Michael Fossel Michael is President of Telocyte

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.

November 1, 2016

Making Things Worse

Imagine a factory which is operating at capacity, with a thousand workers. Some of the workers are doing a great job, but some are ill and not working hard. In fact, they are actively interfering with those who are working hard. In this factory, you can’t hire anyone new, so you have two choices: you can fire the bad workers or you try to improve their health. If you simply fire the bad workers, you have increased the work load for those who remain. Not surprisingly, they begin to get tired and ill as well, so the factory ends up failing even faster and before you know it, everyone is out of a job. On the other hand, if you can improve the health (and the attitude) of the workers who are tired and ill, the factory can become a success.

The factory is human tissue; the workers are your cells.

Let’s look at an example, such as the cells in your knee. Over time, the chondrocytes divide, become gradually more senescent, and begin to fail. The result is osteoarthritis. If you have mild osteoarthritis, you might (naively) consider simply removing senescent cells. This reliefs some of the inflammation and removes the cells that aren’t doing a good job (the tired workers), but the result is that you’ve just asked all the remaining cells to take up the slack (increased the work load for the remaining factory workers). In order to replace the cells that you’ve removed, the remaining cells now have to divide, which accelerates their own senescent changes, and hastens the failure of the entire tissue. In the case of the knee joint, the osteoarthritis improves temporarily, but you’ve just accelerated osteoarthritic changes in the long run. Instead of a slow joint failure, you’ve ensured that it fails even faster.

Several people have, in a charming burst of innocence, recommended that we do just that. Instead of resetting senescent cells and restoring cell and tissue function, they want to remove senescent cells in older tissues. Their hope is understandable, but their understanding is simplistic. Studies show that you may see temporary improvement in inflammation and secretory profiles, but what about long term risks? The problem is that those who want to kill off senescent cells lack a full appreciation of the dynamic pathology and the cellular consequences. They offer a simplistic view, but biology is seldom simplistic.

Why you shouldn't kill senescent cells.

Why you shouldn’t kill senescent cells.

 

Consider the knee again. A common concern is that of chondrocyte senescence (leading to osteoarthritis) in professional basketball players. Because of repetitive high-impact trauma, they lose chondrocytes at an accelerated rate compared to people whose knees are not subject to traumatic cell loss. The remaining chondrocytes divide to replace the lost chondrocytes, accelerating telomere loss, and accelerating osteoarthritic changes. The clinical result is due to tissue failure at an early age.

Those who are trying to treat tissue senescence by selectively removing senescent cells (instead of resetting them to a normal pattern of gene expression) are causing a transient improvement in tissue function, coincident upon the removal of dysfunctional, senescent cells (temporarily decreasing inflammatory biomarkers, for example), but the longer-term result is to accelerate cell senescence in all remaining cells. The result is a transient hiatus in inflammation and other biomarkers of cell senescence, followed by a more rapid decline in cell and tissue function. In the case of OA, for example, the outcome is to relief symptoms temporarily, only to then ensure a more rapid failure of the joint.

Our analogy remains apt. If you have a group of workers in a factory, some of whom are suffering from fatigue and are no longer producing, you have two possible interventions. Intervention #1 might be to fire all the tired workers, but the long-term result is that you increase the workload and failure rate among the remaining workers. Intervention #2 would be to find a way to restore the energy and interest among those workers who are fatigued. The analogy is a loose one, but the outcomes are predictable. Removing the “tired” cells within a tissue will accelerate pathology. Resetting the “tired” cells within a tissue will resolve pathology.

If you want to cure age-related disease, the solution is not to kill senescent cells, but to reset their gene expression to that of young cells.

 

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 .

 

April 26, 2016

The Tempo of Alzheimer’s

Hardly a day goes by, and never an entire week, without my seeing yet another article, often a cover article, that suggests we will soon cure Alzheimer’s disease. If articles were anything to go by, then the increasing tempo of those articles, to say nothing of the increases in both research and funding, would suggest we will soon solve the problem. But, publicity, laboratories, and money are not the same as actual clinical results. In fact, the issue is never the amount of resources, but where you aim those resources. If we wish to cure Alzheimer’s, then we need to put some honest intellectual effort into understanding Alzheimer’s. Until then, publicity, laboratories, and funding are only a reflection of wishful thinking. No one ever cured a disease by injecting money into the patient, let alone making them swallow a laboratory, or listen to publicity.

Yet oddly enough, publicity is often perceived as a goal in itself. I see biotech companies who strive to get themselves mentioned on the news, as though that would create success. But whether are on the cover of Time magazine or mentioned in this week’s edition of The Scientist, news stories are never equivalent to a cure for Alzheimer’s or anything else. In fact, I suspect there is often an inverse correlation: the more your drug or your biotech company is mentioned in the media, the less likely it is to get through FDA trials, let alone improve patient care. Just a suspicion, but founded on frequent observations over the past two decades or more.

Some of us want to find a cure, and never mind the kudos.

Other people just want the kudos.

The fact that we hear about another potential “drug that may cure Alzheimer’s disease” on an approximately weekly basis, underscores not only the frantic need for a cure, but the fact that none of the alleged cures actually work. As we say in medicine, when you have dozens of professed cures for a disease, you can be pretty sure that none of them actually do a damn thing. The more strident the claims for “the cure” the more you should suspect an absence of data. When there is a cure and when it works, it will be a single intervention and you’ll know it works because, guess what, it will actually work.

I regret that the media gets caught up in the inflated claims, but it speaks to the public’s hunger to believe. One of these days, it won’t be a claim and it won’t be inflated, it will simply be the facts. When we finally have the facts, it will be because we have shown we can cure Alzheimer’s disease and it will be Telocyte on the cover, but only after we cure Alzheimer’s.

 

April 12, 2016

Rational Behavior

We waste stunning amounts of money and effort on comprehensively ineffective trials.

As a recent article points out, in the past 15 years, there have been 123 Alzheimer drug failures and, while four medicines have been approved, none of them affect the progress of the disease. Symptomatic therapy at best, we have no medications – none – that have any effect on the disease or on its mortality. A quick look at clinicaltrials.gov lists almost 1,500 interventional trials aimed at treating Alzheimer’s disease, yet once again there is no evidence that any of these trials has resulted (or will result) in an intervention that changes the outcome of Alzheimer’s disease.

Federal funding for Alzheimer’s is estimated at almost half a billion dollars and some have estimated that Eli Lilly’s potential treatment for Alzheimer’s, solanezumab, may end up costing the company one billion dollars to achieve approval of that drug alone, even though there is no evidence that it actually prevents or cures the disease. The most optimistic interpretation of the statistical data of thousands of patients over many years, would be stretching it to suggest it might possibly delay cognitive decline and death by 2-3 months over an eight year period from diagnosis to death. Even that wishful thought is doubtful and scarcely any consolation to those enduring an extra handful of weeks in a skilled care nursing home (or having to pay for it).

No matter what the current target of choice – beta amyloid, tau proteins, inflammation, or any other target-du-jour – none of these targets have ever been shown to offer a glimmer of hope. Despite the history of repeated and consistent failure, we continue to spend (and vote to spend) money on these same drug targets. We eagerly bash our empty heads against the same solid brick wall, naively hoping that one day we fill find that the wall will be made of air (like the air in our brains, which leads to our irrational behavior). The apocryphal observation pertains: the definition of insanity is doing the same thing over and over and expecting a different result. We waste money and effort on ineffective and expensive trials aimed at targets that we know are futile.

The irony – and the tragedy – is that we can both prevent and cure Alzheimer’s disease, both effectively and inexpensively if we understand the actual pathology and target the underlying causes. We could do, effectively and inexpensively, what big pharma has failed to do ineffectively and expensively. What big pharma can’t do for one billion dollars, Telocyte can do for 0.5% of that figure, simply by aiming at the right target.

We need rationality, insight, and just enough funding to prove it can be done.

April 6, 2016

The Rabbits of Research, The Frogs of Alzheimer’s

 

Perspective often shrinks personal problems.

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

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

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

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

March 1, 2016

Changing the World

Perseverance is critical to innovation.

If you try to change the world, you might fail, but if you don’t try, you will certainly fail. In 1616, the church banned Galileo’s theory that the Earth went around the sun, which is now accepted as obviously true. Relativity and quantum theory were once derided by classical physicists, physicists who are now mocked, if not utterly forgotten. Twelve separate publishers turned down J K Rowling’s first book, the first of a series that have so far netted her an estimated one billion dollars and resulted in a brand, itself worth 15 billion dollars. No matter the advance in science, medicine, or the arts, the greater the importance and the greater the innovation, the more it was fought against by those who “knew” better.

The larger the crowd, the louder the cries, the less the truth can be heard.

Today, I was on a call with a major global investor who, data notwithstanding, cannot see how age-related disease can possibly be altered. Despite their investing in a biotech company that focuses on epigenetics, they cannot see how epigenetics can offer anything for age-related disease. Where once astronomers ignored the data and struggled to fit our solar system into epicycles, we now ignore the data, give lip service to epigenetics, and ignore the profound clinical implications that lie immediately in front of us.

Age-related diseases – whether Alzheimer’s, arteriosclerosis, osteoarthritis, or a host of others – are not diseases of “bad genes”, but bad gene expression. Once we look afresh at what causes disease, once we look honestly at the data, once we examine our assumptions and realize we have been wrong, the potential for curing disease, for making our lives better, for bringing hope becomes clear. We believe what the crowd believes, we listen to the loudest voices, while closing our eyes and ears to reality, as though we feared to understand it.

Someday we will look back at age-related disease and (as has so often been true in a myriad of other cases), we will ask what was the key that finally led to progress. The key is not genius, hard work, knowledge, funding, or even insight. The key is to keep going, even when the world seems bent on remaining foolish and bent on keeping you from making the world a better place. No matter how many people, blinders in place, tell you that something can’t be done, that you can’t do it, and that your view is wrong, follow logic, look at the data, think clearly, keep your mind open, examine your assumptions, and – above all – keep going.

The key isn’t genius, but perseverance.

December 21, 2015

Alzheimer’s isn’t just forgetting, it’s forgetting our assumptions

The rate-limiting-step to innovation is assumption.

Often, we have the infrastructure, the knowledge, and even the intelligence we need to move ahead, but stumble and fall over our own assumptions. Why didn’t Europe use immunizations hundreds of years earlier than it did? Why didn’t we discover – and make use of – the steam engine in ancient Rome? Why did flight, electricity, or sailing ships come about when they did? Why not earlier? Occasionally, we lack a critical piece of technology, one that slows us down for decades or even centuries. Occasionally, it’s an odd piece of data, a fact, a small subset of knowledge.

And sometimes, it’s a simple lack of intelligence: we simply aren’t very smart.

One key to being not-being-very-smart occurs when we make the wrong assumptions. Again and again, we misunderstand the nature of reality, while assuming that we already understand completely. Physics was all but certain – just prior to the end of the nineteenth century – that we knew all of physics except for a few niggling little details, but those “little” details left room for quantum physics and, ultimately, an electronics revolution, hence cell phones, the internet, computers, and computer blogs, like this one.

Assumptions have a way of limiting our vision. Obviously we can’t fly because, after all, how could something heavier than air possibly stay up in the air? Yet tons of steel and plastic manage that feat every day throughout the world. Obviously we can’t sail around the world because, after all, how could you avoid falling off the edge? Yet once again, the assumptions about “the world” were a bit off the mark.

Our assumptions about Alzheimer’s disease are – albeit with a desperately tragic languor – slowly beginning to change. The change involves a set of related, but slightly different assumptions, that are finally giving way. One assumption is that beta amyloid and tau proteins, are the cause instead of a result. Another assumption is that the cause lies within the neurons, which are merely innocent bystanders. We likewise assume that the cause lies in the genes, looking harder and harder in the wrong location, while ignoring the role played by changes in gene expression. A final assumption is more subtle: when we look at pools of molecules, such as beta amyloid, we look at them as a static accumulation of damaged molecules. We completely ignore the hallmark of biological processes, the dynamic turnover of all such pools. We then go on to focus myopically on the damage and completely ignore the broader and more critical question: why does molecular turnover slow down as we age, thereby permitting the damage to accumulate in the first place?

Today’s new federal budget has a 60% increase in funding for Alzheimer’s research, bringing total funding ($936,000) to just short of a billion dollars. Next year’s NIH budget also calls for just short of billion dollars ($961,000) for Alzheimer’s funding. Given the money going into Alzheimer’s, the risk is not that we lack funds, but that we lack insight. We will be funding research on sensors, biomarkers, and nursing care. Of the money that goes toward finding a cure, some will be aimed at sleep quality, diet, inflammation, and genetics. But how much of this will be – ultimately – fruitlessly spent on projects that don’t cure Alzheimer’s disease? We need to spend, but spend wisely. Throwing money does not per se conquer a disease that steals the minds and souls of those we love. We need to throw it accurately.

We need to reassess our assumptions and look, very carefully, at reality. If we want to cure Alzheimer’s disease, it will not be solely a matter of good intentions, political will, and funding. It will be because, finally, we chose to understand how Alzheimer’s disease works.

And we chose to cure it.

October 30, 2015

Chaos, traffic, and Alzheimer’s disease

We’re going to take an odd detour into both chaos theory and traffic flow in order to understand Alzheimer’s disease, so fasten your seatbelt. The key cascade of pathology that we’re going to look at (and explain) is the presence of beta amyloid plaques in patients with Alzheimer’s, but the principle applies equally to tau tangles and several other hallmarks of pathology seen in aging human patients with cognitive decline. Chaos theory and traffic flow will serve as useful analogies and help clarify the dynamics involved in human pathology, as well as potential cures.

To start with, let’s consider a simple example of chaos theory, in which a continual, linear event results in a sudden inflection and an unexpected, non-linear outcome. Imagine that you are trying to retrieve your iPhone in the middle of the night in order to listen to, for example, an audible book. The lights are out, your spouse is asleep and you gently pull on the earphones, using them to pull the iPhone toward you. Realizing that the slower you pull it, the less noise you make (and the less likely it is that you will waken your spouse), you provide a very slow, gentle traction. Unfortunately, the iPhone is on the bedside table and once it gets to the edge, it suddenly falls and produces a terrible racket, regardless of how slowly and quietly you’ve pulled it up until you reached the edge. The point here is that regardless of how noise and speed were related until you got to the edge of the table, there will come a sudden inflection point with an unexpected and non-linear increase in noise. In short, the amount of noise correlates linearly with speed until the inflection occurs and then the relationship between speed and noise becomes suddenly non-linear. As we will see, much the same thing happens to the clearance of beta amyloid (or tau tangles) and its relationship to neuronal death. Things seem to be going fine until some inflection point is reached, after which there is a sudden, unexpected inflection and the pathology (and cognitive decline) begins.

For the next analogy, consider traffic flow and construction slowdowns. Commuting to work each day, you (and the traffic generally) are moving along at a steady 55 mph as you approach an area of construction. In this area, the traffic slows to a speed averaging 10 mph, as a result of a traffic light at which the speed is 20 mph half the time (green light) and zero half the time (red light). However, you notice that despite this construction slowdown (which has been going on for several weeks), the traffic congestion always becomes noticeable at about the same spot and it never actually backs up indefinitely (as it might if the road was completely closed while traffic continued to arrive). As you think about it, you realize that the actual speed (55 mph versus 10 mph) isn’t the key here. The key question is the number of cars passing per unit time as they approach and as they go through the congested area. If the 55 mph cars are approaching at a rate of (say) 30 cars per minute (with a good distance between them) and the 10 mph cars are getting through the construction and the traffic light at the exact same rate of 30 cars per minute (although they are almost bumper-to-bumper), then the line of slow moving cars will only grow to a certain length before it achieves an equilibrium. We might find, for example, that despite the traffic congestion and as long as the number of cars passing each point per unit time remains equal (e.g., 30 cars per minute, regardless of how close the cars are to one another), then the line will only grow so far and no further.

But this is only true to a point.

It might be, for example, that (as long as the number of cars per minute is equal both coming into and leaving the traffic congestion) the line will be a half-mile long if the construction zone has an average speed of 15 miles an hour twice as long at 10 miles an hour, but there comes a point – perhaps at 9 miles per hour, when the line suddenly has an inflection point and begins to grow wildly (and non-linearly) because the number of cars leaving per minute has no fallen below the number of cars arriving per minute. The relationship between speed (going through construction) and the length of the traffic line was linear until some critical point, at which the relationship took an inflection, the traffic backs up, and all hell breaks loose. Not merely an example of chaos theory, but chaos in action as traffic gridlock ensues.

Much the same is occurring in the brain as it ages. Microglial cells are perfectly adept at clearing beta amyloid as it is produced. Even as these cells senesce and their rate of clearance falls, the backup of beta amyloid “traffic” is not bad enough to cause pathology and it does not trigger neuronal death – or clinical Alzheimer’s disease. There comes a point, however, when chaos theory enters the picture, a sudden inflection occurs, neuronal death ensues, and inexorable cognitive decline becomes obvious.

Think of it this way. The key questions (with beta amyloid as an example) are these: 1) how fast is beta amyloid being produced (how many cars are coming down the highway per minute), 2) how likely are the beta amyloid molecules to be abnormal perhaps because of APOE4 genes (how fast are the cars moving), and 3) how well are the senescing microglia able to clear the beta amyloid molecules (how many cars can they get through the construction area per minute)?

These same questions play a role in understanding why current interventions (e.g., monoclonal antibodies) fail and why we might want to intervene directly in cell senescence. Most current experimental approaches, such a monoclonal antibodies, only serve to “tow away some of the backed-up cars in the traffic line”, while the critical variable is our ability to move cars through the area of congestion. In short, the problem is not a static one (can we remove cars), but a dynamic one (can we keep the cars moving). Once we get a problem with traffic flow (a non-linear accumulation of beta amyloid plaques), the key intervention is not “towing away cars”, but increasing the flow of traffic through the congested area. We should be treating microglia, not beta amyloid.

Curing Alzheimer’s requires that we understand the pathology and not in a naïve, static fashion. If we want to cure Alzheimer’s, we need to improve the traffic, not the cars. The most effective point of intervention is not beta-amyloid but microglia.

Which is how we plan to cure Alzheimer’s.

October 17, 2015

BioViva and Telocyte

The other day, a friend of mine, Liz Parrish, the CEO and founder of BioViva, made quite a splash when she injected herself with a viral vector containing genes for both telomerase and FST. Those in favor of what Liz did applaud her for her courage and her ability to move quickly and effectively in a landscape where red tape and regulatory concerns have – in the minds of some – impeded innovation and medical care. Those opposed to what Liz did have criticized her for moving too rapidly without sufficient concern for safety, ethics, or (from some critics) scientific rationale.

Many people have asked me to comment, both as an individual and as the founder of Telocyte. This occurs for two reasons. For one thing, I was the first person to ever advocate the use of telomerase as a clinical intervention, in discussions, in published journal articles, and in published books. My original JAMA articles (1997 and 1998), my first book on the topic (1996), and my textbook (2004) all clearly explained both the rational of and the implications for using telomerase as a therapeutic intervention to treat age-related disease. For another thing, Liz knew that our biotech firm, Telocyte, intends to do almost the same thing, but with a few crucial differences: we will only be using telomerase (hTERT) and we intend to pursue human trials that have FDA clearance, have full IRB agreement, and meet GMP (“Good Medical Production”) standards.

We cannot help but applaud Liz’s courage in using herself as a subject, a procedure with a long (and occasionally checkered) history in medical science. Using herself as the subject undercuts much of the ethical criticism that would be more pointed if she used other patients. Like many others, we also fully understand the urgent need for more effective therapeutic interventions: patients are not only suffering, but dying as we try to move ahead. In the case of Alzheimer’s disease, for example (our primary therapeutic target at Telocyte), there are NO currently effective therapies, a history of universal failure in human trials for experimental therapies, and an enormous population of patients who are currently losing their souls and their lives to this disease. A slow, measured approach to finding a cure is scarcely welcome in such a context.

And yet…

We have elected to follow the standard approach – with FDA-sanctioned human trials – for three reasons that we see as crucial: 1) we want to ensure safety, 2) we want to ensure efficacy, and 3) we want to ensure credibility. The issue of safety is not a simple one: Alzheimer’s disease is uniformly fatal, so safety might seem to take a distant back seat to efficacy. True, but we see no reason to try an experimental therapy on despairing patients if we inflict easily avoidable risks (by using safe manufacturing processes for the viral vectors). The issue of efficacy is also not simple: you might think that any therapy, even if remotely effective, might be worth trying. True, but we see no reason to use a minimally effective therapy if we can provide a maximally effective therapy with only a bit more forethought and care. The issue of credibility is also not simple: you might argue that if we can cure even one case of Alzheimer’s disease, that will in itself be sufficient. True, but not if no one will believe the clinical results. It may have cured one person, but what about the millions of patients that won’t be treated if no one believes the result?

At Telocyte, we intend to meet all three of those obligations. The therapy must be sufficiently safe to justify the risk in using it in patients who are already desperately ill, it must be sufficiently efficacious to offer more than simple solace or wishful-thinking, and our human trials must be sufficiently credible that our results can be translated into a therapy that can become the accepted standard of care for millions of patients, not simply for a few people.

We applaud Liz’s hopes, her courage, and her enthusiasm as she makes a splash in the news, but Telocyte will take the more difficult path. We don’t intend to create a splash, but a world without Alzheimer’s. It is easy to act, it can even be easy to act with genuine compassion, but it is hard to act effectively and harder still to ensure that compassion is not only the intent, but the final reality.

 

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