Michael Fossel Michael is President of Telocyte

October 10, 2017

Should everyone respond the same to telomerase?

A physician friend asked if a patient’s APOE status (which alleles they carry, for example APOE4, APOE3, or APOE2) would effect how well they should respond to telomerase therapy. Ideally, it may not make much difference, except that the genes you carry (including the APOE genes and the alleles for each type of APOE gene, as well as other genes linked to Alzheimer’s risk) determine how your risk goes up with age. For example, those with APOE4 alleles (especially if both are APOE4) have a modestly higher risk of Alzheimer’s disease (and at a lower age) than those with APOE2 alleles (expecially if both are APOE2).

Since telomerase doesn’t change your genes or the alleles, then while it should reset your risk of dementia to that of a younger person, your risk (partly determined by your genes) would then operate “all over again”, just as it did before. Think of it this way. If it took you 40 years to get dementia and we reset your risk using telomerase, then it might take you 40 years to get dementia again. If it took you 60 years to get dementia and we reset your risk using telomerase, then it might take you 60 years to get dementia again. It wouldn’t remove your risk of dementia, but it should reset your risk to what it was when you were younger. While the exact outcomes are still unknown, it is clear is that telomerase shouldn’t get rid of your risk, but it might be expected to reset that risk to what it was several years (or decades) before you were treated with telomerase. Your cells might act younger, but your genes are still your genes, and your risk is still (again) your risk.

The same could be said for the rate of response to telomerase therapy. How well (and how quickly) a patient should respond to telomerasse therapy should depend on how much damage has already occurred, which (again) is partially determined by your genes (including APOE genes and dozens of others). Compared to a patient with APOE2 alleles (the “good” APOE alleles), we might expect the clinical response for a patient with APOE4 alleles (the “bad” APOE alleles) to have a slightly slower respone to telomerase, a peak clinical effect that was about the same, and the time-to-retreatment to be just a big shorter. The reality should depend on how fast amyloid plaques accumulates (varying from person to person) and how fast we might be able to remove the plaque (again, probably varying from person to person). The vector (slope of the line from normal to onset of dementia) should be slightly steeper for those with two APOE4 alleles than for two APOE3 alleles, which would be slightly steeper than for two APOE2 alleles. Those with unmatched alleles (APOE4/APOE2) should vary depending upon which two alleles they carried.

To give a visual idea of what we might expect, I’ve added an image that shows the theoretical response of three different patients (a, b, and c), each of whom might respond equally well to telomerase therapy, but might then need a second treatment at different times, depending on their genes (APOE and other genes) and their environment (for example, head injuries, infections, diet, etc.). Patient c might need retreatment in a few years, while patient a might not need retreatment for twice as long.

 

October 4, 2017

The End Hangs on the Beginning

A major stumbling block in our understanding of age-related disease, such as Alzheimer’s, is a propensity to focus on large numbers of genes, proteins, etc., without asking what lies “upstream” that results in the associations between such genes (etc.) and the disease. While some would tout the advantages of using Artificial Intelligence to attack the problem, the problem with AI is that (like most scientists) it focuses on finding solutions only once the problem has been defined ahead of time. If, for example, we define Alzheimer’s as a genetic disease, then we will find genes, but will never reassess our unexamined assumption that AD is genetic. If we assume that it’s genetic, then we only look at genes. If we assume it’s due to proteins, then we only look at proteins. If we assume that it’s environmental, then we only look at the environment. Data analysis and AI, no matter how powerful, is limited by our assumptions. We tend to use large data analysis (and AI) in the same mode: without ever realizing we have narrowed our search, we assume that a disease is genetic and then accumulate and analyze huge amounts of data on gene associations. While AI can do this more efficiently than human scientists, the answers will always remain futile if we have the wrong question. Once we make assumptions as to the cause, we only look where our assumptions direct us. If we look in the wrong place, then money and effort won’t correct our unexamined assumptions and certainly won’t result in cures.

It’s like asking “which demons caused plague in Europe in the middle ages”? If we assume that the plague was caused by demons, then we will never (no matter how hard-working the researcher, how large the data set we crunch, or how powerful the AI we use) discover that the plague was caused by a bacteria (Yersinia pestis). If you look for demons, you don’t find bacteria. If you look for genes, you don’t find senescent changes in gene expression. The ability to find answers is not merely limited by how hard we work or how large the data sample, but severely and unavoidably limited by how we phrase our questions. We will never get anywhere if we start off in the wrong direction.

To quote the Latin phrase, “Finis origine pendet“. The end hangs on the beginning.

September 20, 2017

Genes and Aging

Several of you have asked why I don’t update this blog more often. My priority is to take effective interventions for age-related diseases to FDA phase 1 human trials, rather than blogging about the process. Each week, Outlook reminds me to update the blog, but there are many tasks that need doing if we are going to get to human trials, which remains our primary target.

In working on age-related disease, however, I am reminded that we can do very little unless we understand aging. Most of us assume we already understand what we mean by aging, but our assumptions prevent us from a more fundamental and valid understanding of the aging process. In short, our unexamined assumptions get in the way of effective solutions. To give an analogy, if we start with the assumption that the Earth is the center of the solar system, then no matter how carefully we calculate the orbits of the planets, we will fail. If we start with the assumption that the plague results from evil spirits rather than Yersinia pestis, then no matter how many exorcisms we invoke, we will fail. We don’t fail because of any lack of effort, we fail because of misdirected effort.

Our assumptions define the limits of our abilities.

When we look at aging, too often we take only a narrow view. Humans age, as do all the mammals and birds (livestock and pets come to mind) that have played common roles in human culture and human history. When most people think of aging, they seldom consider trees, hydra, yeast, bacteria, or individual cells (whatever the species). Worse, even when we do look at these, we never question our quotidian assumptions. We carry our complacent assumptions along with us, a ponderous baggage, dragging us down, restricting our ability to move ahead toward a more sophisticated (and accurate) understanding. If we looked carefully, we would see that not all cells age and not all organisms age. Moreover, of those that age, not all organisms age at the same rate and, within an organism, not all cells age at the same rate. In short, neither the rate of aging, nor aging itself is universal. As examples, dogs age faster than humans and, among humans, progeric children age faster than normal humans. The same is true when we consider cells: somatic cells age faster than stem cells, while germ cells (sperm and ova) don’t age at all. So much for aging being universal.

The key question isn’t “why do all things age?”, but rather “why does aging occur in some cases and not in others, and at widely different rates when it occurs at all?” The answer certainly isn’t hormones, heartbeats, entropy, mitochondria, or free radicals, for none of these can explain the enormous disparity in what ages and what doesn’t, nor why cells age at different rates. Nor is aging genetic in any simplistic sense. While genes play a prominent role in how we age, there are no “aging genes”. Aging is not a “genetic disease”, but rather a matter of epigenetics – it’s not which genes you have, but how those genes are expressed and how their expression changes over time, particularly over the life of the organism or over multiple cell divisions in the life of a cell. In a sense, you age not because of entropy, but because your cells downregulate the ability to maintain themselves in the face of that entropy. Cell senescence effects a broad change in gene expression that results in a gradual failure to deal with DNA repair, mitochondrial repair, free radical damage, and molecular turnover in general. Aging isn’t a matter of damage, it’s a matter of no longer repairing the damage.

All of this wouldn’t matter – it’s mere words and theory – were it not for our ability to intervene in age-related disease. Once we understand how aging works, once we look carefully at our assumptions and reconsider them, our more accurate and fundamental understanding allows suggests how we might cure age-related disease, to finally treat the diseases we have so long thought beyond our ability. It is our ability to see with fresh eyes, to look at all organisms and all cells without preconceptions, that permits us to finally do something about Alzheimer’s and other age-related disease.

Only an open mind will allow us to save lives.

 

August 10, 2017

Progeria and Telomerase

Recently, John Cooke at the Houston Methodist Research Institute, showed that telomerase, when expressed in cells from progeric children, caused a “substantial physiologically relevant and meaningful effect on the lifespan and function of the cells.” As many of you know, progeria is a disease in which young children appear old, with baldness and osteoarthritis, and usually die of advanced cardiovascular disease, such as heart attacks, typically around age twelve. In short, they appear to have extremely rapid aging. Cooke’s results suggested that telomerase might offer a therapy. Oddly enough, both Cooke and the media described this finding as “surprising”.

While these results are promising, they are hardly surprising. In 1996, I published a book going into this prospect in detail, then wrote the first medical papers on this the medical potential in JAMA in 1997 and 1998. This was followed up with a medical textbook which explored the entire area in 2004, and another book in 2015 that described the medical potential of telomerase. What is truly surprising is not the most recent results, but that anyone finds the results at all surprising.

While not actually surprising, they present a bitter irony, in that any number of deaths, including deaths of progeric children, might have been prevented and may still be prevented if we only understand and act upon what we have known for two decades and which Cooke’s results only highlight again.

The irony – and my exquisite personal frustration – is that I proposed this approach annually in our global meetings for progeric children, starting twenty years ago. For about a decade, beginning several years before the turn of the millennium, I had been part of the annual global reunion of progeric children. Each year, we gathered with perhaps three dozen progeric children and their families from around the world, giving them a chance to meet one another, to talk with experts, and … to feel normal among other children and families who had the same problems. In 1999, among those progeric children was a young boy, whose parents were both physicians, and who were desperate to find a cure for progeria. Although I explained the potential of using telomerase as an intervention, they founded the Progeria Research Foundation and aimed it solely at genetic markers rather than epigenetic intervention. They managed to get significant funding through the NIH, fund raising, and government contacts in order to fund a set of studies that localized the genetic error responsible for progeria. As I predicted, none of the subsequent therapies based on their approach have had any effect on the disease. Worse yet, and like all the other progeric children I have known over the years, their son died of progeria. Had we gone straight to telomere-based interventions rather than taking the detour, many progeric children – not merely their son — might have been treated more effectively.

John Cooke and his colleagues have done well to show that they can reverse the problems seen in progeric cells, yet others have gone further. Maria Blasco’s group, for example, has shown that she can not merely reset aging in cells, as Cooke’s group has, but can do the same in animals. Moreover, we are collaborating with her group to take this approach in our upcoming human clinical trials next year, initially aiming at Alzheimer’s disease.

The fact that this comes as a surprise, given what we have known about the potential of telomerase for more than 20 years is a tragic example of wasted opportunities, wasted funding, and wasted lives. Telomerase was shown to reverse aging in cells 20 years ago; telomerase showed its value in animals 5 years ago; Telocyte is ready to show the benefits of telomerase in human trials next year.

July 17, 2017

Walking Toward a Cure for Alzheimer’s

Sometimes things go wrong, sometimes they go remarkably right.

        In clinical medicine, Swiss cheese theory is a explanation of why medical disasters occur, even if the explanation has a grizzly sort of humor. Basically, Swiss cheese theory says that “all the holes need to line up” for something to get through the cheese and for things to go drastically wrong in patient care. For example, if the physician is a moron (the first hole in the cheese) and orders the wrong medication, then the knowledgeable pharmacist usually cancels the order. But if the pharmacist is also a moron (the second hole in the cheese) and sends the wrong medication to the nurse, then the experienced nurse refuses to give the medication and stops the mistake long before the patient is injured. But, of course, if the nurse is also a moron (the third hole in the cheese) and simply gives the wrong medication, then you have a problem. When all the morons line up in a row, like holes in adjoining slices of Swiss cheese, then mistakes get all the way through the cheese and you have the perfect setting for a medical disaster. Medical errors are rarely the result of a single stunning error on the part of a truly epic moron; medical errors usually take a grizzly sort of teamwork among morons, all working together like clockwork. Swiss cheese theory strikes again.
Oddly enough, the opposite can also happen. If everything lines up in a positive sense then we have innovation, progress, and (very rarely) a miracle or two. For example, to have a success in the case of a biotech company, you need a series of positive events to line up. Over the past few years, that’s exactly what has been happening to Telocyte. While there have been no truly stunning single events that have created a fleeting (if flashy) success, there have been a collection of positive events that line up exactly as they need to. In our case, all the holes are lining up to build toward a successful cure for Alzheimer’s disease.
I first proposed that telomerase could be successful as a clinical intervention in 1996, but my proposal wouldn’t have gotten anywhere if a whole collection of groups and individuals hadn’t continued to move the field along over these past twenty years. From a purely practical perspective, it was the work of CNIO in Madrid (and that of their director, Maria Blasco) that demonstrated a technique that can easily be applied to human clinical trials. Yet, while we saw the potential for human disease, it was our CEO, Peter Rayson, who moved us along in a practical direction. Two years ago, Peter arranged to meet me in Boston, and we founded Telocyte. Our COO, Mark Hodges, joined us and helped shape our program. We had additional support from volunteers, spouses, and researchers, all of whom saw the value and shared our vision. Investors, such as Rob Beers, joined us, asking little and seeing much. We were approached by large global corporations, such as SAP and Amazon Web Services, who offered us support. We partnered with the world’s preeminent biotech law firm, Cooley LLP, who saw the potential and wanted to help. Other investors have come on board, investors who saw what we could do and who agreed with our goals.
Recently, we signed agreements with a major investor and submitted our protocols for FDA review, and we continue to move ahead, steadily and confidently, as we plan for our human trial next year. None of this has been the result of one person, nor even one group. Instead, it has been the result of a continual concatenation of just the right people at the right time. Everything has gracefully, carefully, and steadily lined up, creating an historic opportunity to save lives and rescue human minds. There have been no miracles, no sudden champagne, no instant success, nor wild celebrations. We haven’t seen wonders, but we’ve seen workers. We haven’t seen miracles, but we’ve met milestones. We haven’t had champagne, but now we have a chance.
With every step, a door has opened, people have helped, another step was taken.
And each step brings us closer to curing Alzheimer’s. Walk with us.

April 12, 2017

We Already Know It Works

Oddly enough, many investors don’t realize how far we are down the road to a cure.

In fact, most people don’t understand why such studies are done and – more to the point – why Telocyte is doing one. Just to clarify: we’re not doing an animal study to prove efficacy. We already know it’s effective in animals.

The reason we do an animal study is because the FDA, quite reasonably, requires an animal safety study in order to assess risks and side effects. Most people assume that animal studies are done to show that a potential therapy works in animals, so that it might work in humans as well. In fact, however, once you have shown that a therapy works in animals, as we have already, then before you can go on to human trials, you first need to do an animal safety study.

Animal studies are done to assess safety, not to assess efficacy.

For an initial human trial, the main question for the FDA isn’t efficacy, but safety. Sensibly, the FDA requires that the safety data be done carefully and credibly, to meet their careful standards. We know telomerase gene therapy works, but we still need to prove (to the FDA’s satisfaction) that telomerase gene therapy is safe enough to justify giving our therapy to human patients. So the question isn’t “Do we have a potential intervention for Alzheimer’s?” (which we do), but rather “Do we know what the risks are once we give it?” We’re fairly certain that we know those risk, but we need to document them rigorously.

In getting our therapy to human trials, you might say that there are three stages:

  1. Animal studies that show efficacy (already done by our collaborators).
  2. Animal studies that show safety (an FDA requirement).
  3. Human trials before release for general use (an FDA requirement).

Telocyte already has good data on the first stage: we know that telomerase is remarkably effective in reversing the behavioral decline seen in aging animals and that the same result will likely occur in aging human patients. In short, we are already confident that we can prevent and at least partially reverse Alzheimer’s disease. The FDA doesn’t need us to demonstrate efficacy: we already have good data on efficacy. What the FDA wants from us is more (and more detailed) data on the probable safety, which we’re about to provide.

While we are now ready to start on the FDA animal safety trial. Doing our FDA animal study isn’t a way of showing that telomerase gene therapy works – which is already clear from animal studies – but a detailed look at side effects, preparatory to our having permission to begin human trials next year.

Telomerase therapy works.

March 21, 2017

The Frustration of (Not) Curing Alzheimer’s

I am deeply frustrated by two plangent observations: 1) we squander scant resources in useless AD trials and 2) AD can easily be cured if we applied those same resources to useful AD trials. Applying our resources with insight, we will cure Alzheimer’s within two years.

The first frustration is that most pharmaceutical firms and biotech companies continue to beat their heads against the same wall, regardless of clinical results. Whether they attack beta amyloid, tau proteins, mitocondrial function, inflammation, or any other target, the results have been, without exception, complete clinical failures. To be clear, many studies can show that you can affect beta amyloid or other biomarkers of Alzheimer’s disease, but none of these studies show any effect on the clinical outcome. In the case of amyloid, it doesn’t matter whether you target production or the plaques themselves. Despite hundreds of millions of dollars, despite tens of thousands of patients, not one of these trials has ever shown clinical efficacy. Yet these same companies continue to not only run into walls, but remained convinced that if they can only run faster and hit the wall faster, they will somehow successfully breach the wall. They succeed only in creating headaches, accompanied by lost money, lost opportunities, and lost patients. The problem is not a lack of intelligence or ability. The researchers are – almost without exception – some of the most intelligent, well-educated, technically trained, and hard-working people I know. The irony is that they are some of the best 20th century minds I know. The problem, however, is that it is no longer the 20th century. If you refuse to adapt, refuse to change your paradigm, refuse to come into the 21st century, you will continue to get 20th century results and patients will continue to die of Alzheimer’s disease. Money and intelligence continues to be dumped into the same clichéed paradigm of pathology, as we aim at the wrong targets and misunderstand how Alzheimer’s works. And the result is… tragedy.

The second frustration is that we already know the right target and we already understand how Alzheimer’s disease works. We are entirely able to cure and prevent Alzheimer’s disease now. At Telocyte, we already have the initial resources we need to move ahead, but it is surprising how difficult it is for some people — wedded to 20th century concepts — to grasp the stunning potential, both clinically and financially of what we are about to do at Telocyte. We can not only reverse Alzheimer’s disease, but we can also cut the costs of health care while creating a stunningly successful biotech company in the process. We have the right tools, the right people, the right partners, and the sheer ability to take this through FDA trials. Already, we have several lead investors committed to our success. We are asking for a handful of additional investors, those who can see what the 21st century is capable of and who can understand why Telocyte is both the best clinical investment and the best financial investment in innovative medical care.

 

January 17, 2017

Intuition and Air Planes

The formulation of a problem is often more essential than its solution, which may be merely a matter of mathematical or experimental skill. To raise new questions, new possibilities, to regard old problems from a new angle requires creative imagination and marks real advances in science.

— Albert Einstein, 1938

 

Most “advances” are purely incremental. We make minor advances in current techniques or technology, we marginally improve our existing surgery or drugs, or we precisely define the specifications of previously known molecules. Rarely do we develop a novel technology, an unprecedented therapy, or a distinctively new theory. Truly innovative, unexpected, and compelling changes require that – as Einstein said – we “regard old problems from a new angle.” Genuine advances in science don’t require experimental skill, they require conceptual creativity.

Advances require us to look at things in an entirely new way.

Our ability to cure age-related diseases, such as Alzheimer’s, does not depend on incremental improvements, but on exactly such changes in how we look at things. The same, it turns out, is true of aging and – oddly enough – telomeres. We automatically view the world through our preconceptions, and this has always been true. Upon seeing the world’s first automobile, and unable to grasp the idea of a “horseless carriage”, we asked where the horse was attached. Upon seeing the world’s first television, and unable to grasp the idea of an electron tube, we asked how tiny people fit into that television cabinet. We continually look at new things, but we see them using old eyes.

As an analogy, imagine a group of castaways who have spend years trapped on a large, unexplored, tropical island. Two of the castaways are exploring an unfamiliar beach, when they come upon a large, entirely unexpected, and unfamiliar object. The first castaway, a bright academic, carefully measures the dimensions of every single part of the object. She tells the rest of the castaways about her measurements and they present her with an award for her hard work. To some acclaim, she explains that the unknown object might actually prove useful: the castaways could use it to 1) hang up their laundry, 2) provide shade from the hot tropical sun, and, 3) offer shelter during tropical storms. The second castaway has a more intuitive and creative bent. He carefully looks over the object, announces that it’s a plane, and offers to fly it off the island and save their lives.

Small Jet Plane

Sometimes, it’s not the measurements, it’s the ability to see new possibilities.

In the case of aging and age-related diseases, the odd thing is that most people don’t see how anything can be done. They still want to hang their laundry on the wings of the plane, without realizing that the airplane can fly them to safety. At best, they concede that aging might be slowed down, perhaps with diet, exercise, stress management, and other behavioral changes. The idea that aging can be reversed, or that age-related diseases can be cured, is anathema to their thinking, despite the solid evidence in cells, tissues, and animal studies. I first described the potential of telomeres for clinical therapy 20 years ago and the evidence has been growing steadily since then, yet the general public, the media, and many academics still think of telomeres as a place to hang laundry, provide shade, and offer shelter from the rain. Is it really that hard to recognize a plane? Apparently so.

It would appear that the only way to show people what telomeres can do is to fly the plane and safe lives.

 

January 9, 2017

Conceptual Blinders

 

A week or so ago, an AI beat the world’s reigning champion in the game of Go.

The odd thing is not that it happened, but how it was done. By itself, the victory would just be one more example of “computers beating humans”, but there is a far more interesting and important facet to this event. Not only did the AI beat the world’s Go masters and the reigning world champion, but it did it, not by being better at using the known strategies and tactics, long the province of Go adepts, but by using “unconventional positions“ and “moves that seemed foolish but inevitably led to victory” (WSJ, January 5, 2017). In short, the AI went into playing the game without conceptual blinders. It developed novel (and effective) strategies based on reality, rather than on preconceived views of how the game “ought” to be played. Had the AI been programmed by Go masters, it wouldn’t have fared as well. It succeeded because it lacked the limitations that we as human beings unknowingly use when we approach a problem.

go-game-boardIF our assumptions create limits, then our outcomes are limited.

The same problem – our own assumptions – proscribes the limits of what we can do in science and medicine. If we simply program a computer to “delay the onset of Alzheimer’s disease by lowering all known risk factors”, it might succeed, but the solution would be limited by how we set up the problem. In short, assumptions limit outcomes. If we merely restrict the program to lowering risks, then a computer program can’t show us how to cure Alzheimer’s. Such a program might, for example, recommend dietary changes, moving away from major highways and pollution, lowering blood pressure, avoiding infections, improving dental hygiene, lowering stress, and a myriad other changes that might delay Alzheimer’s. But the programs, the questions we pose, presuppose that Alzheimer’s can’t cured or prevented, only delayed. If we preclude finding a way to win, then all we find is a better way to lose.

Consider the historical analogs. If I want more efficient communication, I don’t ask a computer to design a better telegraph. If I want more efficient transportation, I don’t ask the computer to design a faster horse. If I want to cure polio, I don’t program a computer to design a better iron lung. And if I want to cure Alzheimer’s, I shouldn’t design a better way to attack amyloid, tau proteins, inflammation, or mitochondrial dysfunction. Merely because I’ve already assumed that those are the only strategies, I have limited my outcomes. If Alzheimer’s interventions are restricted to merely optimizing old strategies, we will never cure it.

Why be satisfied with a better telegraph, a faster horse, or a more efficient iron lung?

Programmed solutions, based on preconceived limits are a case of GIGO: “garbage in, garbage out”. True advances in science and medicine are not incremental; they demand innovative perceptions and constant reexamination of our premises. The example of an AI beating the world’s reigning Go champion wasn’t the result of incremental improvements in coding all of the Go strategies known to previous champions into a program and then tasking the program with implementing those accepted strategies. The AI was tasked with winning, regardless of previously accepted strategies. As a result, the AI actually WON, unexpectedly, but reliably, using innovative, startling, and unexpected approaches.

If we want to cure Alzheimer’s disease, we can’t use incremental approaches to time-worn (and uniformly ineffective) strategies. Like the AI playing Go, we need to stop focusing on accepted strategies and ask the fundamental question: how do we win? Not “how do we optimize the same old strategies?”, but how do we actually WIN? We shouldn’t rely on “programmed” approaches; we should toss out our preconceived programs, and ask how to win. With regard to Alzheimer’s disease, we need to stop asking how to optimize losing strategies and ask how to cure Alzheimer’s. Not “how do we lower amyloid levels?” or “how do we reduce tau tangles?”, but how do we cure and prevent the disease in the first place? If we really want to make a difference, then we need to free ourselves from our preconceptions and our old programming, and begin to ask the fundamental question: how can we cure Alzheimer’s?

Truly innovative approaches demand a ruthless reassessment of our assumptions.

We will cure Alzheimer’s only if we have the wit to truly use our own intelligence, with honesty, perceptiveness, and a willingness to examine reality.

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).
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