Michael Fossel Michael is President of Telocyte

February 24, 2016

New Thinking, Better Therapy

Filed under: Uncategorized — admin @ 3:40 pm

The problem with prediction is that everyone disagrees about the future (and don’t look ahead anyway). Most of us look backward and assume that the view will be just the same (but more so?) if we turned around and looked ahead. The wonderful thing about hindsight is that not only is it easy, but everyone claims that they knew it all along once they can look in the rear-view mirror, but why not look ahead?

Let’s turn around and, just for a moment, try to look at where we’re going. We are right on the edge of a revolution in human medicine, and it’s easy to see if you look forward, not backward. Most people, researchers included, don’t look forward. Not only do they disagree that we’re about to change clinical medicine, but almost no one realizes that the change is already in progress. Oddly enough, even those who think of themselves as “at the forefront” of medicine are usually still looking backwards. They still focus on genes, genomics, and personalized medicine – all useful, but all of them 20th century concepts with 20th century assumptions – and miss the immense shift going on in epigenetics and our fundamental understanding of age-related disease.

It’s a though we were to search for our lost keys in the one place we didn’t lose them and that we’ve already searched – unsuccessfully – for years. We spend billions (actually hundreds of billions) of dollars and endless human resources searching for the key to Alzheimer’s disease in the one place that it doesn’t exist, then, rather than looking in a far more logical place, we give up or – perhaps worse – continue to throw immense amounts of money into the wrong place.

Do we really have endless money to waste ensuring failure?

The problem is that we can no more use genomics to understand and cure age-related disease than we could have prevented smallpox and polio using standard pharmaceutical drugs. Just as we needed to change our concepts and our tools – using immunization to address viral illness – so to do we need to update our concepts and our tools to cure Alzheimer’s disease and the entire gamut of other age-related diseases. Small wonder that we haven’t a single effective agent that actually changes pathology of any of these diseases. Not a one.

We throw money at symptoms, we turn our back on diseases.

Unfortunately, this basic naiveté with regard to disease also has inertial costs. I was on a call today with a major global pharmaceutical firm, whose stated criteria for which approaches to try next against Alzheimer’s disease is, first and foremost, the “consensus of current researchers”, those same researcher who consistently fail to find any effective interventions, anything that alters the progress of these diseases. If everyone agrees to continue searching in the wrong place, small wonder when no one finds anything. Worse yet, using consensus (it’s the way we did it in the 20th century, so it’s good enough for the 21st century), they ensure that other researchers will search the same place and that we will continue to throw money at failed assumptions and futile trials, rather than trying to actually understand fundamental pathology, reevaluate our assumptions, and moving into the 21st century.

Finding a cure for Alzheimer’s is feasible, but only if we look in the right place. We need to stop looking in the rear view mirror and focus on where we are going. It’s time to understand the role, not of genetics, not of genomics, not of personalized medicine, but the ongoing revolution in epigenetics and what it tells us about Alzheimer’s and other diseases, diseases that we once thought impossible to cure.

Things remain impossible only as long as your assumptions ignore reality.

 

February 16, 2016

Unexamined Assumptions

The problem with curing Alzheimer’s is, as with so much of our understanding of aging and age-related diseases, that we make unexamined assumptions. Let me admit that many of our unexamined assumptions are either useful or reasonable. I assume that the sun will come up again tomorrow morning and that’s a useful and reasonable assumption. Useful, in that it allows me to plan my future, reasonable in that the sun has been coming up every morning for quite a while and is therefore likely to do so tomorrow as well. Certain unexamined assumptions are equally justifiable in dealing with Alzheimer’s disease. In the strictly poetic sense, Alzheimer’s certainly is the disease that “steals our souls”, yet no physician or researcher would actually make the assumption that the mind is some vague ethereal quantity that can be stolen by demons, let alone go on to promulgate a theory of Alzheimer’s pathology based on this assumption.

Yet we make exactly that same error, using an unexamined assumption, when we blithely assume that aging is simply the accumulation of damage and, pari passu, that Alzheimer’s disease is simply the accumulation of damaged molecules, be they amyloid, tau tangles, or altered mitochondrial enzymes. This unexamined assumption lies behind almost innumerable multi-million dollar FDA trials, academic papers, and clinical interventions. We assume, without even realizing we have made the assumption, that Alzheimer’s is merely the accumulation of damaged molecules.

We make the same unexamined assumption in looking at other age-related diseases and in the broader field of aging itself. We delve into the details of advanced glycation end-products (AGE), lipofuscin, cross-linking, and other molecular pools showing “accumulative damage”, all the time never realizing that we are making the same fallacy. We are working with completely unexamined (and erroneous) assumptions about how aging works. We naively assume that aging occurs – and age-related diseases follow – merely because things “rust” over time. We age because “molecules fall apart.”

 

Yet the data and logic both say differently. Let me give you a useful analogy: the cell phone. Consider a large pool (several thousand) of people who own cell phones. We know that if we examine any SINGLE cell phone, the best predictor of failure is how long it has been since production. If, however, we want to predict the percentage of failures in any large pool of owners, the best predictor is not time-since-production, but length-of-contract, that is, how often does it get turned over and replaced? Imagine two large pools of cell phone owners. In group A, the cell phones are replaced annually, with a failure rate (at equilibrium) of approximately 1%. In group B, the cell phones are replaced every ten years, with a failure rate (at equilibrium) of approximately 80%. In both groups, the rate of failure of any individual phone is the same. Furthermore, the rate of failure is only marginally related to the “genes”, i.e., whether the phone is an Apple iPhone, an Android, or some other type (a different “allele”). As the turnover rate (contract length to replacement) lengthens, the percent of failed cell phones climbs dramatically, regardless of the failure rate of any individual cell phone. In a pool of cell phones, “aging” is not a matter of passively accumulated damage, but of how actively we replace them.

The same is occurring in molecular pools in biological systems. The key predictor of “denatured” or dysfunctional molecules (e.g., AGE, beta amyloid microaggregates, cross-linking, elastin failure, collagen stiffening, etc) is not the rate of damage but the rate of turnover. In the case of cell aging, when we reset gene expression (reset telomere length) we reset the turnover rates (anabolism and catabolism rates) of all molecular pools to those typical of “young” cells. The outcome is that molecule pool turnover is more than sufficient to deal with typical rates of damage.

Without realizing it, most of us make the mistake of thinking of molecular pools as static and damage as purely accumulative. The reality is that such pools are dynamic and the key dependent variable (as with cell phones) is not the passive rate of damage, but the active rate of turnover.

Unless we understand – and examine – our assumptions, we can never expect to cure age-related diseases. Once we start down the wrong path, all the logic and data in the world can’t make up for the fact that we are looking in the wrong place. It’s time we stopped blaming “demons” and starting thinking carefully.

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