Telomerase gene therapy is very different from the drugs that have been pursued by Sierra Sciences and others. If you have a problem with a drug, you can stop taking it. It’s difficult or impossible to do that with gene therapy.
Evolution works with tradeoffs. Large, long-lived mammals are extremely conservative with the activation of telomerase in somatic cells. Some very long-lived species like elephants, over-express anti-tumor genes naturally, which helps them avoid cancer. But mouse somatic fibroblasts do have active telomerase. Mice live a couple of years, and to a great degree, cancer in animals is a function of probability. The number of cells in a mouse is less than the number of cells in a human hand. The more cells there are, the higher the odds should be of changes leading to cancer in one of those cells. And the longer an animal’s life span, the more time it has for something to go wrong.
We know, for instance, that radiation late in human life has little chance of triggering cancer – even very large doses. When we look for effects of small radiation doses, we look for them appearing after irradiation in childhood, and even then, those effects are extremely weak. A small, short-lived animal has less reason to minimize telomerase to control cancer.
In human skin, approximately 25% of adult cells exposed to sunlight show pre-cancerous changes. Adding a gene critical to transforming those cells into cancer isn’t wise. I have read the opinion on a blog that telomerase expression will defeat cancer, but there is no evidence I am aware of this is true. If there is evidence for it in science, I would like to know about it.
How could it be that Alzheimer’s could be made worse? Well, in this mouse model of Alzheimer’s, whatever triggers the amyloid plaque is pretty clearly independent of telomerase. So turning telomerase on once plaques develop only makes those cells better at making plaques. Telomerase is only one clock in the genome. There are many of them and we are just beginning to catalog those clocks and how they work.
The mice in the second telomerase restoration study did not live longer than normal mice. And while the first telomerase study above claimed no increase in cancer rate, that study’s numbers (23 TERT treated mice) were not remotely high enough to make that claim. If cancer had been seen with such small numbers, it would mean that this therapy was astoundingly dangerous. In human populations, a cancer increase from 15 in 100,000 to 20 in 100,000 is meaningful.
In this first study, the increase in life span was 20% for mice 1 year old at injection, and 13% for mice 2 years old at injection. That’s a significant increase in life span, but equaled by quite a few other therapies as we can see in the chart. When you look at this chart you can see several things. First, there are a number of drugs that extend life-span. And second, that in different studies of the same drug at the same dose there is wide range of results. What this tells us is that there are many variables that affect life-span, and those other variables are changing the drug results. For instance, rapamycin can extend life by 7.5% or 22%.
Given this context, marketing unofficial, tiny, clinical trials to the public with overblown unsupported claims is not ethical. Biology is very complex, and amateurs picking up blog posts or speculations off the internet are not helpful to the field. I understand the impatience. I had a career in software, and worked for multiple startups prior to my grad school work on gene therapy and vaccines. Investors in the Silicon Valley who are used to software startups want the impossible, and seem to prefer it.
Biopharma is very different from software. Biology is slow because one frequently finds apparently paradoxical results, and the systems are slow to tell you. Usually, when you affect one thing, you affect quite a few others as well. When you do find out that you have made a mistake, it’s a very big deal when it’s a human involved.
So far, there are 7 patients killed by gene therapy clinical trials.
Brian Hanley is the founder of Butterfly Sciences, a company developing gene therapies for aging. He has a range of papers in biosciences, economics, policy and terrorism, in addition to a recent text on radiation treatment. He obtained his PhD in microbiology with honors from UC Davis, has a bachelors degree in computer science, is a multiple entrepreneur and guest lectured for years to the MBA program at Santa Clara University.
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