Telomerase and Cancer
The Reserve Capacity Hypothesis: Evolution's Tradeoff Between Tumor-Suppression and Tissue Repair
Today, I found a paper that helps explain the association of telomerase with cancer "Reserve-capacity hypothesis (Weinstein & Ciszek 2002)". This paper mentions two steps in carcinogenesis: (1) runaway cell division that ends when the cells' telomeres are too short to continue dividing (a benign tumor); and (2) resumption of runaway cell division in any cell that begins to produce telomerase, thus restoring the telomeres. In the overwhelming majority of cases, the tumor dies out before any of its cells starts making telomerase, but if it doesn't, then cancer will result. The authors argue that the cessation of telomerase generation is a defense against cancer. During the reproductive years, when telomeres are still long, the principal threat is cancer. Later on, senescence becomes a major problem, and paradoxically, cancer rates rise rapidly even though telomerase hasn't been present since the fifth month of gestation, and more and more cells are losing the power to divide. The authors are convinced that evolution has reached the best balance it can make between early cancer and senescence (and later cancer)... one that minimizes cancer during the reproductive years. And after the reproductive years are over, who cares? Not Mother Nature.
The cornerstone idea is that lack of telomerase provides an upper bound upon replicative capacity of runaway somatic cells that generate benign tumors. For example, if a cell enters the first phase of carcinogenesis and divides 40 times before reaching senescence and halting mitosis, it would have spawned about 240 or 1,000,000,000,000 cells. One trillion cells would occupy about one liter (one quart). If it happened later in life, when the cell had 30 doublings remaining, the benign tumor would reach about one cubic centimeter in size. And if it happened in one's 80's, with 20 doublings left, the tumor would attain a size of only about one cubic millimeter. The idea is that because these runaway cells lack telomerase, they can only grow so far before they senesce and die. Once in a great while, a cell will appear that will produce telomerase, and then we have a full-blown cancer on the loose.
The concern is that if you flooded the body with telomerase, these runaway cells would run away. Even if they never developed the ability to produce telomerase, they could get so large as benign tumors that they could kill their host (or hostess) if there were a plethora of them.
Cancer Probabilities Versus Cell Count
I'm going to guess that a fruit fly has something like 100,000 cells. A mouse would have something like 20 billion cells, or 200,000 times as many cells as a fruit fly. Humans have approximately 10 trillion cells, or about 500 times as many cells as a mouse, and 100,000,000 times as many cells as a fruit fly. If we take the lifetime risk of developing cancer to be 1/3rd for a human, then given comparable defenses, a mouse should have a 1/1,500 chance of developing cancer if it lived out its average lifespan. A whale would have about 10,000 trillion cells... about 1,000 times as many cells as a human, about 500,000 times as many cells as a mouse, and about 100,000,000,000 times as many cells as a fruit fly. How do whales escape cancer? It would seem to me that it can't be done by simply avoiding the production of telomerase. Eliminating telomerase in humans (except in skin, bone marrow, the immune system, and testes) allowed evolution to reduce the lifetime human cancer risk to 1/3rd. But what did evolution do for whales? What did it do for an encore? Whales must replenish red blood cells, their immune systems must pour out new white cells, and their testes must be refreshed even if they don't need to replace skin.
What about horses (e. g., Percherons) and cows? What about elephants and grizzly bears? What's their cancer incidence? What happened to brontosaurs? How did they fight cancer?
At the other end of the scale, mice shouldn't have to worry about cancer. And laboratory mice have enormously long telomeres-- ten times as long as humans. Furthermore, their somatic cells can produce telomerase. The authors' propose that laboratory mice, because of their sheltered environments and because they've been bred from young, sexually prolific breeder mice, have developed much longer telomeres than wild mice. But that raises several questions.
Laboratory Mice Die With Their Boots On
The authors argue that lab mice have developed such long telomeres because they're protected from mutagens. Evolution, as a by-product of their vigorous parents and a lack of carcinogenic challenges, has bred these mice for extremely long telomeres. But then the question arises: with their cell count that's 1/500th of the human cell count, why would mice, tame or wild, have to defend against cancer, anyway?
A second question is: if their telomeres are so long, why do they grow old and die? What do they die of? The authors quote someone saying that laboratory mice don't really look old when they die of senescent causes.
Adequate telomeric length may be a necessary condition for juvenescence, but it sounds as though it isn't a sufficient condition. There must be more to aging than just telomeres. The authors cite other "patchwork quilt" problems that might arise when backup cells such as stem cells replace cells that have died.
Why Don't Telomerase-Enabled Human Cells Develop Cancer More Often?
The authors postulate that skin doesn't develop cancer very often even though it's continually dividing because it's protected from topical mutagens by the epidermis, and it continually sloughs off cells that have begun to divide uncontrollably. (But you can certainly develop skin lesions that don't slough off. Keratoses don't slough off.) Also, there are other bodily tissues that are protected from mutagens.
What About Fruit Flies?
Fruit flies certainly shouldn't have work out evolutionary telomerase tradeoffs to fight cancer. How is it that fruit flies live for such a short time? And of course, this argument applies to all other miniscule, multicellular organisms. If, in large mammals, telomerase and youthful vigor had to be sacrificed in order to combat cancer, why would it be necessary in very tiny animals?
The Authors Take Age-Remediation Gerontologists to Task
The authors argue that if you think that senescence occurs simply because evolutionary selection mechanisms haven't favored longevity much beyond reproduction age, then you might suppose that you could intervene and "pursue a technological solution to fill in where selection leaves off. But (say the authors) gradual senescence results from evolutionary tradeoffs that favor good health during the reproductive years at the expense of longer telomeres in old age, and not from "incidental effects or a lack of selection". And then the question becomes: how well has evolution optimized the trade-offs in terms of overall viability? The authors conclude that trading off carcinogenesis against later senescence has already greatly extended our lifespans. Longevity can't be greatly extended without a dramatic increase in the rate of tumor formation. Extending our "youth spans" would increase our cancer rates. I think the authors' picture of what would happen if you administered telomerase to a human subject is that cancers would suddenly be everywhere among cells that can divide. Innumerable benign tumors would grow to lethal sizes..
As indicated above, I have questions about this paper. It's not difficult to believe that there must be some good reason why evolution didn't render life forms immortal. Still, there seem to me to be lacunae in this story.
I may have a different perspective on it after I've had more time to digest it.
To Be Continued