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.

 

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

 

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