There is currently a notion circulating that
cancer is primarily due to “random mutations”.
I have come across this statement twice, first in a Cell Biology text (I
won’t name it out of deference to the authors), and in a January 2015 issue of Time magazine. My gut reaction to this hypothesis is that it
is either patently false, or at best only a half-truth. I indicated as much to an undergraduate class
while teaching Cell Biology in the following way. I quoted the text on the lecture slide and
then, in capital letters, bolded, inscribed beneath it: FALSE. Evidence from more than half of the last century
flies in the face of this theory, and I will not allow current advances in
genetic analysis to defend it. To
attribute all cases of cancer to random mutation cognitively diminishes several
causes of cancer that have been definitively proven. A list is not that difficult to come up with
--- ionizing radiation, ultraviolet light, ingestion of radioisotopes, various
DNA viruses, the retroviruses, and a long list of chemicals that are frank
carcinogens, including benzanthracene, benzo[a]pyrene, and dioxin, a
contaminant of the defoliant “Agent Orange” that was widely used during the
Vietnam War.
Perception is not always reality, and while
these are in fact the cause of what
may be called “random” mutations, the ability of these agents to cause
transformation of normal cells to a proliferative phenotype devoid of growth
control cannot be called a random
event. While the length of this article
does not permit an examination of the mechanism of each of these agents, some
brief details are quite illustrative. In
the era of atmospheric nuclear weapons testing, an epidemic of thyroid cancer
in young teenagers was traced to radioactive iodine isotopes that settled out
on the grass of dairy farms. Drinking
the milk containing them resulted in concentration of the
isotopes in the children’s thyroid glands (Barry Commoner, “Science and
Survival”, Viking Compass, 1967). Had this
epidemic been ascribed to random chance, the nuclear test ban might never have
been arrived at or maintained. This
phenomenon was repeated following the meltdown at the Chernobyl nuclear
reactor, hardly a random occurrence given the
geographical distribution.
The literature on multicyclic aromatic compounds
goes back as far as 1949, when Setala noted a synergistic effect of
benzanthracene on the microtubule disruptor colchicine during the development
of skin cancer in mice. To this day, benzanthracene and
benzo(a)pyrene are standard compounds used to induce cancers in laboratory
animals. Unfortunately, they are also
described as “ubiquitous” carcinogens, found in diesel exhaust particulates and
asphalt, with small amounts even generated during grilling of food. Perhaps it is easier to accept the continued
introduction of these compounds into the environment from crude oil derived
products if any dire consequences are attributed to “random” causes. During my undergraduate work at the
University of Texas at Austin, I had the great privilege to take a course under
Dr. David T. Gibson, a graduate of Leeds.
He determined how bacteria break down benzene as a sole carbon source, using a strain of Pseudomonas putida.
There is a difference in the metabolism of
aromatic compounds in bacteria and eukaryotic cells. In both cases, the first intermediate is an
epoxide, basically a triangular oxygen bridge between two adjacent carbon
atoms. Hydrolysis of this strained intermediate
produces a cis-dihydrodiol in bacteria, but a trans-dihydrodiol in animals. The
diols can then be cleaved by further oxidation, thus cracking open the ring. There’s a problem with some compounds, in
that the epoxide is not easily hydrolyzed to the diol, but remains highly
reactive, and will easily form bonds to polynucleic acids such as DNA and
RNA. This is the case with benzo[a]pyrene,
in which the formation of a diol at the 7,8 position serves to stabilize an
epoxide linkage at carbons 9 and 10. Mutations
in genetic material due to binding of such reactive intermediates can result from
steric hindrance during replication or outright strand breakage. However, highly specific mechanisms for tumor
induction have recently been revealed, including an aromatic (aryl) hydrocarbon
receptor, involvement of P450 cytochromes, and even upregulation of microRNAs that favor cell
transformation.
Thus, while some generated mutations may
be random, there is nothing random in either the ability of these aromatic
hydrocarbons to cause them or in the complexity of the mechanisms used. Dr. Gibson was concerned not only with the
metabolism of aromatic compounds, but especially those bearing a halogen such
as chlorine, fluorine, or bromine, like dioxin (2,3,
7,8-tetrachlorodibenzo-p-dioxin), one of the most carcinogenic
substances known. He also introduced
us to the plethora of multicyclic compounds present in crude oil, especially
those in the heavy “asphaltene” fraction that are resistant to degradation and
may persist for decades after a crude oil spill. The spectacle of FDA inspectors doing a
“sniff test” for hydrocarbons shortly after the BP Gulf oil spill would be
ridiculous if it were not so alarming.
To allow consumption of any organisms
drawn from the Gulf fishery so soon after the spill without full analysis,
including GC/MS of any organic compounds was, in my mind, unconscionable. I am not an organic chemist or a toxicologist
--- my dissertation studied the modulation of the immune system by
intracellular pathogens. I came by it
during a career in the diagnostic and pharmaceutical industries. But I never forgot what David Gibson taught
me so many years ago --- that the ability of some agents to cause mutations is
not a random phenomenon. The assault of carcinogenic
viruses and chemical mutagens in our environment will continue. But I for one will not allow them to remain
unnamed and anonymous under a cloak of randomness.
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