Michael Fossel Michael is President of Telocyte

June 23, 2015

It’s the Forest, Not the Trees

Filed under: Uncategorized — admin @ 10:15 am

Last weekend, a global entrepreneur asked me about the difference between much of the current research and what we’re doing. He cited the example of a particular compound (NAD+), but any number of other compounds could be given as examples. My answer was that most researchers are focused on their one particular tree and can’t see the forest.

Almost all current research narrows itself by looking at results, and ignoring causes. Imagine that I’m treating a patient with diabetic ketoacidosis by only treating one of their many metabolic results, such as a low potassium or an elevated blood acid level. Both of these results are typical in patients with life-threatening ketoacidosis, but neither of them is the cause of the problem. If I treat these results by adding potassium or lowering acid, will it solve the problem? No, not even close. That’s not to say that such narrow approaches don’t have benefits, but they don’t strike to the cause of the problem and they certainly don’t cure the patient. I may raise the potassium to normal levels, but I still haven’t made the patient healthy. In the case of severe diabetic ketoacidosis, giving potassium is fine, but giving hydration and insulin is better, and replacing the insulin-producing cells that made the patient a diabetic in the first place would be best of all.

Cure the cause, not the result.

We make the same error in trying to treat Alzheimer’s disease by thinking that it’s just a problem of beta amyloid deposits or tau protein tangles. What we should be doing is going “upstream” and asking why the deposits and tangles occur in the first place. Never mind the results, what’s the cause? It’s not surprising that all of the hundreds of human trials aimed at beta amyloid in Alzheimer’s disease have uniformly failed to modify the course of the disease. These trials attach results, not causes. We should be aiming at the microglial cell aging that initiates the process. I wish the best of luck to my colleagues who focus the results of disease, but they focus on single trees and they completely ignore the forest.

They go after diseases result-by-result, and tree-by-tree.

In Alzheimer’s disease research, focusing on arginine, tau tangles, APOE4, or beta amyloid is like focusing on specific instruments when we should be looking at the entire orchestra. We need to replace the score, but most current research is aimed at the specific instruments and saying that we need to replace the violin. And then the flute. And also the bassoon. And what about that oboe? And we almost forgot the piano! Oh, and don’t forget the piccolo. And the bass drum while we’re at it. Oh, my god, where’s that cello gone?

The reality is that if they’d just get the conductor (the telomere) to play the right score (the epigenetic pattern typical of a young microglia), then they wouldn’t have to deal with a hundred different instruments one-by-one, piecemeal and — if the truth be told — completely ineffectively. Whether we look at symphony orchestras or forests, the same answer applies. To put it back into the forest metaphor, the cure for Alzheimer’s lies not in a particular lichen growing on the funny-looking root on the northwest corner of one particular beech tree in the 186th quadrant of the forest, but in the entire forest itself.

It’s the forest, not the trees.

 

June 9, 2015

Epigenetic versus Genetic Disease

Last week I attended a global conference on aging research. The presentations were professional and thoughtful, as befits an organization of researchers with impeccable academic and clinical credentials. These are bright, well-educated people who work hard to understand not only the basic science that underlies aging, but the possible interventions that might cure age-related diseases. My role was to consider becoming their executive director and to discuss my thoughts on how to improve — and ensure the viability of — the organization.

Oddly enough, my biggest fear was that they might find themselves side-lined and outmoded by the plethora of advances that are leading the way, advances that promise to revolutionize both our understanding of aging and our ability to treat disease. I had the nightmarish image of a group of well-meaning and well-trained researchers who are blithely marching off the cliff en masse, happy and blind, certain of their small (and ultimately unimportant) piece of the aging puzzle.

The problem is that science changes.

Science has a history of progressing in straight lines until reality abruptly intrudes. We happily refined the epicycles needed to prove a geocentric universe until Galileo substituted a heliocentric universe. We happily refined classical physics until Einstein and quantum mechanics showed us a more complex reality. At the moment, in biology, we happily refine the genetics of disease, while most age-related disease is — as it turns out — actually epigenetic.

Whether we look at the role of APOE4 in Alzheimer’s disease, or the role of cholesterol metabolism is atherosclerosis, a careful view of the literature (and the pathology) shows us that these and other age-related diseases are not genetic in the classical sense. We might reasonably call sickle cell disease genetic, but Alzheimer’s disease is epigenetic. Where genetic diseases are relatively simple to understand, epigenetic diseases are a bit more complex.

An analogy that might help understand the critical difference can be found in my new book, The Telomerase Revolution. Imagine a large lake on which we speed back and forth during our lives. A few of us, unfortunately, have exposed rocks — genetic diseases — that tear out the bottom of our boat, ending our lives. All of us, however, have hidden rocks as well — epigenetic diseases — that are innocuous enough unless we lower the water level. In the case of aging, exactly such a lowering occurs: as telomeres shorten, they change the pattern and extent of gene expression. It is this epigenetic change — lowering the water level — that results in our increasing risk of disease as we age.

Now in the case of a strictly genetic disease — such as sickle cell, we might reasonably ask how we can “fix” the gene. In the case of epigenetic disease — such as Alzheimer’s — however, the problem is not the hidden rocks (the various alleles that associate with Alzheimer’s, such as APOE4), but the fact that the water level is too low. The way to cure Alzheimer’s disease is not to find each and every rock and try to “fix the gene, but to simply raise the level of the water again.

This is precisely the aim of genetic therapy aimed at telomerase.

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