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May 28, 2014

On Peto's Paradox

"Peto's Paradox is the observation ... that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism."

Do blue whales seldom get cancer?

Being a cautious fellow I don’t know whether or not it is true that blue whales get less cancer than (say) mice but I do accept that fewer cases of cancer have been reported in blue whales than in smaller vertebrates. Caution also tells me that neither I (nor anyone else) has, at present, access to technology that enables one to observe an animal’s somatic cells as they are transformed to the cancerous state. Nor can we observe whether such cells are promptly extinguished by agents of an adaptive immune system (which all vertebrates possess) before producing cancerous daughter cells in sufficient numbers. Sufficient, that is, to cause death from cancer or to produce detectable symptoms. 
So, my starting point is different from others who have written extensively on this subject. My view is that—most probably—blue whales, because they consist of greater numbers of somatic cells, produce a greater number of cells transformed to the cancerous state than do mice but, as I will explain below, their greater size enables them to minimize production of detectable cancer.

Before explaining how large sizes protect certain animals let’s briefly consider why I also think that smaller sizes protect other animals.

(Sorry, but achieving real understanding of Bilaterian evolution requires careful thought.)

Animals without an adaptive immune system: the small body defense

According to my peer-reviewed theory, all Bilaterians (and no other multicells) experienced lethal cancer and all cancers were initiated by a triggering mechanism embedded in oncogenes. As I concluded in my 1984 Letter published in the Journal of Theoretical Biology those oncogenes “have been present in every cell of every specimen of every species of the Bilateria that ever existed, and … they have existed nowhere else in nature.”

If my theory is correct and the earliest Bilaterian gene pools could survive only if they produced a sufficient number of breeding multicells, each consisting of somatic cells all equipped with cancer triggers—death triggers—would those gene pools tend to produce breeding animals with an abundance of those triggers or would those gene pools “learn” to minimize the number of such potentially lethal parts, to favor small animals over large animals? 

To me the answer is clear: they would minimize the risk of death by minimizing the number of cancer triggers; small-bodied animals would have presented less risk of cancer-death than larger bodies. When the ancestors of insects left the marine environment they entered one that was more carcinogenic; sea water moderates radiation. I believe that's the reason most insects are smaller than their (likely) marine ancestors. 

Animals with an adaptive immune system: the large body defense.

As a cancer-evolution  theorist I do not need to follow medical protocols in deciding when cancer exists; I don't look for tumors. Agreeing as I do with the standard conviction that cancer begins when a single cell has been transformed into the cancerous state, but knowing our present technologies do not enable anyone to actually monitor all cell divisions in any wild animal, I begin with reasonable assumptions and apply probabilistic thinking.  

I propose two thought experiments. If a single leukemic cell comes to exist in two different mammalian specimens, one a mouse and the other a blue whale, but neither of these imaginary specimens possesses an adaptive immune system or any other post-initiation means of preventing death from leukemia, which animal would be the first to die? If you believe, as I do, that the mouse would most likely perish before the much larger whale then perform a second thought experiment. This experiment is the same as the first except that both animals possess fully-functioning adaptive immune systems which are equally efficient at exterminating individual leukemic cells: the anti-cancer agents of the immune system kill malign cells one-at-a-time and they kill at the same rate of speed. In this experiment does the mouse or the whale have the better chance of actually surviving this episode of  leukemia?    

In pondering that question remember that despite the vast difference in the size of individual specimens the populations of mice-cancer cells and of whale-cancer cells are alike in one essential respect: they begin with a single transformed cell and grow by producing malignant daughter cells. There is no reason to think that in the earliest stages that mouse-cancer cells multiply faster than whale-cancer cells or vice versa. Barring any unknown qualitative difference can we not assume that the size of the populations of cancer cells in the early stages, before the formation of detectable symptoms, are virtually equal? Now ask this question: which animal—the huge whale or the tiny mouse—has access to the greater number of individual killing-agents of its adaptive immune system, including cells capable of destroying the comparably-sized populations of cancer cells? I think it obvious that the enormous whale can marshal a far greater number of killer cells (including cellular components of its innate immune system)  than can the tiny mouse. (Moreover, if, as the first thought experiment suggests, smaller animals die more quickly from cancer the much larger whale has more time to organize its defense than does the mouse.)

Because the size of the target—the young, relatively small, population of malignant cells—is unaffected by the size of the host animal but the numerical strength of the arsenal of defending killer cells is directly related to the size of the individual specimen, my conclusion is this: in all species with adaptive immune systems capable of destroying cancer cells larger animals are more likely not to experience detectable cancer than smaller animals. There is no paradox.


 Previous publications

1. In my April 1983 Letter in Journal of Theoretical Biology I wrote the following on the significance of the immune system in evolution.

"The evolution of efficient cancer-specific immunological defenses in all vertebrates would have enabled those species to adapt characters, functions, etc., which might have increased the incidence of cancer initiation. The following all suggest the lowering of first line defenses against cancer in vertebrates: increased mitosis as evidenced by large body size and extended pre-reproductive life, increased exposure to radiation as the result of migration from aquatic to terrestrial habitats, and the elimination, in many mammalian species, of opaque external protection from UV radiation. Bilaterian invertebrates do not have a lymphoid system which, according to Good and Finstad (1968), has as its primary raison d'etre surveillance against malignancy. Unlike animals equipped with such immune systems, the invertebrate germ lines seem not to have produced any large, long-lived terrestrial specimens, and none seem to have shed ancestral radiation-protective shielding to the extent found in some vertebrate species. On the other hand, as noted by Gateff and Schneiderman (1968), experimental data suggest that in the largest group of terrestrial invertebrates, the insects, somatic cells exhibit karyotypic and genetic program stability greatly in excess of that found in vertebrates."
2. In Chapter Nine of my 1992 book I write extensively on the adjustment of Bilaterians to terrestrial life with its greater exposure to carcinogenic radiation than the marine environment and the profound difference between the preventive defenses available to invertebrates and the vertebrates' adaptive immune systems . A pdf of Chapter Nine can be downloaded here

Comments and questions to the author are welcomed here.

At this site you will find links to additional material including my original Letters to the Journal of Theoretical Biology and  the 1992 Nature review of my book.

Copyright © 2014 by James Graham

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