Michael Fossel Michael is President of Telocyte

April 28, 2015

Telocyte Begins

Things are slowly beginning to move ahead on our project to cure Alzheimer’s disease. It’s clear that not only is the role of microglia slowly becoming accepted, but there are more and more investors who see an opportunity to help move biotech and medicine from the old paradigm (BAPP and Tau cause disease) to the new paradigm (cell senescence triggers a far more complex cascade than we had once thought). One example of this shift is the recent review by Boccardi et al (Boccardi V, Pelini L, Ercolani S, Ruggiero C, Mecocci P. From cell senescence to Alzheimer’s disease: the role of telomere shortening. Ageing Research Reviews 22:1-8, 2015).

On a personal note, we now have investors pushing us to move ahead with our Telocyte project and we have a commitment from one of the leading research organizations in the world to form a collaborative effort. Our intent is to move ahead with the remaining animal trials necessary to get an IND, then commence FDA-sponsored human trials. Those of you who are interested in either helping our effort or being on a registry of potential patients with early Alzheimer’s may contact me.

April 21, 2015

Biotechs on the Edge

An odd thing is happening in the world of biotechnology: an avalanche is starting.
The context is also interesting, for over the past twenty five years, a profound revolution has occurred in our understanding of aging. Where once we took aging for granted, we now reexamine the process, looking for a way to reverse it. Where once only the most avant-garde of researchers thought that perhaps we might someday learn to slow the process, now the belief that we can turn back the fundamental cellular processes has gradually become a tenet of the mainstream. Where once we looked at diet or hormones, now we look at cell aging; where once we looked at genes, we now look at epigenetics.
And where once we were pessimistic, we now see the logic behind optimism.
In my upcoming book, The Telomerase Revolution, I explain how aging works and how we can intervene to cure age-related diseases, but I also look back over the past twenty five years of biotech in aging research. Oddly enough, in every single case, the failures have not been due to flawed science, but to flawed human beings. Poor decisions, paranoia, an inability to believe one’s own data, distrust, poor public relations, bad business ethics, these are all the failures of flawed human beings, unable to avoid shooting themselves in the foot — often fatally, which is an extremely odd anatomic result, but there it is. Biotech death by foolish behavior.
And yet the science was solid.
So perhaps it’s not surprising that I finally see a new generation of biotech startups, all aimed at the holy grail of age-related disease: resetting gene expression in aging cells and thereby curing age-related disease. Perhaps it was due to the gradual growth of inescapable data, as mice and rats in Boston and Madrid have driven home the point that aging can be altered and that diseases can be reversed. Perhaps it was the coming-of-age of a generation who, when asked to explain aging, began their answers with a short explanation about telomeres and aging cells. Or perhaps it was simply about time that we got things right.
Whatever the reason, the avalanche is beginning. I see investors, lay people, entrepreneurs, and businessmen moving steadily to support biotech ventures aimed directly at resetting gene expression, resetting cell aging, resetting age-related disease, and doing what was assumed to be impossible a mere generation ago.
It’s an avalanche that — by 2020 — will demonstrate that we can not only commiserate about Alzheimer’s disease, but we can cure it. In most cases, we will not merely slow the diseases of aging, not merely fight them to a grudging standstill, but reverse their pathology. None of our current therapies for vascular disease, osteoporosis, osteoarthritis, or (least of all) Alzheimer’s disease are “disease modifying”. Our current therapies offer little solace and no hope of cure, yet a cure is precisely what the newest crop of biotechnology companies are pursuing. Of the growing number of biotechnology companies now on the edge of success, some will fail, but the avalanche is already heading down the mountain and it’s gathering speed.
It won’t stop until we get to the bottom of age-related disease.

April 15, 2015

Alzheimer’s, Microglia, Mitochondria, and Arginine

Every several weeks, I notice publication of yet another article trumpeting another aspect of Alzheimer’s. Where once it was APOE-4, AB42, or SS31 (an antioxidant peptide), more recent work emphasizes arginine metabolism in the microglia. The good news is that research community has — ponderously and hesitantly — finally begun to shift the clinical focus from the neuron to the microglial cells, a shift that many of us have been pushing for almost two decades. Neuronal damage was always the more obvious pathology, at least under the optical microscope, but it was never the underlying cause of the cascade of damage that results in Alzheimer’s disease. Gradually, we have come to realize that the microglial cells, and often vascular changes, play an early role in starting the avalanche of this horribly tragic pathology.
And yet, even now, it is frustrating to watch how much of the research creeps along, staring myopically down at trivial and secondary problems. It’s not so much that we see the trees and ignore the forest, but that we see the specific lichen on the specific root of a specific type of tree, while missing the interactions and overall pathology that drives the entire forest. The recent focus on arginine is a case in point, but SS31 is a parallel example. In the case of arginine, we notice the microglia; in the case of SS31 we notice the mitochondria, but in both cases we fail to look harder and deeper and we fail to understand the broad processes that drive these changes.
Mitochondrial dysfunction within the microglia is a good example. The dysfunction is not seen in germ cells, nor in young somatic cells, but is prominent in aging somatic cells. How can a germ cell lineage, carrying a line of 1.5 billion year old mitochondria, have normal function, while a somatic cell, having undergone a few dozen divisions in a few dozen years, suddenly have a dysfunctional mitochondria that was doing well for the last few billion years? Actually, we know the answer to that. Not only is it due to changing gene expression within the cell nucleus, slowing the production of many key enzymes needed in the citric acid cycle within the mitochondria, but we know that when we reset this pattern of gene expression in the nucleus, the mitochondria resume normal function. While the aging cell makes less ATP and a higher proportion of ROS as the damaged mitochondrial enzymes permit electrons to “slip” down the chain, but these changes are entirely reversible when we reset telomere lengths within the nucleus.
Nor does it stop there. Just as the aging cell begins to have a lower ATP/ROS ratio, so too do the lipid membranes begin to leak those ROS species, so too do our scavenger enzymes (like SOD) fail to capture those escaped ROS species, and so too do our cells fail to rapidly recycle the molecules damaged by those ROS species. And in every case, these four issues can be traced directly back to the slower turnover induced by a changing pattern of gene expression within the nucleus, which is orchestrated by a gradual telomere loss.
Such changes can be (and have been) reset in human cells, in tissues, and in animal models. So why not reset the microglial telomeres and cure Alzheimer’s?

April 7, 2015

Biotech and Alzheimer’s

At the moment, there are four companies planning human trials to reset telomeres using telomerase genes. In every case, the intent is to put the telomerase genes (hTERT and hTERC) into human patients in an effort to cure age-related diseases. Let’s look at the diseases and then the companies involved.
Essentially, all age-related diseases occur because of cell aging. In the cases of osteoarthritis (chondrocytes) and osteoporosis (osteoblasts and osteoclasts), this process is straightforward. In the case of heart disease, it’s a bit more complex: the heart cells don’t die because they age, but because the arterial cells age. The endothelial cells, that line your coronary arteries for example, divide, loose telomere length, alter their gene expression (which is the key to the whole cellular pathology), and become dysfunctional. The result is gross changes in the wall of the artery: cholesterol plaques, inflammation, mast cells, foam cells, and general histological mayhem. And when the artery gets clogged, or when clots break off, the heart (and other organs) pay the price. In the case of a heart attack, the heart is the innocent bystander, whose cells die not because they age, but because of the pathology in the vessels that supply them. Much the same occurs — indirect aging — in neurodegenerative diseases such as Alzheimer’s disease. The innocent bystander is the neuron, that neither divides nor ages, but which is critically dependent upon the surrounding cells, especially the microglial cells. These cells, responsible for metabolically supporting the neurons and clearing beta amyloid, for example, show the initial aging changes. Their telomeres shorten , their gene expression changes, and they no longer clear beta amyloid as well. This process — “microglial activation” — is the initial step in Alzheimer’s dementia and — like all other age-related disease — is ultimately the result of cell aging.
As we finally begin to understand age-related disease and the cell aging that causes it, we are faced with the obvious question. Can we reverse the process? At present, medical therapy has no way of altering the underlying disease processes of any age-related disease, whether osteoarthritis, osteoporosis, atherosclerosis, Alzheimer’s disease, or any other common aging condition. But what if we could reset gene expression, reset the epigenetic pattern to that of young cells? We’ve known that we could do exactly that — in the lab — since 1999, but can we do it in humans? A number of studies have shown we can do exactly that in mice and rats, particularly in Maria Blasco’s lab in Madrid, but what about human patients? How long must we wait to cure Alzheimer’s disease?
At present, there is a small Canadian company that has failed to “gel” (or get financing), a new biotech group in Seattle that intends to go “offshore” (if they can get financing), and two linked companies that intend to progress to human trials as rapidly as possible. These latter two consist of a US-based biotech company (Telocyte) and a sister organization (non-profit) in the UK. Telocyte is aimed directly — and solely — at curing Alzheimer’s disease.
Telocyte sees no reason to wait, nor should you.

Powered by WordPress