Has the Telomerase Revolution Arrived? Part One


Today, we have part one of a two-part interview with Dr. Michael Fossel, the driving force behind Telocyte, a new company focused on telomerase therapy for various diseases, and a strong advocate of telomerase therapy to treat human disease over the past three decades. You can find part two of the interview here.

I interviewed Dr. Fossel as an individual thought leader in this field and not in his role representing Telocyte, so the opinions stated here are purely his own.

Born in 1950, Michael Fossel grew up in New York and lived in London, Palo Alto, San Francisco, Portland, and Denver. He graduated cum laude from Phillips Exeter Academy, received a joint B.A. and M.A. in psychology in four years from Wesleyan University in Connecticut, and, after completing a Ph.D. in neurobiology at Stanford University in 1978, went on to finish his M.D. at Stanford Medical School in two and a half years. He was awarded a National Science Foundation Fellowship and taught at Stanford University, where he began studying aging with an emphasis on premature aging syndromes. Dr. Fossel was a Clinical Professor of Medicine at Michigan State University for almost three decades and taught the Biology of Aging at Grand Valley State University.

His academic textbook, Cells, Aging, and Human Disease, was published in 2004 by Oxford University Press. The book takes an in-depth look at the fields of telomere biology and cell senescence as they apply to human clinical diseases and aging. It includes in-depth discussions of Alzheimerโ€™s disease, progerias, atherosclerosis, osteoporosis, immune senescence, skin aging, and cancer as well as the potential for using telomerase therapy to address these diseases.

His most recent book, The Telomerase Revolution, was published in 2015 and discusses aging, clinical disease, the potential for cheap telomerase therapy in the near future, and many other topics. My understanding of Fosselโ€™s research and forecasts comes primarily from this very readable book.

I interviewed Dr. Fossel by phone in April of this year. The following interview has been edited for length and clarity.

How are things going with your telomerase research?

Where we are, without getting into the details of my new biotech company, Telocyte, is that we now have a technique that we can use. It has been philosophically consistent; the theory has been internally consistent. Most people don’t understand it, but it’s been internally consistent and predictively valid up until now. For example, 21 months ago, Eli Lilly announced its results with solanezumab, and I predicted the exact curves several months before they released the data. That kind of thing has gotten pretty easy. I can tell what’s going to work, what’s going to work a little bit, which way it’s going to work, and how. More importantly, Telocyte’s intervention [not solanezumab] ended up working well in animals [in early studies]. So, we’re now going to take it to humans, and human trials will be started in about a year.

So, you cannot talk about Telocyte beyond what you just said?

I’d prefer not, and I’ll give you some of the background of why. It’s a matter of credibility. If I’m Eli Lilly, and I publish a study like the solanezumab study, and I get negative results, people are going to say, “Yeah, I kind of expected that, there are more than 400-plus registered Alzheimer’s trials that all failed, so we’re not surprised.” If I talk, and I have, to major pharma groups and biotech companies, none of them believe that they can reverse, stop, or prevent Alzheimer’s, but most of them feel that if they catch it early enough, they can slow it down. That’s really their sweet spot, currently. Most of them are fairly honest about it, too. The problem is that, based on what we’re seeing [in our research], we should be able to take Alzheimer’s patients with a moderate degree of cognitive decline and actually reverse some of that cognitive decline. That’s a hell of a thing to say, so we’re trying not to say it that boldly, and as a biotech company, Telocyte won’t make such a claim.

Personally, I believe that we will be able to cure Alzheimer’s disease, but our position at Telocyte is simply that we see an enormous clinical potential and we will pursue it. Frankly, we expect that anybody rational who sees what we expect to be our data to question it on a historical basis and say it’s nonsense. All the other companies are looking for early Alzheimer’s patients, preferably somebody with no symptoms whatsoever, what the FDA is currently calling a Stage 1, which means that you’ve got some markers but your cognition’s fine. We’re not, and part of the reason is because we know full well that if we take patients with what used to just be called early Alzheimer’s or MCI, and we show that we can reverse the cognitive decline, people will say, “Clearly you can’t, so they must not have had Alzheimer’s.” With early Alzheimer’s, it’s sort of a soft, squishy diagnosis. So, we can’t afford to undercut ourselves.

Everything we’re doing is aimed at credibility. We are following everything the FDA and SCE want while staying out of the public limelight. When we bring this to the Alzheimer’s Association, we won’t announce that we’ve cured it; we’ll just say, “Here’s the data.” To push this a little further, one of the reasons we’re going after Alzheimer’s is that if I do something for skin wrinkles, osteoporosis, or even vascular disease, it hasn’t got nearly the same oomph as going after what’s clearly ‘the impossible moonshot’, the high-hanging fruit.

One more piece of this is to say that I have a friend who’s a physicist, and he says it’s like anti-gravity. It’s not that either one of us believes in anti-gravity, but if we did, we wouldn’t bother writing articles about it, because people know it can’t be done. We’d simply build the thing, sail it down the National Mall, and hope nobody shot us down. I think that’s where we are for reversing aging or Alzheimer’s. I don’t see the value of putting out academic papers about it. People tend to disagree and not understand their own unexamined assumptions. So, we’re just going to do it to prove our point. A theory is good, but data trumps it every time.

In terms of getting to that point, where you could put up good data and show results with completed clinical trials, donโ€™t you need to have some pure research under your belt first, or are you saying you have enough funding and data now to go more directly to trials?

The quick and dirty way of saying that is that we don’t need to convince anybody but our investors. That’s almost true. We still need to convince the FDA and the global clinical community, but we need to convince them with clinical trial results. When you come to the FDA, and again, this is an overstatement, they’re more concerned about safety than efficacy. At least in our FDA phase 1 trial, we donโ€™t have to prove efficacy, we just have to prove that the risk is sufficiently low, given our rationale.

That’s still not [entirely] true, because they’ll want a good enough rationale that they can accept a certain degree of risk, even with Alzheimer’s patients. Still, our role is not to convince the academic community first and not to convince the public first; it’s to convince the investors and the FDA, who are the key players in this.

You wrote your latest book, The Telomerase Revolution, in 2015. How is that revolution going three years later?

Always slower than I’d like it to be. I sometimes have said to my wife that there has never yet been a day when I’d come home and say “Let’s break out the champagne.” But there’s been a lot of days when the answer is “Yes, let’s pour a glass of wine.”

Things have been moved on perhaps more steadily and optimistically than I might reasonably have worried about, but there’s been nothing sudden, except maybe the last two weeks because of what’s been going on in gene therapy with AveXis and spinal muscular atrophy at the FDA. Have you followed this?

I have not; what has been happening?

Basically, gene therapy has been around for about 20 years, and there was an initial death with Jesse Gelsinger. In the last couple of years, things have begun to move again. Back in November, a friend of mine, Brian Kasper, published an article in the New England Journal of Medicine, and he’s the chief scientific officer and founder of AveXis, the gene therapy company (as well as a member of Telocyte’s Scientific Advisory Board). What this showed is that we can actually cure spinal muscular atrophy, which is a single-gene disease. It was safe, it went through the FDA, everybody is excited about it, and they used the vector that Telocyte will also be using. There had been some questions about it, but Brian and I both knew it was safe.

The viral vector?

A viral vector is the delivery agent, AAV9. One of the lead researchers for the initial gene therapy 20 years ago (that resulted in the death of Jesse Gelsinger) wrote an article back in January of this year saying that AAV9 is dangerous and it would be unsafe. None of the current clinical data backs that up, and that’s not what we saw in the human trials of these kids.

In any case, all of this has come to light in the last two weeks, and more importantly, two weeks ago, Novartis bought AveXis for $8.7 billion, which dropped a lot of jaws on the ground because that’s gene therapy; “They spent how much on this?” So, for the last two weeks, suddenly things have been moving along very nicely.

We’ve been moving along anyway. We’ll be going to the FDA and will probably have our committee meeting with the FDA in Q3 of this year. We’re just reviewing all of our protocols and our FDA application. We’ve got investors now lined up ready to do the term sheet. We have our provider for the vector lined up; we’ve got everything lined up. It’s just a matter of pulling the trigger and moving ahead, but still, it always takes at least twice as long as you think it would.

So when you say Telocyte is ready to go with the FDA application, that’s for clinical trials, right?

Correct. The FDA requires that you do what’s called animal toxicity studies. We already have one, but they’re going to require one with more animals and looking at some different data than the academic group did at CNIO in Madrid, and that group did the original proof-of-concept work. We’ll be doing that starting later this year, and the human trial will follow that in the next year or so.

2019 looks pretty good for the Alzheimerโ€™s human trials to begin?

I hope so, but the timing depends upon the investor, the producer, and the FDA, which are outside my control.

And that’s using the viral vectors and the gene therapy approach?

Yes. We’re an unusual gene therapy company in that most gene therapy companies like AveXis want to go in and either replace the gene with a new one or rewrite it, as in the case of CRISPR technology. We don’t. What we’re doing is putting in a gene, and we’re perfectly happy if it’s no longer expressed in several months; we just want transient expression. No other gene company in their right mind wants that; they want permanent gene expression. We don’t. We’re perfectly happy with that limitation of the technique.

That transient expression is enough to lengthen the telomeres to achieve the desired result?

That’s all we need.

Most of us understand that telomere shortening leads to cells that can’t replicate anymore; the Hayflick limit is around 50 or so replications. What’s less clear to most people, including me, is how telomere erosion, in general, leads to cell senescence and worsens cell functions. Could you flesh this out?

Sure. You ever notice how people will use the same word and mean very different things by it? That’s happened with cell senescence. Many people, when they read an article about cell senescence, think it’s a black-and-white, all-or-nothing, digital phenomenon; it happened, or it didn’t happen. Zero or one. You’ve got a cell that’s capable of division, then the telomere shortens and it stops dividing.

Well, no; it’s more of an analog process. As the telomere shortens, several things happen, including slowing down of cell division. (Why is it in biology that division and multiplication are the same thing; have you ever noticed that?) Before that, what you see is an alteration of the pattern of gene expression. Let’s say I’ve got a fibroblast that’s got 30 cell divisions left to go. The pattern at 25 is different from that at 20, is different from that at 15, is different from that at 10 in terms of division, or we can look at it in kilo-base pairs: the same routine. There is a subtle but pervasive pattern of changes in gene expression.

So, when I’m looking at cell senescence, if you want to talk about a binary senescent or non-senescent cell, then you’re missing most of the important processes involved. The change in gene expression that occurs has ubiquitous effects throughout the cell, but among them, it turns down the rate of DNA repair, it turns down mitochondrial function, it turns down lipid turnover, it turns down beta-amyloid turnover between cells, it turns down the rate of turnover in elastin, collagen, and hundreds of other critical molecules. Those things are what’s going on as cells become senescent.

Granted, at the very end, you’ve got a cell that won’t divide, and it’s putting out all sorts of factors that are not very pleasant for the cells sitting next to it. Prior to this, there are subtle changes that have not only an internal effect but affect the cells around it as well, because the cell is becoming dysfunctional. What we have known since 1999 from Walter Funk’s article is that we can reset that [by lengthening telomeres again], and we know that when we do that, it works very nicely. That’s where we are.

Getting to the heart of the matter for any kind of practical treatments: in your book, you state that within the next decade, we’ll more than double the healthy human lifespan. You describe going into a clinic and getting a cheap IV treatment for about a hundred bucks by about 2025 that’ll turn the clock back by a few decades. You also acknowledged in the book that there’s no reliable telomere lengthening medications available today. So, given the lack of human clinical trials and data, do you stand by that prediction?

I do, but I have to say that I put that out there as sort of an argument. You and I both know that I don’t know [this with any real certainty]. Maybe I could say that it’ll make your life one year longer; I could say that maybe it’ll make your life a thousand years longer. The first wouldn’t intrigue anybody; for the second one, everyone would laugh hysterically, and they wouldnโ€™t listen to you.

So, when I say double the human lifespan, what I’m trying to say is that we’re talking about something serious here; we’re talking about a big change. I don’t know how big it is, but we’re not talking about one year. So, I don’t know. If I look at the mouse data, for example, we’re looking at things like about a 24% increase in healthy lifespan. That depends on when you gave it and what changes in what gene we’ll be using; in short, we’re back to square one, which is “I don’t know; we’ll have to wait and see.”

I stand by it as a point of argument, but I wouldn’t bet my pension on it. I’ve bet my pension already on doing what we’re about to do. I only picked a figure so people would say, “God, are you really serious about that?” I am serious. I’m not sure how long it’s going to add to our lifespans and healthspans, but I’m not talking about [something as trivial as] an extra two years in a nursing home.

On a similar note, you mentioned already that you’re moving ahead with applications for clinical trials, and you’re discussing a lot of interesting new research; are we in a new boom in telomerase research? Have you arrived after 30 years of looking at this stuff?

Back when I wrote that first book 22 years ago and the articles back then, I had the thought that I was going to push the first couple of rocks in an avalanche, and it never happened. I have since come to realize that there are several problems.

One is that science, for all that it likes to think of itself as objective, rolls in fashion trends. There are waves of things that are in fashion and things that aren’t. Telomerase and telomeres went out of it for a while, came back, and went out again. That happens.

The other thing is something I mentioned also in the book, which is that most biotech and a lot of other companies don’t fail because of bad science; they fail because of human problems. I’ve seen that again and again in companies I won’t name, but it’s hard to get these things going, and sometimes it’s chance, like a California couple that once offered me more than a billion dollars to take all this to translational work. I didn’t know they were going to get a divorce [and the deal would go south]. I can’t control that.

As it turns out, my prediction back in ’96 was that we’d be able to show we could do something within 20 years. It took 11 years for the first of the astragaloside compounds to be out. We have made some progress, not nearly as much as I thought we would, but yes, I think we’re now finally about to do it because a lot of serious players are finally pushing on this.

In terms of research done to date, you’ve acknowledged in your book that there’s not a whole lot of data in humans for telomerase therapy. There is a lot of data for mice and other animal models. But mouse cells donโ€™t express telomerase (they have much longer telomeres naturally and much shorter lifespans, so telomere erosion is generally not an issue for mice) and they have different telomere mechanics as a result. Given this difference, how can mice be a useful model for human aging?

Actually, mice are a good animal. Part of the problem with mice started with Jerry Shay almost 20 years ago when he pointed out that certain mice have telomeres that are literally 10 times longer than mine but those same mice have lifespans that are literally 40 times shorter than mine. And the upshot of that was that, obviously, telomere length doesn’t have anything to do with aging. It isnโ€™t telomere length that matters but changes in telomere length, because changes in length change gene expression. Telomere length per se is an uninteresting variable in most cases.

In mice, what you find is that telomeres do play a role, it’s just not the simplistic one that people like to criticize. The strawman is that telomere length cannot be a reason we age. Thatโ€™s true of telomere length, but thatโ€™s not the model. If you look at mice, what you find is that itโ€™s not the telomere length, but the change in length that matters. As telomeres shorten, you get all of the changes in gene expression and the clinical issues associated with telomere attrition that Iโ€™ve talked about. Itโ€™s not the absolute length, itโ€™s the relative length.

Is that with non-modified mice telomeres? I know that researchers have shortened them artificially and then re-lengthened them, so what you’re saying applies to mice with natural telomere length?

Yes, it does, although we’d have to go through article by article if you want to talk about it in detail. I’m on a committee with the Alzheimer’s Association. We’re trying to find proper animal models, for example. So, we’re dealing with genetically modified mice. Part of the problem is that people still tend to think of Alzheimer’s as a beta-amyloid problem, a tau protein problem, or a fill-in-the-blank problem.

There are a number of us, and I’m thinking of the president of Intervivo Solutions, which is a company that does dog models, and they feel that the appropriate model is an aging animal, not an animal where you’ve altered the beta-amyloid gene to reflect the human beta-amyloid protein.

So, when we’re dealing with altered mice, we’re already changing the rules. You have to go through study by study to decide what’s relevant and what’s not. If we’re looking at natural aging, almost all mammals – I can’t think of any exception, and there are a lot of non-mammals, too – you’re dealing with the same underlying mechanism, and it’s not a matter of telomere length. In some sense, I would argue that telomeres don’t cause aging; it’s the changes in gene expression that are critical. It just happens that, in the cases, I’m talking about, changes in gene expression are modulated by changes in telomere length. So, you have to be careful what you’re talking about.

So, in this case, even though mice have longer telomeres, they don’t die from telomere shortening. You’re saying that telomere attrition is as much a problem in mice as it is in any other mammal?

Let me say this boldly: absolute telomere length has nothing to do with aging. It’s the changes in telomere length that affect gene expression, which has to do with aging. For the past 20 years, the title “telomere theory of aging” has stuck, and I understand why: it’s short and sweet. It’s the wrong title; it should be called “the epigenetic theory of aging” or the “gene expression change theory of aging.”

But in a very realistic sense, the only thing important about telomeres is that they provide an effective point of intervention. Let’s say (this isn’t actually true), but let’s say that there are a hundred genes whose changes in gene expression over time resulted in everything you’d want to know about aging. Theoretically, you could come up with a hundred gene therapies that affected each and every one of those hundred genes. Pretty inefficient. Whereas if I go after telomere length, it resets them all very nicely. So, again, telomeres don’t cause aging, changes in telomere length are whatโ€™s important, but telomeres are an effective point of leverage, that’s all.

So if you called your theory the telomere attrition theory of aging, would that be more accurate?

I still wouldn’t, if I had my way. Mike West used to argue that we should never talk about embryonic stem cells; we should talk about pluripotent stem cells, because if you talk about embryonic, you get into this ethical debate that does you no good. I think the same thing is true here without quite all of the ethical implications and the emotions. It’s not a telomere theory of aging; it’s a change in gene expression theory of aging or an epigenetic theory of aging, which is shorter and sweeter.

Telocyte is looking to go to clinical trials by 2019 or 2020, it sounds like. How many clinical trials are there going on, or planned, for the various telomerase therapy approaches out there?

As far as I know, globally, we’re the only one that’s using telomerase therapy in the sense that I’m talking about. I know a group, again, in Korea, that’s doing it with a protein, but they’re not doing gene therapy, and they’ve got some problems. So, I think we’re the only one globally that’s doing telomerase gene therapy. To be more specific, we’re the only company that intends to go to FDA human trials and ensures credibility as well as clinical efficacy and medical safety.

If you use an epigenetic/telomerase therapy approach, you could potentially resolve the problem of gene expression that we’ve talked about already, but you are still going to get to AGEs and extracellular damage, right?

Let me give you an example that’s more common for most people. Let’s take elastin and collagen. If I look at, right now, the skin line below my mouth, I begin to see wrinkles forming as I get older. If you delve down into the extracellular space and ask why, what you find is that there are cross-links in the collagen, for example, the elastin isn’t as elastic, and so forth. People have a tendency to assume that that’s a static problem, and this is not true. They tend to believe that youโ€™re born with collagen, you’re born with elastin, and after a while, everything breaks down; what do you expect?

The reality is that it’s a dynamic process. So, if you look at any protein what you find is the dynamic turnover of the protein. In the case of collagen, elastin, and beta-amyloid, for example, theyโ€™re continually being created in the extracellular space and being broken down. The extracellular proteins are bound, internalized, and degraded, and all of those processes slow down with age. So, what’s happening to collagen, elastin, beta-amyloid, etc., is that they tend to sit around externally longer than they did when you were ten years old. The upshot is, the percentage of damage goes up. But it’s still getting turned over, and all we’re doing when we reset gene expression using telomerase is turning it back up again.

Let me give you an example, say you’ve got a big law firm, and let’s say that they’ve got to clean their building every day, because every evening that the cleaning crew comes in, and they sweep, mop, and clean the windows, and every month or three, they come and paint the thing and fix the nicks in the wall. Let’s say they’re spending half a million dollars a year on all of this, but then the managing partner says that’s a waste of money: “Let’s turn that down to a hundred and fifty thousand dollars a year.” With the same amount of damage occurring, the building begins to become dirtier over time, and your clients are upset with you. Thatโ€™s similar to whatโ€™s happening to our cells as they senesce.

The reason buildings get old is not simply because damage occurs, it’s because upkeep fails, and that’s what’s going on between skin cells. So, whether you’re looking at AGE byproducts, lipofuscin in cells, collagen, elastin, beta-amyloid, or tau proteins, in all those processes, you’re looking at a slowing down of the turnover rate. The recycling rate, if you will. That’s what gets turned back up [when we lengthen telomeres], and we’ve got a pretty good reason to think we can turn that back up in cells, tissues, and animals.

So if we rejuvenate cells through telomerase therapy, they’ll be active enough to clean up all the old damage?

That’ll take a while. I’ve got a house from 1836, and as I look up at the outside of it here, I think there are some things I should do. If I spend ten times as much maintaining it every year, it would slowly get better. It’s not going to get better tomorrow, next week, or next month. But, if I increase the budget substantially, if I improve the maintenance, then it’ll slowly get better. The same thing is true with cells and bodies.

The animal data suggests that if I’m looking at, for example, a human patient, and I’m looking at Alzheimer’s, it is not going to take ten years for them to get better. It isn’t going to happen in one day, either; it’s going to take a number of months. That’s not bad; in fact, thatโ€™s quite remarkable. Increasing the rate of turnover will improve the cell function, whether youโ€™re looking at AGE byproducts, ROS damage, inflammation, or mitochondrial function.

We will be back tomorrow with part two of this interview as we delve deeper into the world of telomeres and aging with Dr. Fossel.
About the author

Tam Hunt

Tam Hunt is a lawyer and writer with a background in biology. Among other things, he runs a blog on Medium.com calledย Forever Young? devoted to the science, technology, and philosophy of combating aging.
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