Michael Fossel Michael is President of Telocyte

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).

December 13, 2016

Telomeres: The Purloined Letter of Aging

     “What is only complex is mistaken (a not unusual error) for what is profound.”

                                                Edgar Allen Poe

 Edgar Allen Poe is still well-known for his poetry, he is less well-known for his detective stories. Some 170 years ago, his Parisian amateur detective, Dupin, was the conceptual forerunner for Sherlock Holmes, who made his London debut almost half a century later. Poe also made a series of observations that echo, even today, as we try to understand aging, age-related disease, and how we can cure them.

Poe’s detective pointed out that even intelligent, meticulous investigators are often oblivious to the obvious. The same can even be true of modern scientific investigators, who may focus so closely on their hard-won facts that the relationships between those facts – and their implications – are often overlooked. In aging research, for example, many investigators focus so intensely on genes, proteins, and small-molecular therapies, that they can miss the broader picture and miss an effective approach to curing the diseases of aging. Putting it simply, too often we focus our intellect, our education, and our strenuous effort on the “nouns”, but we entirely miss the “verbs”. We know the data, we fail to see what it means.

The intellect, the education, the dedication, and the funding are enormous, but our focus is off-target and the results, as expected, are futile. Truth, Poe tells us, is frequently overlooked, regardless of how intense our investigation. In describing such a case (in Poe’s case a policeman, in our case a scientist), Poe put it this way:

“… he erred continually by the very intensity of his investigations. He impaired his vision by holding the object too close. He might see, perhaps, one or two points with unusual clearness, but in so doing he, necessarily, lost sight of the matter as a whole. Thus there is such a thing as being too profound. Truth is not always in a well. In fact, as regards the more important knowledge, I do believe that she is invariably superficial.”

 As Poe suggest, we seek truth in the depth of a well in a valley, while truth is usually sitting in plain sight on the (easily visualized) mountain tops surrounding that valley. Such is the case with aging. It’s not that the truth is simple, for aging is far more complex than most of us give it credit for, but the truth is not found in the narrow details so much as it found in the overview of those details. The truth really is on the mountain tops, not in the bottom of a well, even when that well includes reams of data. It’s not the amount of data that is crucial, but the implications of that data. To give an example from clinical medicine, I may know everything about a patient’s fever, their hypotension, their abnormal white count, and their vomiting, but the numbers alone aren’t nearly as important as the realization that the patient has Ebola. Curing an Ebola infection cannot be relegated to lowering a fever, increasing the IV fluid, removing white cells, and given an anti-emetic. It’s not the individual therapies that cure Ebola, it’s the realization that you’re dealing with a viral infection and the use of a more general – and more effective – therapy, whether an antiviral or an immunization.

There is a parallel in understanding aging.

Treating the diseases of aging is not a matter of using individual therapies, but a matter of understanding the more profound relationships that change in aging cells. Until we do so, we will continue to fail when we try monoclonal antibodies for beta amyloid – as Eli Lilly finally realized with its Solanezumab trials – or merely attack tau proteins, mitochondrial changes, inflammation, or other targets. In each case, we have mistaken a plethora of data for a profundity of data. Only when we realize the actual complexity, the dynamic biological relationships, the profound effects of epigenetic changes, the role of telomeres as a therapeutic target, and that the fundamental pathology of aging and age-related diseases is rooted in cell senescence, only then will we — to our own vast and naïve surprise — discover that we can cure most of the diseases that still plague humankind.

 

November 22, 2016

Teaching Cells to Fish

Aging is the slowing down of active molecular turnover, not the passive accumulation of damage. Damage certainly accumulates, but only because turnover is no longer keeping up with that damage.

It’s much like asking why one car falls apart, when another car looks like it just came out of the showroom. It’s not so much a matter of damage (although if you live up north and the road salt eats away at your undercarriage, that’s another matter), as it is a matter of how well a car is cared for. I’ve see an 80-year-old Duesenberg that looks a lot better than my 4-year-old SUV. It’s not how well either car was made, nor how long either car has been around, but how well each car was cared for. If I don’t care for my SUV, my SUV rusts; if a car collector gives weekly (even daily) care to a Duesenberg, then that Duesenberg may well last forever.

The parallel is apt. The reason that “old cells” fall apart isn’t that they’ve been around a long time, nor even that they are continually being exposed to various insults. The reason “old cells” fall apart is that their maintenance functions slow noticeably and that maintenance fails to keep up with the quotidian damage occurring within living cells. If we look at knees, for example, the reason that our chondrocytes fail isn’t a matter of how many years you’ve been on the planet, nor even a matter of how many miles a day you spend walking around. The reason chondrocytes fail is because their maintenance functions slow down and stop keeping up with the daily damage. As it turns out, that deceleration in maintenance occurs because of changes in gene expression, which occur because telomeres shorten, which occur because cells divide. And, not at all surprisingly, the number of those cell divisions is related to how long you’ve been on the planet (how old you are) and how many miles you walk (or if you play basketball). In short, osteoarthritis is distantly related to your age and to the “mileage” you incur, but not directly so. The problem is not really the age nor is it the mileage; the problem is the failure to repair the routine damage and THAT failure is directly controlled by changes in gene expression.

So what?

The telomeres and gene expression may play a central role, but if your age and the “mileage” is distantly causing all those changes in cell division, telomere lengths, gene expression, and failing cell maintenance, then what’s the difference? Why bother with all the complexity? Why not accept that age and your “mileage” are the cause of aging diseases and stop fussing? Why not simply accept age-related disease?

Because we can change it.

The question isn’t “why does this happen?” so much as “what can we do about it?” We can’t change your age and it’s hard to avoid a certain amount of “mileage” in your daily life, but we CAN change telomeres, gene expression, and cell maintenance. In fact, we can reset the entire process and end up with cells that keep up with damage, just as your cells did when you were younger.

Until now, everyone who has tried to deal with only the damage (or the damaged cells) failed because they focused on damage rather than focusing on repair. For example, if you focus only on cell damage (as most big pharma and biotech companies do when they go after beta amyloid or tau proteins in trying to cure Alzheimer’s disease), then any clinical effect is transient and the disease continues to progress – which is why companies like Eli Lily, Biogen, TauRx, and dozens of other companies are frustrated. And small wonder. Or if you focus only on the damaged cells (and try removing them), then the clinical effect is not only transient, but will end up accelerating deterioration (as discussed in last week’s blog, see figure below) – which is why companies like Unity will be frustrated. Their approaches fail not because they don’t address the damage, but because they fail to understand the deceleration of dynamic cell maintenance that occurs with age – and fail to understand the most effective single clinical target. The key target is not damage, nor damaged cells, but the changes in gene expression that permit that damage, and those damaged cells, to lead to pathology. We can’t cure Alzheimer’s or osteoarthritis by removing senescent cells, but we can cure them by resetting those same cells.

Why you shouldn't kill senescent cells.

Why you shouldn’t kill senescent cells.

In the cases of removing senescent cells (an approach Unity advocates), wouldn’t it be better to remove the damaged cells and then reset the telomeres of those that remain? But why remove the damaged cells if you can reset them as well, with the result that they can now deal with the damage and remove it – as well as young cells do?

Why remove senescent cells at all?

While you could first remove senescent cells, then add telomerase so that the remaining cells could divide without significant degradation of function, why would you bother? You could much more easily, more simply, and more effectively treat all the cells in an aging tissue, reset their aging process and have no need to ever remove senescent cells in the first place. Instead of removing them, you simply turn them into “younger” and more functional cells. For an analogy, imagine that we have a therapy that could turn cancer cells into normal cells. If that were true, why would anyone first surgically remove a tumor? If you could really “reset” cancer cells into normal cells, there would be no need to do a surgical removal in the first place. While there is no such therapy for cancer cells, the analogy is still useful. Removing senescent cells is not only counter-productive, but (if we reset gene expression) entirely unnecessary.

Removal is unnecessary (both as to cost and pathology), risky, and medically contraindicated. You’d be performing a completely unnecessary procedure when a more cost-effective and reliable procedure was available. It would be exactly like removing your tonsils if you already had overwhelming data showing that an antibiotic was reliable, cheap, and without risk.

A cell with full telomere lengths – regardless of prior history – is already superior. The accumulated damage is not a static phenomenon, but a dynamic one. Reset cells can clean up damage. This is not merely theory, but supported well in fact, based on both human cells and whole animal studies. We shouldn’t think of damage as something that merely accumulates passively. All molecules are continually being recycled. The reason some molecular pools show increased damage isn’t because molecules denature, but because the rate of turnover slows, thereby allowing denatured molecules (damage) to increase within the pool.

Try this analogy: we have two buildings. One is run by a company that invests heavily in maintenance costs, the other is run by a company that cut its maintenance budget by 50%. The first building is clean and well-kept, the second building is dirty and poorly-kept. Would you rather raze the second building and then rebuild it or would you rather increase the maintenance budget back to a full maintenance schedule and end up with a clean building? This is precisely the case with young versus old cells: the problem is not the dirt that accumulates, the problem is that no one is paying for routine maintenance. There are cells that are “too senescent” to save, but almost all the cells in human age-related disease can be reset with good clinical outcome. There is no reason to remove senescent cells any more than (in the case of a dirty building), we need to send in the dynamite and bulldozers.

Too often, we try to approach the damage rather than looking at the longer view. Instead of addressing the process, we address the outcome. It’s like the problem that often occurs in global philanthropy, where we see famine and think we can solve the problem with food alone. While the approach is necessary – as a stopgap – many are surprised to find that simply providing free food for one year, results in bankrupt farmers and recurrent famines in the following years. Or we provide free medical care in a poor nation, then wonder why there is a dearth of medical practitioners in years to come, without realizing we have put them out of business and accidentally encouraged them to emigrate to someplace they can make a living and feed their families. We intend well, but we perpetuate the problem we are desperately trying to solve. Treating famine or medical problems, like treating the fundamental causes of age-related disease, is not simple and cannot be effectively addressed with band aids and superficial interventions, such as addressing damage alone or removing senescent cells. Effective clinical intervention – like effective interventions in famine or global healthcare – require a sophisticated understanding of the complexity of cell function, an understanding of the dynamic changes that underlie age-related pathology.

An adage (variously attributed to dozens of sources) about fish and fishing provides a useful analogy here:

Give a man a fish, and you feed him for a day.

Teach a man to fish, and you feed him for a lifetime.

If we want to intervene effectively in age-related diseases – whether Alzheimer’s, osteoarthritis, or myriad other problems of aging – we shouldn’t throw fish at medical problems.

We should teach our cells to fish.

 

November 15, 2016

Close to a Cure

We are now within two years of a cure for Alzheimer’s disease.

What a brash and disruptive claim! What hubris! Yet events are coming together, underlining a new and far more complete understanding of the disease, illuminating the cause, supporting the ability to intervene, safely and effectively. We finally see a way to intervene in the basic pathology, underlining the potential to both prevent and cure Alzheimer’s disease.

But why has it taken so long? Why was Alzheimer’s disease first defined 110 years ago, and yet remains totally beyond our ability to intervene even now? Why have all other approaches, whether those of big pharma or those of biotech, failed utterly? Why has not a single clinical trial shown any ability to change the progress of this frightening disease? Why is Alzheimer’s disease not only called “the disease that steals human souls”, but also called the “graveyard of companies”? Why has every single approach (which has at most shown only an effect on biomarkers, such as beta amyloid), still failed to show any change in the cognitive decline in patients with this disease? Why have we failed universally, until now?

Because every approach has concentrated on effects, not on causes.

Currently, most approaches target beta amyloid, many target tau proteins, and some target mitochondrial function, inflammation, free radicals, and other processes, but no one targets these problems as a single, unified, overarching process. Alzheimer’s isn’t caused by any one of these disparate processes, but by a broader, more complex process that results in every one of these individual problems. Beta amyloid isn’t a cause, but a biomarker. Equally, tau proteins, phosphodiesterase levels, APOE4, presenilins, and a host of other markers are effects, not causes. The actual cause lies upstream and constitutes the root cause of the dozens of separate effects that are the futile downstream targets of every current FDA trial aimed at Alzheimer’s disease. Understanding this, we will be targeting the “upstream” problem, rather than the dozens of processes that others target individually and without success. Our animal studies support the ability to effectively intervene in human disease: when we say that we are about to cure Alzheimer’s disease, we base claim that on a clear and consistent theoretical model, supported by equally clear and consistent data.

Within the next few months, we will begin our FDA toxicity study, preparatory to obtaining an IND that will permit us to begin our FDA human trial. Our toxicity study will take 6 months and will meet FDA requirements for human safety data. Our first human trial is planned to begin one year from now and is intended to show not only safety, but a clear efficacy. We will include a dozen human volunteers, each with (not just early, but) moderate Alzheimer’s disease and our human trial will last 6 months, including a single treatment and multiple measurements of behavior, laboratory tests, and brain scans. We expect to show unambiguous cognitive improvement within that six-month period. We are confident that we cannot merely slow, not merely stop, but reverse much of the cognitive decline in our twelve patients. We intend to demonstrate an ability to cure Alzheimer’s disease clearly and credibly.

Curing Alzheimer’s requires investments of money, time, and thought. The toxicity study costs 1 million dollars; the human trial costs 2.5 million dollars. Telocyte has half a million dollars committed to this effort and at least one group of investors with a firm interest in taking us all the way through the human trials. We are close and we grow closer each day.

After 110 years, we are about to cure Alzheimer’s.

November 8, 2016

Revolution in Medicine

Every pharmaceutical firm, every biotech company, every hospital, every clinic, and every conference makes revolutionary claims, albeit seldom with any logic or thought behind the claims. Every product is a “revolutionary” therapy, every surgery is a “revolutionary” procedure, and everyone has a “revolutionary” way of looking at clinical medicine. Reality is strikingly different. Despite claims to the contrary, almost all advances in medicine are accretionary, not revolutionary. About sixty percent of all FDA applications for “breakthrough” status are turned down for not being breakthroughs, but merely incremental advances (if that). Even granting a third of these applications is overly kind, but then breakthroughs, like revolutions, are remarkably rare. I am reminded of my years consulting for hospitals around the world, where I was entertained to find every hospital, in every town, in every country, bragging that they were ranked as “one of the best ten hospitals!” Sometimes, they bragged that they were THE best hospital. Somehow, it appears that thousands of hospitals are among the best ten hospitals and hundreds are THE best hospital. In the entire world or on that block?

It clearly depends on who’s counting and on who does the ranking.

Therapies are much the same: they are seldom “the best” (in the world?) and they are almost never revolutionary. To the contrary, almost all current therapy is based on incremental change: we find a slightly better statin, an antibiotic with slightly less resistance (at least this year), and a procedure with a slightly lower risk. We rank our interventions by statistical significance and we deal with percentage points in the adverse effect profile. Scarcely the stuff of revolution.

We can do better; much better. To do so, however, requires both an open mind and a very disciplined one. We need both creativity and intelligence to envision a path to revolutionary therapies. If we do so, we may be able to cure diseases that are thought to be “incurable”, a true revolution I both clinical thinking and clinical practice.

Many people, in a totally practical vein, think of diseases in three categories. The first includes those diseases that we have “cures” for, by means of vaccines, antibiotics, and routine surgeries (think of tetanus, cellulitis, and appendicitis). The second category includes diseases for which we have no cure yet, but for which we see a cure on the horizon (think of treating sickle cell anemia with gene therapy). This second category includes type 1 diabetes: while we use insulin to good effect, we eagerly imagine the days when we simply replace the missing cells in the pancreas and truly cure diabetes. While we have – or imagine that we may soon have – true cures for these diseases in both the first two categories, the third category brings a sense of futility. When it comes to age-related disease (think of Alzheimer’s disease, cardiovascular disease, osteoporosis, etc.), we are caught up by the assumption that while we can treat symptoms, use grafts or stents, lower the risk factors, or replace the damaged part (a total knee replacement comes to mind), we will never be able to entirely prevent or cure the underlying disease. After all, they’re simply the outcome of aging, yes? And who could possibly change the aging process?

Oddly enough, we already have.

We first showed we could reverse cell aging in 1999, followed by the reversal of tissue aging (in the laboratory) in the following few years. The question isn’t “can we reverse the aging process in human cells or tissues”, but “can we reverse the aging process in human patients”? Can we take someone with age-related disease, treat them, and reverse the disease reverse at the cellular and genetic levels? Can we prevent and cure age-related disease? Based on both theory and animal data, the answer is almost certainly to be “yes, we can”. All it requires is intelligence, a modicum of work, and a small commitment of funding.

Instead of treating Alzheimer’s as something to live with, we can treat it and have it be something we can live without. Only then we will have a true revolution.

October 18, 2016

The Carpets of Alzheimer’s Disease

Why do Alzheimer’s interventions always fail?

Whether you ask investors or pharmaceutical companies, it has become axiomatic that Alzheimer’s “has been a graveyard for many a company”, regardless of what they try. But in a fundamental way, all past and all current companies – whether big pharma or small biotech – try the same approach. The problem is that while they work hard at the details, they never examine their premises. They uniformly fail to appreciate the conceptual complexity involved in the pathology of Alzheimer’s. They clearly see the technical complexity, but ignore the deeper complexity. They see the specific molecule and the specific gene, but they ignore the ongoing processes that drive Alzheimer’s. Focusing on a simplistic interpretation of the pathology, they apply themselves – if with admirable dedication and financing – to the specific details, such a beta amyloid deposition.

But WHY do we have beta amyloid deposits? Why do tau proteins tangle, why do mitochondria get sloppy, and why does inflammation occur in the first place? Focusing on outcomes, rather than basic processes explains why all prior efforts have failed to affect the course of the disease, let alone offer a cure for Alzheimer’s.

Let’s use an analogy: think of a maintenance service. Any big organization, (university, pharmaceutical firm, group law practice, or hospital) has a maintenance budget. Routine maintenance ensures that – in the offices, clinics, or laboratories – carpets are vacuumed, walls are repainted, windows are cleaned, floors are mopped, and all the little details are taken care of on a regular basis. These are the details that make a place appear clean and well-cared for, providing a pleasant and healthy location. In most offices (as in our cells), we are often unaware of the maintenance, but quite aware of the end result: an agreeable location to work or visit. In any good workplace, as in our cells, maintenance is efficient and ongoing.

That’s true in young cells, but what happens in old cells?

Imagine what happens to a building if we cut its maintenance budget by 90%. Carpets begin to show dirt, windows become less clear, walls develop nicks and marks, and floors grow grimy and sticky. This is precisely what happens in old cells: we cut back on the maintenance and the result is that cells becomes less functional, because without continual maintenance, damage gradually accumulates. In the nervous system, beta amyloid, tau proteins, and a host of other things “sit around” without being recycled efficiently and quickly. Maintenance is poor and our cells accumulate damage.

All previous Alzheimer’s research has ignored the cut back in maintenance and focused on only a single facet, such as beta amyloid. You might say that they focused only on the dirty carpet and ignored the walls, the windows, and the floors. Even then, they have focused only on the “dirt”, and ignored the cut back in maintenance. Imagine an organization that has cut its maintenance budget. Realizing that they have a problem, they call in an outside specialist to focus exclusively on the loose dirt in the carpet, while ignoring the carpet stains, ignoring the window, walls, and floors, and then only coming in once. What happens? The carpets look better for a few days, but the office still becomes increasingly grungy and unpleasant. In the same way, if we use monoclonal antibodies (the outside specialist) to focus on beta amyloid plaque, the plaques may improve temporarily, but the Alzheimer’s disease continues and it is definitely unpleasant. Various companies have focused on various parts of the problem – the floors, the walls, the windows, or the carpets – but none of them have fixed the maintenance, so the fundamental problem continues. You can put a lot of effort and money into treating only small parts of Alzheimer’s, or you can understand the complex and dynamic nature of cell maintenance. Ironically, once you understand the complexity, the solution becomes simple.

The best solution is to reset cell maintenance to that of younger cells. Neurons and glial cells can again function normally, maintaining themselves and the cells around them. The outcome should be not another “graveyard for companies”, but life beyond Alzheimer’s .

 

August 8, 2016

Regenerative Medicine: What Is It? Where Is It Going?

What is regenerative medicine?

To bystanders, regenerative medicine might be merely a catch-all category or simply a current medical fashion. The reality, however, is that regenerative medicine represents a conceptual, material, and historical transformation of human medical care. Even the key researchers and clinicians who are moving this field ahead are often so busy in advancing the technology that they are less aware of the extraordinary changes that they represent, changes that are about to change the face of human medicine forever.

Regenerative medicine has marked differences, both conceptual and concrete differences, when compared to previous approaches to clinical intervention. These differences not only define the field, but they point our way to future progress and, frankly, to improvements in our health and in our lives.

The conceptual key is that regenerative medicine results in long-term (rather than transient) clinical improvements. Regenerative medicine is just that: an intervention that re-generates. Effective regenerative interventions change the body itself – and not merely a set of biomarkers or symptoms. Bluntly, regenerative medicine aims to improve biological function, rather than merely attempting to normalize abnormal biomarkers or symptoms of biological dysfunction. Even admitting the often impressive utility and efficacy of our standard medical interventions to date – for certainly we have come a long way in our ability to treat human disease – such approaches act as pharmacological Band-Aids. In contrast, regenerative medicine seeks to optimize the underlying genetic, cellular, and tissues processes that go awry.

Nor is this the only conceptual difference, for the time course is equally different. Standard clinical interventions generally have transient effects, for example in modifying inflammation, cholesterol, glucose levels, etc., while regenerative interventions generally have long-term (even permanent) changes to tissue and organ function. When most standard interventions may last for hours to days, regenerative interventions may last for years to decades. Even “definitive” surgical approaches (CABG, joint replacements, etc) have no effect upon the underlying disease process and are often merely recurrent stopgaps. Why replace an artificial joint (every decade or so), if we can possibly regrow a normal joint that might last a lifetime?

At its conceptual core, regenerative medicine offers us a more accurate and enlightened view of biological function. Regenerative medicine encompasses a view of biology that is active and dynamic, a view in which we aim to alter the processes rather than the products of biology. Consider diabetes, in which a regenerative approach strives to recreate normal islet cell function, where standard approaches strive to manage glucose levels. The difference is critical to understanding the efficacy of regenerative medicine: it views pathology as a dynamic process and aims to alter the process itself, rather than focusing on the products of such processes and aiming to alter the clinical results of those processes. The same pertains to surgical interventions in which regenerative medicine aims to alter the process of joint failure, rather than the product of joint failure. Regenerative medicine would regenerate a normal joint, where standard approaches implant an artificial joint.

Essentially, regenerative medicine aims to reset biological processes to those of a normal, healthy body.

The material features of regeneration medicine are equally distinctive. Instead of employing what are current called “small molecular” approaches, regenerative medicine uses “large molecular” approaches, generally by employing genes, stem cells, and other large biological structures. We might legitimately include immunization in this category: it not only employs a large biological structure (i.e.., an active virus or a complex set of antibodies), but it also results in a long-term change to the organism (i.e., improved immunity). Contrast this approach to the more common “small molecular” approach, typified by the use of non-steroidal anti-inflammatories, statins, blood pressure medications, antibiotics, etc. While many such molecules are fairly complex and certainly not simple, nor are they large-scale biological structures such as viral vectors, plasmids, genes, or stem cells.

Regeneration medicine is typified by two common approaches: genes and cells. In either case, these interventions are large and active biological structures rather than small and passive chemical structures. Genes and cells do not merely interact with biological structures, they ARE biological structures. They not only interact with genes and cells, they ARE genes and cells.

The historical perspective on regenerative medicine is enlightening. What can the past tell us and what does the future hold? An apt historical analogy is that of infectious disease, particularly when we compare antibiotics and immunization. No one would be so naïve as to underestimate the value of antibiotics, but nor should we underestimate the limits of antibiotics. Faced with most viral infections, such as polio, tetanus, or diphtheria, antibiotics are ineffective. Those same viral infections are readily preventable, however, by immunization, using large and active biological structures (whether antigens or live virus).

Immunization is essentially a form of regenerative medicine, in that it results in a long-term change in the human body, a change that results in long-term health. The one difference is that immunizations don’t “re-generate” so much as they “generate” a healthier organism. Nonetheless, the similarity in addressing basic biological functions, in having a long-term effect, and in using large, active biological structures places immunization an historical forerunner for regenerative medicine. Consider a further analogy, that of Ebola. During the height of the Ebola epidemic, small molecular approaches (IV fluid, pressor support, etc) were useful, but far from optimal. Only an effective Ebola vaccine promises to lower the fatality rate into the single digit percent range. In viral infections (as we look backwards) and for the entirety of medicine (as we look forward) standard small molecular approaches are simply not good enough.

Such is the past, but what of the future? Our current standards of medical care cannot reasonably be considered optimal standards of care. We can do better, but only by moving to a regenerative approach. The upcoming standards of medical care will encompass two main approaches: genetic interventions and cellular interventions. In the first case, we will deliver both genes meant to replace pathologic genes and genes that are intended to reset gene expression. In the second case, we will deliver cells that are meant to replace pathologic (or absent) cells.

Genetic interventions encompass both genetic and epigenetic optimization. While the bulk of interest is currently focused on gene changes, remember that genes that regulate expression are far more important than genes that express proteins, both clinically and in terms of percentage of genes in our genome (we have 10-20 times more regulatory genes than we have protein-expressing genes). Although 20th century medicine has made dramatic inroads in our understanding of genes and disease, it remains to the 21st century to move into the far more difficult – and more important – task of understanding patterns of gene expression. In short, it is not genetics, but epigenetics that will prove to be the key to medical interventions. Viral delivery, telomere effects, cell senescence, and a host of other factors will define what we will soon be capable of. We have scarcely begun to enter this complex and confusing field.

Cellular interventions encompass a spectrum of cells, from somatic cells to pluripotent stem cells – and the entire gamut in between those extremes. It has become clear that pluripotent stem cells need not derive from fetal sources, but equally clear that our understanding of the complex path from stem cell to somatic cell is still inadequate – although increasing by the month.

Using an historical perspective to project forward, we begin to see where we can – finally – begin to address diseases that we have long ignored as being “facts of life”, such as the diseases of aging. Although public understanding (indeed, even academic understanding) lags behind the tantalizing and growing data, there is mounting evidence that we will be able to slow, stop, prevent, and even reverse diseases that we have no current treatment for. Consider, for example, osteoporosis. Until now, we have had no therapy that alters the clinical course that begins in the aging osteocyte and the bony matrix. Likewise, our treatment for osteoarthritis, joint replacement, may have value to the patient, but is an admission of failure when we realize that we have no therapy that alters the clinical course of this pathology, that begins in the aging chondrocyte and its matrix either. Arterial disease, Alzheimer’s disease, and a host of other diseases, almost all of which appear to be linked to basic cellular-related aging processes, are fast becoming viable targets for the advances of regenerative medicine.

From a purely practical perspective, how will a regenerative approach change medical care? Currently, medicine is – to a large extent – organized by organ (nephrology, neurology, cardiology, dermatology, etc.), although with an overlay based on the type of intervention (surgical versus medical). At the moment, regenerative medicine is something of a step-child, although gaining traction yearly. Although the approach is innovative, the tools themselves are adaptable within the current framework of medical specialties. There is, for instance, no reason that gene or cell therapy cannot be adopted by and adapted to most current medical specialties, a process that will come to completion within the coming two decades. Regenerative medical techniques equally become the intervention-of-choice for the pulmonologist, the gastroenterologist, or the endocrinologist. For medical specialties, regenerative medicine is an approach which is largely specialty-agnostic.

Surgical specialties, however, will fare a bit differently: where is the need for cardiovascular or orthopedic surgical approaches when we can regenerate both normal coronary arteries and normal joints? Over the next two decades, the face of surgical practice will change rapidly and will lose many of the most common procedures, as regenerative medicine makes effective inroads. Yet there will remain a place for both standard medical care (small molecular drugs) and for surgical procedures, even within a transformed medical landscape. The landscape will continue to change, requiring rapid adaptation for specialties and their practitioners as our knowledge and our capacity to intervene evolve.

Ultimately – if the word is even remotely appropriate to the future of medicine – medical care will still be left with two prongs: a medical approach that fixes the genetic, epigenetic, and cellular problems and a surgical approach that deals with acute, externally imposed disasters, such as trauma. The role of the first specialty will be to deal with non-emergent and known problems at cellular levels. The role of the second specialty will be to deal with emergent and largely unpredictable problems at the organ (rather than cellular) level. The parallel with the modern division between medicine and surgery is apt, but the tools will have evolved, as will the ability to not merely ameliorate, but actually cure disease and to optimize health.

If we are to define regenerative medicine, we might best understand its conceptual underpinnings, its materially different approach, or the historical inflection point that it now represents. In the venue of human disease, regenerative medicine thinks differently, uses different tools, and represents an historic sea-change. Looking at it practically, however, the most striking feature – and perhaps the defining feature – of regenerative medicine is that it offers all of us a more compassionate and a far more effective medical future.

This article is cross-posted at Regenera Global: http://bit.ly/2aMPKIq

 

July 20, 2016

Curing Disease: More Insight Instead of Mere Effort

 

Curing disease correlates with insight, not blind effort.

There is an eternal trade-off between insight and effort. If we think carefully, understand the problem, and plan, then effort is minimized. If (as too often happens) we think carelessly, misunderstand the problem, and rely on hope instead of planning, then effort is not only maximized, but is usually a complete waste. Lacking insight, we foolishly flush both money and effort down the drain. In the case of clinical trials for Alzheimer’s disease – and in fact, all age-related diseases – this is precisely the case.

The major problem is a naïve complaisance that we already understand aging pathology.

If there was a single concept that is key to all of aging, it is the notion that everything in our organs, in our tissues, and in our cells is dynamically and actively in flux, rather than being a set of organs, tissues, cells, and molecules that statically and passively deteriorate. Aging isn’t just entropy; aging is entropy with insufficient biological response. Senescent cells no longer keep up with entropy, while young cells manage entropy quite handily. At the tissue level, the best example might be bone. We don’t form just bone and then leave it to the mercy of entropy, rather we continually recycle bony tissue throughout our lives – although more-and-more slowly as our osteocytes lose telomere length. This is equally true at the molecular level, for example the collagen and elastin molecules in our skin. We don’t finish forming collagen and elastin in our youth and then leave it to the vagaries of entropy, rather we continually recycle collagen and elastin molecules throughout our lives, although more-and-more slowly as our skin cells lose telomere length. Aging is not a process in which a fixed amount of bone, collagen, or elastin gradually erodes, denatures, or becomes damaged. Rather, aging is a process in which the rate of recycling of bone, collagen, or elastin gradually slows down as our shortening telomeres alter gene expression, slowing the rate of molecular turnover, and allowing damage to get ahead of the game. We don’t age because we are damaged, we age because cells with shortening telomeres no longer keep up with the damage.

The same is true not only of biological aging as a general process, but equally true of every age-related disease specifically. Vascular disease is not a disease in which our arteries are a static tissue that gradually gives way to an erosive entropy, but an active and dynamic set of cells that gradually slow their turnover of critical cellular components, culminating in the failure of endothelial cell function, the increasing pathology of the subendothelial layer, and the clinical outcomes of myocardial infarction, stroke, and a dozen other medical problems. Merely treating cholesterol, blood pressure, and hundreds of other specific pathological findings does nothing to reset the epigenetic changes that lie upstream and that cause those myriad changes. Small wonder that we fail to change the course of arterial disease if our only interventions are merely “stents and statins”.

Nor is Alzheimer’s a disease in which beta amyloid and tau proteins passively accumulate over time as they become denatured, resulting in neuronal death and cognitive failure. Alzheimer’s is a disease in which the turnover – the binding, the uptake, the degradation, and the replacement – of key molecules gradually slows down with telomere shortening, culminating in the failure of both glial cell and neuron function, the accumulation of plaques and tangles, and ending finally in a profound human tragedy. The cause is the change in gene expression, not the more obvious plaques and tangles.

Our lack of insight, even when we exert Herculean efforts – enormous clinical trials, immense amounts of funding, and years of work – is striking for a complete failure of every clinical trial aimed at Alzheimer’s disease. Naively, we target beta amyloid, tau proteins, phosphodiesterase, immune responses, and growth factors, without ever understanding the subtle upstream causes of these obvious downstream effects. Aging, aging diseases, and especially Alzheimer’s disease are not amenable to mere well-intended efforts. Without insight, our funding, our time, and our exertions are useless. Worse yet, that same funding time, and exertion could be used quite effectively, if used intelligently. If our target is to cure the diseases of aging, then we don’t need more effort, but more thought. However well intentioned, however much investment, however many grants, and however many clinical trials, all will be wasted unless we understand the aging process. Aging is not a passive accumulation of damage, but an active process in which damage accumulates because cells change their patterns of gene expression, patterns which can be reset.

Curing Alzheimer’s requires insight and intelligence, not naive hope and wasted effort.

 

 

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