Michael Fossel Michael is President of Telocyte

May 12, 2016

Telomeres: Are They Worth Measuring?

It’s funny how often we make assumptions that are not only wrong, but that we are completely unaware of making. Having spent more than twenty years dealing with the clinical implications of cell aging, telomeres come to mind as an immediate example of this mistake.

Hardly a week goes by without another claim that some particular intervention alters telomere lengths in human patients. Without exception, they are measuring telomeres in peripheral white blood cells. It’s easy to get blood samples and measure telomeres in circulating white cells. Unfortunately, not only are these telomeres the ones that matter least, but (if you’re trying to prove the value of your intervention) they’re almost worthless.

Measuring telomeres in your blood to see how old you are is a bit like looking at your hat size to figure out how tall you are. Whether it’s your peripheral blood telomeres or your hat size, it’s still the wrong measurement for the job.

There are two problems with measuring telomeres in blood cells (even totally ignoring arguments about technical methods, unreliable laboratories, and the mean length versus the shortest lengths of those telomeres).

The first problem is that the blood cells aren’t the key cells when it comes to aging and age-related diseases. If you really want to know where you stand clinically, you should be measuring the telomeres in the endothelial cells lining your coronary arteries, the glial cells in your brain, the chondrocytes in your joints, or several other places more closely related to the most common (and fatal) aging diseases. Few of us are willing to have biopsies taken from our coronary arteries, our brain, or our joints, but just because we are a lot more relaxed about giving a blood sample doesn’t mean that the blood sample is worth getting. It barely reflects what’s going on in your white cells, let alone what is going to end up causing disease and death.

The second problem is a more subtle, but more important. It boils down to this: most of your white cells aren’t circulating in your blood and the ones that do circulate are changing and dividing all the time, making them a poor reflection of what’s happening to the stem cells in your marrow. I wrote an academic review article about this in 2012 and discussed it in The Telomerase Revolution, but let’s look at it here. Imagine you can instantly and accurately measure every telomere in the body, including those in the bone marrow and peripheral venous circulation. Oddly enough, you’d discover that the blood tests aren’t reliable indicators of what’s happening in the marrow.

Let’s say that you measure all of the telomeres at time A and again at time B. In between A and B, you use an intervention such as gene therapy, TA65, mediation, dietary change, or whatever you think might be effective. At time A, you find that the telomeres in the hematopoietic cells of the marrow are 12 kbp long. At the same time (due to stress, infection, poor diet, inflammation, and generally poor health habits) there is rapid peripheral turnover, cell division, and telomere loss in the peripheral blood. As a result, the mean telomere length in the blood sample is only 8 kbp.

We then intervene.

At time B, you find that the telomeres in the hematopoietic stem cells in the marrow are now only 11 kbp long (showing that the patient has gotten older). Also at time B, since we might now have lowered stress, removed infections, decreased inflammation, and generally made the patient “healthier” with whatever intervention we may have chosen, their peripheral cells are now turning over more slowly, dividing less frequently, and losing less telomere lengths once they leave the marrow and enter peripheral circulation, so that the mean telomere length in the peripheral blood sample is now 9 kbp.

We could claim (as many articles do) that our clinical intervention “lengthened the peripheral telomeres!” The truth is that our intervention didn’t lengthen anything and we’re deluding ourselves (and whoever believes our claims). The peripheral telomeres that we sample at time B might be longer than the ones we sampled at time A, but the telomeres of the cells back in the marrow now have shorter telomeres. Our intervention may well have made the patient healthier and we might actually have slowed down the rate of telomere loss, but we definitely didn’t lengthen any telomeres, no matter how proudly we pat ourselves on the back.

Peripheral leukocytes are routinely used to assess telomere lengths (which is fine as far as it goes) and then used to assess clinical interventions, which is overreaching. If we do serial measures of peripheral telomeres every few months for a few years, then the validity will increase somewhat, but peripheral telomere measurements (no matter how often you measure them) are intrinsically an unreliable and invalid biomarker for what we really want to assess, which is “whole body telomere changes” or at least “marrow telomere changes” (in the case of blood cells).

Most of the available literature which suggests that we can slow or reverse telomere losses is – if it’s based on peripheral blood samples – misleading at best and unethical at worst.

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.

 

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.

 

Powered by WordPress