Michael Fossel Michael is President of Telocyte

December 31, 2017

Human Nature

Many of you have written to me, expressing surprise about the lack of public reaction (such as media interest) regarding the potential for telomerase therapy to treat age-related diseases. Some of you wonder why people (and particularly the media) “don’t get it”. I’ve had the same thought for a bit more than two decades now, since I published the first book and the first articles on the potential of telomerase therapy. The lack of understanding applies not only to the media, which is neither critical nor surprising, but to many in the investment community and to the pharmacology industry, which is critical if we are to save human lives.

The major reason for that lack of understanding is human nature. Most people have a firmly-held misconception about how aging works and never realize the error. Without thinking about it (which is the fundamental problem), most people think of aging as entropy. In reality, aging is a lot more complicated (as are most things). Aging isn’t the same as entropy; aging is the gradual inability of cell maintenance to keep up with entropy, which is a very different kettle of fish. Aging hinges on the balance between entropy and maintenance. If you think about it, that’s really what biology is all about: maintaining a extremely complex system in the face of entropy. Life is resistance to entropy. Life is continually building, recycling, and maintaining a complex system, that is continually coming apart, thanks to entropy. This is a balance that works quite well generally, which is why life still continues quite splendidly on this planet, a good three and a half billion years after it began. Who says you can’t resist entropy indefinitely?

Nor is aging universal, just because we see it in ourselves, our pets, and the animals we raise. In some organisms (some multi-cellular and some unicellular), aging never occurs. In other organisms (again, some multi-cellular and some unicellular), aging occurs quite predictably as maintenance slows down, allowing entropy to have its way as the organism ages, fails, and dies. While aging is a lot more than just entropy, most people never even begin to consider the facts and sail along with the unexamined assumption that “aging is entropy”.

It’s not that simple. It never is.

Nor are telomeres the “cause” of aging. Telomeres don’t cauase aging, they are just one (very important) part of an enormously complicated cascade of processes that result in age-related pathology and aging itself. Telomeres are important only because they play a key role at the crossroads of this cascade of pathology. Being at the crossroads, telomeres represent the single most effective point of intervention, both clinically and financially. Theye are the only place that we can entirely reset the gradualy deceleration in cell maintenance with a single intervention and it’s the only place that we can leverage our interventions into a strikingly lower cost of health care. Better care, for less cost.

The other problem that keeps people from appreciating the potential of telomerase therapy is inertia, or perhaps inertia and the fear of undermining their own careers. It’s not merely the inertia of never examining our assumptions, but the professional inertia that occurs when we suspect that – should we examine those assumptions – our entire professional lifetime of work may have been not only misdirected, but be seen as valueless, a truly frightening thought and an understandable fear. Human nature being what it is, the result is a stolid inertia from professionals who have spent many decades pursuing a faulty (and incomplete) model of aging and age-related disease. If any of us had spent 40 years of our professional life working for certain global pharmaceutical firms, for example, we would be loathe to give up the assumption that beta amyloid causes Alzheimer’s disease. After all, that model (despite lacking any support) has been the central focus, the raison-d’etre, for everything we have done professionally for several decades. Would any of us be willing to look clearly at reality, knowing that an honest, thoughtful, and careful appraisal of reality might suggest we had wasted those years, along with our personal efforts and dedication? It is asking too much of human nature. In a corporate, rather than a personal sense, this is equally true of drug companies that have invested hundreds of millions of dollars in what has now been proven to be a fruitless endeavor. The endeavor has been aimed at the wrong target, but it’s a lot of years, a lot of money, and a lot of effort, making it difficult to be honest about the prospects, let alone willing to go back to square one and ask if our assumptions were wrong in the first place. Old adages notwithstanding, people and institutions really do “throw good money after bad” and we do it both with a will and stunning consistency.

Yet, there is reason for a realistic optimism. Over the past two decades, there are a growing number of people who look at the data, reexamine their assumptions, and develop a close relationship with the reality of how aging works. That number continues to escalate, and the time when we can take telomerase therapy to an effective clinical trial continues to shrink. We see resources and commitment moving steadily toward a more sophisticated understanding of both Alzheimer’s disease and aging itself. The combination of resources and commitment will soon bring us to a new ability to treat diseases that, until now, have been beyond our understanding, let alone beyond our help.

We have the compassion to save lives; we will soon have the ability.

December 1, 2017

Big Pharma: Still Looking for the Horse

About a century ago, in a small American town, the first automobile chugged to a stop in front of the general store, where a local man stared at the apparition in disbelief, then asked “where’s your horse?” A long explanation followed, involving internal combustion, pistons, gasoline, and driveshafts. The local listened politely but with growing frustration, then broke in on the explanation. “Look”, he said, “I get all that, but what I still want to know is ‘where is your horse?’”

About three hours ago, in a teleconference with a major global pharmaceutical company, I was invited to talk about telomerase therapy and why it might work for Alzheimer’s, since it doesn’t actually lower beta amyloid levels. I explained about senescent gene expression, dynamic protein pools whose recycling rates slow significantly, causing a secondary increase in amyloid plaques, tau tangles, and mitochondrial dysfunction. The pharmaceutical executive listened (not so politely) with growing frustration, then broke in on the explanation. “Look”, she said, “I get all that, but what I still want to know is how does telomerase lower beta amyloid levels?”

In short, she wanted to know where I had hidden the horse.

The global pharmaceutical company that invited me to talk with them had, earlier this year, given up on its experimental Alzheimer’s drug that aimed at lowering beta amyloid levels, since it had no effect on the clinical course. None. They have so far wasted several years and several hundred million dollars chasing after amyloid levels, and now (as judged by our conversation) they still intent on wasting more time and money chasing amyloid levels. We offered them a chance to ignore amyloid levels and simply correct the underlying problem. While not changing the amyloid levels, we can clean up the beta amyloid plaques, as well as the tau tangles, the mitochondrial dysfunction, and all the other biomarkers of Alzheimer’s. More importantly, we can almost certainly improve the clinical course and largely reverse the cognitive decline. In short, we have a new car in town.

As with so many other big pharmaceutical companies, this company is so focused on biomarkers that they can’t focus on what those markers imply in terms of the dynamic pathology and the altered protein turnover that underlies age-related disease, including Alzheimer’s disease. And we wonder why all the drug trials continue to fail. The executive who asked about amyloid levels is intelligent and experienced, but wedded to an outmoded model that has thus far shown no financial reward and – worse yet – no clinical validity. It doesn’t work. Yet this executive met with me as part of a group seeking innovative approaches to treating Alzheimer’s disease.

Their vision is that they are looking for innovation.

The reality is that they are still looking for the horse.

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