Michael Fossel Michael is President of Telocyte

December 29, 2016

The Ethics of Gene Therapy for Alzheimer’s Disease

The Ethics of Telomerase Treatment

 

The rationale behind telomerase therapy was first published in the medical literature two decades ago1 and has been updated and supported in academic textbooks2 and a more recent book for the public3 as well. The theoretical basis was cogent, even twenty years ago, and evidence has continued to support the hypothesis since then, in human cells, in human tissues, in informal human trials, and in formal animal trials. The potential implications of telomerase interventions in human age-related disease are unprecedented, well-supported, consistent, and feasible. The surprise is not that this approach is practical, but that it has taken so long to get telomerase therapy into clinical trials.

The reasons for the delay are complex and subtle, but are part of human nature.

For one thing, the clinical use of telomerase requires a novel and more sophisticated understanding of the aging process itself – at the genetic and epigenetic level – than has been the case until recently. Whenever a new scientific paradigm comes into play – whether a geocentric solar system, biological evolution, quantum mechanics, relativity, or anything else – it takes time for us to outgrow previous, less accurate models and to accept a more complex, but more accurate understanding of reality. Reality is not a democracy and a consensus is no guarantee of truth.

Putting it bluntly: old theories never die, their proponents do.

A second problem is credibility. In the case of telomerase clinical trials, there have been a number of cases in which individuals or companies (impatient with the regulatory delays so common in modern drug development) have attempted “end runs” of social and regulatory acceptance. Unfortunately (and perhaps unfairly), these off-shore human trials are often judged as lacking credibility and this can also undercut the credibility of other attempts. If a company evades the FDA (or the accepted regulatory agencies in other countries, such as the EMA or CFDA) and runs small off shore trials their results are not only specifically disbelieved, but result in general disbelief, even of serious biotech endeavors that DO attempt to meet FDA requirements. Moreover, the companies that attempt “end runs” often seek publicity and the outcome can be a perception that while there is significant publicity, that’s all there is. Unfairly or accurately, the academic judgement becomes one of “incredible claims, but no credible data”. Fair or unfair, just or unjust, such is human nature and such is the nature of clinical research in today’s world.

A third problem is a general misunderstanding of the role of telomerase in cancer. Telomerase never causes cancer, although small amounts can be necessary to permit cancer. More striking, however, is the role of telomerase in genomic stability: telomerase upregulates DNA repair, drastically lowering the risk of cancer. Dividing cells – including cancer cells – require at least minimal telomerase, yet a significant presence of telomerase (and sufficiently long telomeres) is protective against cancer. Some have even suggested that cancer is a disease of the young, and attribute it to the presence of telomerase, but the clinical reality is that cancer increases exponentially with age and that this increase is directly attributable to the down-regulation of DNA repair due to telomere shortening. In short, telomerase can be used to prevent cancer.

A fourth problem is a naïve conception of the pathology that underlies Alzheimer’s disease (and other age-related diseases). Citing data on mice, genetically altered to express a human amyloid protein, they extrapolate the results to human Alzheimer’s patients without appreciating the complex cascade of pathology that actually occurs in humans, let alone the differences between mice and human patients.

Finally, some people argue with the ethics of treating Alzheimer’s disease in clinical trials at all, let alone by using gene therapy. One wonders whether they have ever spend a year or two watching a loved one slide down into the abyss. I have known hundreds, perhaps thousands, of Alzheimer’s patients and their family members. Almost without exception, most would do literally anything, try literally anything in an effort to find a cure. The pity of AD is that it is 100% fatal and there is NO effective therapy – at the moment. While few of us would risk an experimental gene therapy (even one as promising at telomerase) to treat wrinkles or osteoporosis (particularly since neither one is fatal), all of us would consider such therapy to treat Alzheimer’s disease. It is scarcely surprising that scarcely a day goes by without someone contacting me, asking about potential treatments for Alzheimer’s disease. These are not people who live in ivory towers, these are not people with a “degree in microbiology”, these are people who are deeply and personally affected by the tragedy.

They’ve BEEN there. They UNDERSTAND.

One critic of gene therapy noted that: “there are 7 patients killed by gene therapy clinical trials” (over the past 20 years). Compare this with the seven hundred thousand Alzheimer’s patients who died in 2016 alone of not having had gene therapy. Why would I choose to be one of 700,000 deaths per year?

For those of us who have spent decades treating dying patients, for those of us who have Alzheimer’s disease, and for those of us who are terrified by what is happening to those we love who have Alzheimer’s disease, the ethics of using gene therapy to try curing the most frightening disease on earth are clear enough.

The ethical weight lies on the side of compassion.

 

 

  1. Fossel: Reversing Human Aging (1996) . Banks and Fossel: Telomeres, cancer, and aging – Altering the human lifespan (JAMA, 1997). Fossel: Telomerase and the aging cell – Implications for human health (JAMA, 1998).
  2. Fossel: Cells, Aging, and Human Disease (Oxford University Press, 2004).
  3. Fossel: The Telomerase Revolution (BenBella Press, 2015).

April 6, 2016

The Rabbits of Research, The Frogs of Alzheimer’s

 

Perspective often shrinks personal problems.

Late Sunday night, I received a cry for help from a woman whose mother has Alzheimer’s disease: she asked me to meet her family and offer professional advice. Their concern was not only her medications, but the ability of her physician, the stress on the family, and the patient’s own medical and psychological problems. Not surprisingly for someone with Alzheimer’s, the patient not only had paranoia, depression, panic episodes, and confusion, but the heart-rending loss of memory and reasoning that really lie at the heart of Alzheimer’s – if Alzheimer’s can be said to have a heart, which is a stunning oxymoron for such a horrifying disease.

We each have our own problems and – such is human nature – we get wrapped up in those personal problems, losing sight of greater issues. I had been thinking about a dozen issues that play into any biotech effort: potential investors, vendor specifications for plasmids, approaching the FDA for pre-IND meetings, conference calls with our IP attorneys, details of our preclinical research, and whether or not one of our scientific advisory board members had time to define a sequence for us. Amazing how large these – and many more – issues loomed in my life, then suddenly became so much smaller and less important when I heard from someone whose loved one has Alzheimer’s. It’s true that the only lasting way that my colleagues and I can help her – and hundreds of thousands of others – is to complete the research and offer a cure, but there is much more to helping than curing. Sometimes, it’s simply a matter of small acts of compassion, such as finding a referral to someone who can help with day-to-day problems, even if they can’t cure the deeper problem itself. And sometimes, of course, it’s simply a matter of understanding how unimportant our own problems are, in perspective.

Two thousand five hundred years ago, a story teller described the panic of a group of frightened rabbits who, in turn, suddenly surprise a group of frightened frogs, whose panic sends them into the pond. Aesop was right about human life: there will always be rabbits, there will always be frogs. No matter how much the “rabbits” of research need our attention and our hard work, the “frogs” of Alzheimer’s patients must always have our care and our compassion.

And, perhaps quite soon, we will change those frogs into healthy humans, whose fear becomes a thing of the past.

March 23, 2016

Soliloquy, Requiem, and . . . Hope

Early last Saturday, I received a short, sad email from an old friend. Many of you may know Leonard Hayflick, who first pointed out that cells age, more than fifty years ago. He stood up for himself and for the truth of his data, in the face of strong opposition and irrationality, and finally proved that cells do not age because of the passage of time, but because of cell divisions. From that one observation – and his willingness to stand by his observations – we have come to realize that not only do cells age, but that it is cell aging that causes our bodies to age and causes all the myriad diseases of aging: “the thousand natural shocks that flesh is heir to.”

Len Hayflick’s wife, Ruth, died last Friday night, leaving Len alone physically, but by no means alone in spirit. He has admirers and friends throughout the world and will have them throughout time. He deserves more than we can possibly give him.

As we age, we have long suffered the slings and arrows of fortune, yet only now do we – almost, tantalizingly – have the ability to end them. The pity is, that we do so too late, not only for those who are already gone, but for those who will yet succumb before we can help. It is aging itself , and the diseases of aging, that “makes calamity of so long life”. We are so close to curing the diseases of aging, yet even that very proximity, compounded by our pressing need, makes a cure feel so tragically far away. The greater the need, the closer the goal, the more pitiable that we have yet to achieve it.

Over the next few years, many of us will suffer, and suffer needlessly. If only we could have moved faster yesterday, if only we were moving faster today, if only we will move faster tomorrow: we would have saved lives yesterday, we would be saving lives today, we will have been saving more lives tomorrow. And yet, here we are more than fifty years since one honest man stood up and – with his “native hue of resolution” — pointed out reality. Why has it been half a century and yet we still suffer from diseases that could have been cured? Why does it take so long to save the lives and souls of those who still endure the sea of troubles that comes in, seemingly inevitably, as we age?

Soon, very soon, we will cure Alzheimer’s and a host of other diseases, yet however soon it will be, it will have been too late for too many of us. And far too late for some of those we love, those we long for, those we will long remember.

May those memories soon push us to create a more compassionate world.

December 31, 2015

A Gerontological Reality

An odd thing came across my desk yesterday: a reminder that some people, without meaning to, encourage not only a sense of futility and gloom, but in their dark view of the world, they end up encouraging disease, including Alzheimer’s. In the middle ages, it was common to attribute disease and suffering to god’s will and, after all, who were we to intervene in what god intended? Labor pain, plague, and a myriad sufferings were – again with a sense of futility and gloom – accepted and instead of encouraging our fellow human beings to alleviate suffering, we actively suppressed the compassion that might have brought relief.

Now, we look back on the misguided superstitions of the middle ages as something we have – in our maturity as civilized human beings – outgrown. And yet, we haven’t grown up enough, for while we no longer blame god for our troubles, we are just as eager to ensure that we can’t solve them. In my recent book, The Telomerase Revolution, I suggested that not only could we cure Alzheimer’s disease and that we could make such care affordable, but that it would be more affordable than our current health care, both for the individual and for society. Far from being a treatment for the few, it would be a treatment for all. After all, why pay enormous costs for long-term nursing home care, when we could pay a small cost to be healthy? Far from further dividing us into “two kinds of human beings” (consider that we currently divide the old and the infirm, or those with Alzheimer’s, from the young and healthy), we could provide the gift of sanity and health to all of us, without regard to age, without regard to wealth.

The consequence? A healthier, more compassionate culture.

If this is a utopia, the it’s not the first one. Prior to the discovery of antibiotics, prior to the availability of insulin, prior to polio vaccine, each of these ideas were utopian, yet now they are merely reality. Or perhaps not merely, for these utopian medical advances saved lives. Oddly though, we have never lacked for naysayers, who once – as they now do for Alzheimer’s – view these advances with fear and trepidation, seeing not the joy, the love, or the improved health, but the “ruin of their hopes in an utterly alien world”. How does curing polio ruin hopes? How does curing Alzheimer’s give us an alien world? The ruin of hopes, the alien world is the world that Alzheimer’s patients live in now, along with their families who watch the premature loss of their loved ones (of which there are already far too many). Would anyone really want to live in a world without Alzheimer’s? Yes, most of us hope for exactly such a “utopian” world and some of us are working hard to make it a reality. Curing Alzheimer’s is an attainable dream, not a utopia and most certainly not a dystopia.

May you all have a happy new year, and may the coming years soon see a future beyond Alzheimer’s disease.

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