[Dean's World] Aziz P: An intriguing hypothesis argued poorly

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Posted by Aziz P:
An intriguing hypothesis argued poorly
http://www.deanesmay.com/posts/1177693918.shtml


   Cancer surgeon and researcher [1]Orac reviews Duesberg's SciAm piece
   about cancer aneuploidy over at Scienceblogs, and has a lot of
   insightful comments. Overall, he credits Duesberg with promoting an
   interesting hypothesis, though he rightly shoots down the
   [2]ridiculous notion that Duesberg work on AIDS is in any way relevant
   - positively or negatively - to his cancer theory:

     [Duesberg's supporters] think nothing conflating the scientific
     validity of Duesberg's ideas concerning cancer, which might indeed
     be partially or mostly correct, with his discredited hypothesis
     that HIV does not cause AIDS, implying that because he might be
     correct about cancer implies that he is correct about AIDS. It
     doesn't. Sorry, but the two issues are at best peripherally and
     weakly related and at most not related at all.

   Orac then goes on to consider the aneuploidy hypothesis on its own
   merits, completely independently of his opinion about the HIV issue.

   He starts out with some history about the aneuploidy hypothesis, which
   he notes has been around for about 50 years:

     First, the concept that chromosomal abnormalities cause cancer
     dates back at least to 1914, when the German zoologist Theodor
     Boveri, based on studies of sea urchin development, first suggested
     it. Indeed, this featured prominently as a milestone in cancer
     research in a display in at the recent 100th anniversary meeting of
     the American Association for Cancer Research. Thus, the basis of
     Duesberg's idea is quite old. Indeed, the concept that chromosomal
     derangements caused cancer predominated for 40-50 years, until the
     solution to the structure of DNA, the elucidation of the genetic
     code, and study of genetics led to an emphasis on genetic causes of
     cancer. Combined with the observation that tumor cells are
     genetically unstable, leading to many mutations, the genetic
     hypothesis led to the discovery of oncogenes and tumor suppressors.
     Now, potential chromosomal causes are again being looked at, and
     for whatever part Duesberg's advocacy had in spurring this he is to
     be acknowledged, even if his boosters do have an annoying tendency
     to make it sound as though scientists would have zero interest in
     studying chromosomal causes of cancer were it not for Duesberg,
     which, given the attention shown to this topic at recent meetings
     that I've attended, is ridiculous.

   In a nutshell - aneuploidy is an old idea, and Duesberg isto be
   credited with reviving it, but the renewed interest in it is not
   solely due to Duesberg's advocacy.

   In fact, it seems that the issue of gene mutation vs aneuploidy in
   cancer is really a chicken and egg problem, like the nature vs nurture
   debate on child rearing. Duesberg takes oe extreme, but the mainstream
   science on cancer aneuploidy is hardly at the other extreme, if
   anything it's largely in the middle.

     On the one extreme, there is the argument that aneuploidy is the
     primary cause of cancer, causing the accumulation of genetic
     mutations through breaks in chromosomes. On the other extreme is
     the argument that aneuploidy is a consequence, not a cause, of
     cancer. Duesberg, as you may guess, takes the extreme version of
     the former view. These days, most other scientists studying this
     question tend to consider both important to varying degrees in the
     development of cancer, the present pressing scientific question
     being: Which causes which and how? It's very much a
     chicken-or-the-egg problem. Does mutation lead to aneuploidy or
     aneuploidy lead to large numbers of genetic derangements that lead
     to cancer? Or are both aneuploidy and mutation responsible in
     differing proportions depending on the cancer?

   And Duesberg very much occupies the extreme end of that spectrum -

     In essence, he argues that aneuploidy comes first and is the prime
     inciting event that starts the cascade of genetic changes that lead
     to malignancy. DNA is damaged, either through mutagens or other
     causes, and then, through what becomes a self-catalyzing process,
     aneuploidy leads to progressive chromosomal alterations that lead
     to increasingly widespread genetic alterations in a process that
     feeds on itself, leading to chromosomal instability and cancer.
     Indeed, Duesberg postulates that carcinogens work as
     "aneuploidogens" rather than as mutagens.

   Orac points to this [3]concise summary by grrlscientist of Duesberg's
   arguments in support of this perspective. In a nutshell, these
   arguments are:
    1. Cancer risk increases with age. Lamentably common, cancer afflicts
       about one in three people at some point in their lives, but mostly
       after the age of 50, which is when chances for malignancy soar.
       Thus, cancer is, by and large, a disease of old age. The gene
       mutation theory of cancer's origins, however, predicts that the
       disease should be quite common in newborns.
    2. Carcinogens take a very long time to cause cancer. Numerous
       chemicals and forms of radiation have been shown to be
       carcinogenic in animals or established as the source of
       occupational or accidental cancers in humans. But even the
       strongest carcinogens at the highest survivable doses never cause
       cancer right away. Instead the disease emerges only after delays
       lasting years or even decades. In contrast, when substances known
       to cause gene mutations are administered to bacteria, the cells
       begin displaying new phenotypes within hours; in larger organisms
       such as flies, the effect is seen within days.
    3. Carcinogens, whether or not they cause gene mutations, induce
       aneuploidy. Scientists have looked for the immediate genetic
       effects of carcinogens on cells, expecting to see mutations in
       many crucial genes, but instead have found that some of the most
       potent carcinogens known induce no mutations at all. Examples
       include asbestos, tar, aromatic hydrocarbons, nickel, arsenic,
       lead, plastic and metallic prosthetic implants, certain dyes,
       urethane and dioxin. Moreover, the dose of carcinogen needed to
       initiate the process that forms malignant tumors years later was
       found to be less than one-thousandth the dose required to mutate
       any specific gene. I
    4. Patterns of aneuploidy are seen in different tumors
    5. Gratuitous traits do not contribute to cancer's survival
    6. Cancer cells change much faster than genes

   Orac takes each of these in turn. With respect to argument 1 about
   risk and age, Orac notes,

     This argument is a strawman and neglects other factors, to boot.
     For one thing, contrary to what Duesberg states, the "gene mutation
     theory of cancer" does not necessarily predict that cancer should
     be quite common in newborns.

   And provides much more detail (I am only giving an overview, not a
   summary).

   For argument 2, Orac asks,

     Does anyone see the flaw in an argument comparing humans to
     bacteria or flies in this manner? Let's look at flies, because they
     are eukaryotes. The average lifespan of, for example, Drosophila is
     much shorter than a human's, on the order of 30 days or so.
     Carcinogens generally require cellular replication before cancer
     can develop. So, let's see, a latency period for cancer after
     exposure to carcinogens of few days in the life of a fruit fly like
     Drosophila is not unlike a latency period of a couple of decades in
     a human, if you compare it to the organism's overall life span.
     Bacteria reproduce amazingly rapidly; so it is not surprising that
     they respond to chemicals even faster. As for strong carcinogens
     not causing cancer right away, nothing in the genetic mutation
     theory of cancer demands that they must, particularly given that
     strong doses may result in more deleterious mutations and that the
     ability of a normal cell to repair its own DNA is quite prodigious.

   For Argument 3, Orac notes that Duesberg's foundational assumption is
   again simply wrong:

     Sure, carcinogens induce aneuploidy, but just because some
     carcinogens do not directly damage DNA does not necessarily mean
     that the induction of aneuploidy must be the mechanism by which
     they cause cancer. It might be, but it doesn't necessarily have to
     be.

   And provides an example using asbestos (used by Duesberg too) to
   illustrate why.

   Orac finally touches more briefly on the remaining arguments, saying
   that they "range from the 'so what?' to the more intriguing" and again
   provides details with specific counterexamples. However, he then
   retreats from his critical stance:

     Lest one think that I'm hostile to Duesberg's hypothesis, let me
     disabuse you of the notion right now. Although I think Duesberg's
     an utter crank and pseudoscientist when it comes to his HIV/AIDS
     denialism, I find some of his work in cancer intriguing, and I
     disagree with Mark and Larry that it was such a horrible thing to
     feature him in an article in Scientific American, especially given
     the disclaimer. It is clear to me that epigenetics (cellular
     factors other than genes that regulate gene activity) and
     chromosome structure are very important in carcinogenesis, more so
     than had been appreciated before.

   In a nutshell, Orac's beef (and keep in mind he is both a cancer
   surgeon as well as a researcher in the field, so his qualifications
   for comment are equal and greater than Duesberg's in this regard) is
   that Duesberg is onto something, but is overselling it as "The One
   True Cause of Cancer" and portraying himself as the Prophet of
   Aneuploidy when in fact its an old idea whose time has come:

     What really irks me about Duesberg with respect to his ideas about
     cancer is that he may be on to something, but he can't seem to stop
     himself from the same black-and-white, either-or thinking that
     apparently led him down the road of HIV crankery, nor can he seem
     to resist massively overselling his hypothesis as the be-all and
     end-all hypothesis to explain cancer initiation and progression. As
     I said at the beginning of my post, whenever someone postulates
     theirs as The One True Cause of Cancer, my skeptical antennae start
     twitching, and Duesberg's aneuploidy hypothesis is no exception.
     Cancer is a complex and resourceful foe, not to mention that it's
     hundreds of different diseases, not a single disease. Duesberg
     neglects a variety of other new hypotheses for causes of
     carcinogenesis that hold equal or greater promise than the
     chromosomal chaos hypothesis. Among these are cancer stem cells,
     tumor angiogenesis, and the aforementioned metabolic hypothesis of
     cancer (a.k.a. the Warburg effect). He even neglects what I
     consider to be a far more fascinating and sophisticated version of
     the chromosomal hypothesis, specifically Tom Misteli's concept that
     derangements in the higher order three dimensional structure of
     chromosome territories can lead to cancer by alterations in gene
     expression.

   Orac closes by [4]quoting Walter Giaretti, of the National Cancer
   Research Institute in Genoa, Italy:

     It is likely that new studies directly comparing DNA copy number
     and gene expression will be performed in the near future on the
     role of aneuploidy in cancer, on what genetic events may induce
     chromosomal instability and on the validation of novel criteria for
     early diagnosis. It is predictable that these studies will vanish
     the conflicting views that either aneuploidy or gene mutations are
     a unique cause of the origin and progression of cancer negating the
     role of the alternative mechanism. Today, these conflicting
     interpretations are increasingly being abandoned to let a more
     complex mixed paradigm take over from previous concepts. In brief,
     ideas stemming from the old Boveri theory and from the modern
     theories may soon be seen as cooperative and equally important to
     cancer.

   and notes that Giaretti's question, "Don't we have now enough
   experimental evidence that cancer originates and progresses with the
   contribution of both gene mutations and aneuploidy?" may ultimately
   have the answer, "Yes." - but Duesberg is dogmatically wedded to the
   answer being "No."

   If one's goal is a genuine solution to cancer, there is no dog in the
   fight between aneuploidy and genetic mutation' the issue is really how
   much of a dependent role each of these and other mechanisms play, so
   that the global understanding of the system can be improved. Only that
   way lies the hope of a true cure.

References

   1. http://scienceblogs.com/insolence/2007/04/peter_duesberg_chromosomal_chaos_and_can.php
   2. http://barnesworld.blogs.com/barnes_world/2007/04/pewter_duesberg.html#comment-66506212
   3. http://scienceblogs.com/grrlscientist/2007/04/chromosomal_chaos_and_cancer.php
   4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16675877&query_hl=39&itool=pubmed_docsum