Not being a biologist, I had assumed that telomerase was “hard-coded” with the telomere DNA sequence it writes at the end of a chromosome. This is actually not quite the case; the coding for a telomere is encoded in a sequence of RNA that the telomerase wraps around (making it a ribonucleoprotein) called TERC.
I, probably like many others, had once thought that inactivation of telomerase would result in a cure for many different cancers. However, for some reason, probably due to activation of other immortality pathways, this is not the case (although drugs that rely on this principle appear to be among the more successful treatment modalities in trials). This also appears to be one of those ideas that everyone is aware of but no one is acting on – I blame the way that science currently works for this (as I’ve mentioned before, how you express your values tangibly affects the impact you will have on reality; if you prefer to publish a lot and have a stable job, then you will not have the time to embark on the sorts of long-range high-risk research projects that actually make a difference).
Anyway, mere inactivation is unlikely to work. However, because TERC actually provides a template for what telomerase writes on the end of the cell’s chromosomes, inactivation is not necessary.
Here’s the fun part where I get to speculate wildly about the current state of the art because I can’t get the training that actually matters to actualize these sorts of ideas (you want your “committee of experts” and I’m the computer scientist. Fine, but the whole team suffers for the lack of synergy and vision):
Modification would do as well. If we could change what telomerase writes out to the end of the cell, we can write anything we want to it – and it would be specific to telomerase-immortalized cells (few normal cells carry this immortality, but it is very common in cancer cells), which means a treatment based on this idea would have few to no side effects.
What could we code for? I’m really not qualified to answer this, but some choices that seem obvious to me are the tumor suppressors that the cancers are inactivating in the first place, such as p53. Reactivate the suppressors, stop the tumors, and they won’t harm normal cells that produce telomerase but are making tumor-suppressors already. Again, minimal to no side effects.
And that’s the idea! It’s another interdisciplinary fusion:
This is what, in computer science, we would call a “buffer overflow with arbitrary code execution”. The code in this case is DNA. The “program counter” is the position of the ribosome. The end of the buffer is the telomere. Telomerase writes code out to the end of this buffer. You can take advantage of software this way by executing whatever code you want; you should be able to do the same to cells.
Robert,
Thanks for your comment. It was quite informative (I suppose I should expect that, given your email address!) – I knew a bit about the trial of GRN163L (although not about Geron’s plan to lengthen telomeres to combat aging): the results I’ve read of so far have been very promising, but not what I would call curative. The lack of side effects is also encouraging, though not particularly surprising. Perhaps combination with another treatment modality would increase the effectiveness, although the other modality may have its own side effects. The inhibition of invasion and metastasis demonstrated in several studies was also a surprising, but welcome, benefit.
Why would oligonucleotide drugs as a class cause thrombocytopenia? I attempted to find this information, but could only find this pattern empirically observed, rather than a theoretical reason why this may be the case.
I’m actually a bit surprised I haven’t seen more literature on Geron’s drug recently, since there were many papers on it written around 2005. I’m not sure whether this is due to ongoing trials (I did notice a few in the course of browsing the literature) or whether the research community has latched onto a different idea. Either way, I think the idea of targeting telomerase is too intuitive for people to ignore it for long, so I’ll be eagerly awaiting further results as they are published. I may not be active in this field now, but I one day plan to be.
Thanks again,
Michael
But per Eliz. Blackburn et al, when the RNA template of telomerae is inhibited or missing, 76 genes known to be associated with cancer and growth, do not get activated. The presence of functional overexpression of telomerase as in cancer is a master cancer gene in effect, switching on other genes. Then there are another 144 genes of unknown effect that also do not get activated when telomerase is absent, inhibited at the RNA template, or have a missing template.
Conversely, increasing telomerase expression in normal cells makes cancer less likely per some work by avoiding a “telomeric crisis” where cells with “issues” arrive at a crossroads where it either,
a. becomes cancerous, or
b. dies.
“Normal” levels of telomerase activation in normal cells makes cells live longer and healthier lives.
Geron Corp, http://www.geron.com is currently in multiple human trials with the first in man telomerase inhibitor drug. So far the only side effect noted is manageable thrombocytopenia which would expected with an oligonucleotide drug. They skip a week to avoid it happening. These are good trials to watch.
Geron and/or its associate also have a telomerase activating compound that is derived from astragalus, a pretty expensive extraction and complex too. But people are paying about $40,000 per year to try it. Such a treatment would be actually good for healthy people, it increases T cell count, hair growth, etc.,, signs of youth. Probably kicking repair stem cells in the butt, making them young and productive and back to work renewing the body.
Its appraent that you can inhibit telomerase in a cancer patient and probably either cure him, and greatly increase the utility of existing chemo even at a lower dose. Many cancer types have very short telomeres, even though they are making a lot of telomerase. This is due to the rapid growth rate of cancer and fetuses. Even though telomerase is full-on, it can’t keep up with the growth rate which ravages telomere lenth with each cell division.
Its also apparent that you can lengthen teloemeres in healthy cells.
Many chemos shorten telomeres, but with huge toxicity, and they shorten the telomeres in all cells, making cancer recurrence more likely from telomeric crisis. One answer might be to activate telomerase again after the cancer is defeated.
Telomerase activates glycolysis in cancer. Mohamed Kasani-Sabet UCSF
Otto Warburg first recognized the similarities between a cancer and a fetus:
1. they grow at the same approximate rate
2. they use the same fuel source, glycolysis (sans oxygen)
I’d add a third, ,, they are both telomerase dependent, they are both stem cells. Cancer stem cells are a reality in the research and get much attention as of late. E.V. Gostjeva et al , in her Jan 2006 paper on bell shaped nuclei, image colon cancer stem cells and fetal colon stem cells. They were identical, each trying to make a new colon, each making the same exact 7 different cell types.
Cancer stem cells are about 3-5% of the tumor population, and responsible for most of the growth, spreading, and can pump out chemo, and grow faster after radiation (unless well fried). This is why the war on cancer hasn’t been won. We have been targeting the wrong cells all this time. Its hard for many to accept perhaps that the same mechanisms that result in a beautiful baby, are also responsible for the misery of cancer.
We badly need to be able to study both embryonic stem cells and cancer stem cells for this incredibly important reason. All of the above applies to this paragraph. Ignorance in this case is not bliss. I greive for those sick and dying who have been denied by the delays caused by this administrations war on the science. Science that would extend our lives, and cure most of human disease.
Don’t know when I can post again, but email is prime 3 end ,, at yahoo , ,, dott com
God Bless
Robert