cells lose telomere length. Aging is not a process in which a fixed amount of bone, collagen, or elastin gradually erodes, denatures, or becomes damaged. Rather, aging is a process in which the rate of recycling of bone, collagen, or elastin gradually slows down as our shortening telomeres alter gene expression, slowing the rate of molecular turnover, and allowing damage to get ahead of the game. We don’t age because we are damaged, we age because cells with shortening telomeres no longer keep up with the damage.

The same is true not only of biological aging as a general process, but equally true of every age-related disease specifically. Vascular disease is not a disease in which our arteries are a static tissue that gradually gives way to an erosive entropy, but an active and dynamic set of cells that gradually slow their turnover of critical cellular components, culminating in the failure of endothelial cell function, the increasing pathology of the subendothelial layer, and the clinical outcomes of myocardial infarction, stroke, and a dozen other medical problems. Merely treating cholesterol, blood pressure, and hundreds of other specific pathological findings does nothing to reset the epigenetic changes that lie upstream and that cause those myriad changes. Small wonder that we fail to change the course of arterial disease if our only interventions are merely “stents and statins”.

Nor is Alzheimer’s a disease in which beta amyloid and tau proteins passively accumulate over time as they become denatured, resulting in neuronal death and cognitive failure. Alzheimer’s is a disease in which the turnover – the binding, the uptake, the degradation, and the replacement – of key molecules gradually slows down with telomere shortening, culminating in the failure of both glial cell and neuron function, the accumulation of plaques and tangles, and ending finally in a profound human tragedy. The cause is the change in gene expression, not the more obvious plaques and tangles.

Our lack of insight, even when we exert Herculean efforts – enormous clinical trials, immense amounts of funding, and years of work – is striking for a complete failure of every clinical trial aimed at Alzheimer’s disease. Naively, we target beta amyloid, tau proteins, phosphodiesterase, immune responses, and growth factors, without ever understanding the subtle upstream causes of these obvious downstream effects. Aging, aging diseases, and especially Alzheimer’s disease are not amenable to mere well-intended efforts. Without insight, our funding, our time, and our exertions are useless. Worse yet, that same funding time, and exertion could be used quite effectively, if used intelligently. If our target is to cure the diseases of aging, then we don’t need more effort, but more thought. However well intentioned, however much investment, however many grants, and however many clinical trials, all will be wasted unless we understand the aging process. Aging is not a passive accumulation of damage, but an active process in which damage accumulates because cells change their patterns of gene expression, patterns which can be reset.

Curing Alzheimer’s requires insight and intelligence, not naive hope and wasted effort.

 

 

July 5, 2016

Dynamic versus Static – Going to Mars or Curing AD

Innovation requires novel thinking, not incremental actions.

We can cure age-related diseases – such as Alzheimer’s – not with funding, intelligence, or effort alone, but only if we reassess our assumptions. Until we look carefully at our conceptual foundations, we cannot expect to build a therapeutic structure. Ironically, the key problem lies in our looking at biology, medicine, and disease as static, passive processes. One would think we would see these processes as active and dynamic, but oddly enough, we don’t.

Consider an analogy: going to visit Mars.

Clearly, we need some essentials of life-support, such as oxygen and water. If we start by asking ourselves how much of each we need per day per person, then how many days and how many persons, we end up with an enormous need for both: huge amounts of oxygen, huge amounts of water. After all, we don’t want to run out of oxygen or water, do we?

Remember, however, that in a closed system (such as a vehicle going to Mars), that neither oxygen nor water are actually used up en route, only changed from one form (such as oxygen molecules) to another (such as carbon dioxide molecules). The water molecules may be in the form of body waste, but they are still present in the vehicle. And both oxygen and water – given energy and technical forethought – can be recycled and reused indefinitely. The practical question is not simply “how much oxygen and water do we need”, but “how efficiently and quickly can we recycle oxygen and water?” In short, the key question isn’t the static and passive one of “how fast are we using up our oxygen and water?”. The key question is the active and dynamic one of “how does the rate of recycling compare to the rate of oxygen and water use?”

The analogy is exact.

In the case of Alzheimer’s, for example, the key question isn’t “how can we prevent the accumulation of beta amyloid and tau protein?”, but rather “how can we increase the rate of recycling of molecules such as beta amyloid and tau proteins?” The former question would be like asking “how can we prevent the use of oxygen and water?”, while we should be asking “how can we increase the recycling efficiency of oxygen and water?”

Current approaches to treating Alzheimer’s disease focus inordinate funding, intelligence, and effort on the wrong question. Small wonder they fail.

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