An intriguing hypothesis argued poorly

Below the fold, I am reprinting a post I made at Dean's World which basically is a rehash of Orac's critique/endorsement of Peter Duesberg's ideas about aneuploidy in cancer.

 

Cancer surgeon and researcher 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 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 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 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.