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Potshot at Duesberg

Surgeon-biologist Orac tackles Duesberg’s cancer idea with limited respect

Hostile to Duesberg on AIDS, he labors to rescue oncogenes from the aneuploidy gold rush

The first attempt at a public critique of Peter Duesberg’s cancer initiative, his leadership of a return to exploring the aneuploidy which marks all cancer cells (their excess chromosomes, sometimes even double the normal number), has been made. Orac, whose blog on Seed magazine’s Science Blogs site, is Insolence, has managed quite a lengthy treatment, laboriously raising objections to Duesberg’s explanation in Scientific American (earlier post).

The post attempts to save oncogenes from the stampede over to aneuploidy, reminding us that Duesberg both pioneered the field of cancer genes and repudiated it soon afterwards. Thus the first section of the Duesberg article, which is being carried by You Bet Your Life in the form of a pdf , mentions how Duesberg found the first example of ‘oncogenes’‘, the quickly fashionable cancer field that he afterwards rejected and now is threatening to replace with more productive aneuploidy research.

Chromosomal Chaos and Cancer

Current wisdom on the role of genes in malignancy may not explain some features of cancer, but stepping back to look at the bigger picture inside cells reveals a view that just might

By Peter Duesberg

When I first began to study cancer as a young postdoctoral fellow in the early 1960s, it looked to leading scientists as though viruses could be the cause of most, if not all, malignancies. That idea was based on the discovery of several tumor- and leukemia-producing viruses that could infect a host cell and insert their own genetic material into its genome, sparking a cancerous transformation and proliferation of the cell. I was optimistic and naive enough to hope that if researchers could understand the exact molecular mechanisms by which such viruses caused cancer, we could develop vaccines to eliminate one of humanity’s most dreaded diseases.

My own contribution to that pursuit came in 1970, when my colleagues, Michael Lai and Peter Vogt, and I managed to isolate a specific gene, src, which was suspected to be the tumor-initiating culprit in avian Rous sarcoma virus. Within a few years, more creative scientific minds than mine had followed this lead to a realization that a closely related gene was already present in the normal DNA of animals, including humans. And a new cancer model was born: it proposed that some triggering event, such as a mutation in a human cell’s own version of src, could ignite tumorigenic powers like those possessed by its viral counterpart. The cancer-promoting potential of such a time bomb buried in our personal genomes earned it the title of “proto-oncogene.” Once the mutation occurred, it would become a full-fledged oncogene. …. (cont. in Scientific American or on the pdf copy of the Duesberg article here

Here is a Wall Street Journal blog note on the appearance of the piece:

A Cancer Theory From a Controversial Scientist

Researchers have been looking in the wrong place in the body for cancer’s origins, writes Peter Duesberg in Scientific American (subscription required). What makes the publication of his theory remarkable is that the magazine’s editors felt obliged to include a note disavowing the work Mr. Duesberg is most famous for—his claim that HIV doesn’t cause AIDS. While Mr. Duesberg is “surely wrong” about HIV, the magazine’s editors write, his work on a new theory about cancer—that an aberration in chromosomes, not genes, ignites malignant cells—has gained enough traction in the scientific world that it merits publication.

Mr. Duesberg, a professor of molecular and cell biology at the University of California, Berkeley, is treated as a pariah in the scientific community for his ideas about HIV and AIDS. At the same time, he has carried out groundbreaking cancer research and gained fame in 1970 for being the first virologist to identify a cancer-causing gene.

In the late 1960s and 1970s, Mr. Duesberg and others began looking into the role of mutations in a few key genes that regulate cell function. He has since shifted the hunt for cancer’s origins one level up in the cell, to chromosomes, rod-like structures made up of thousands of genes. Unlike genes, chromosomes barely vary across a species. The smallest difference in them can be catastrophic. In cancer cells, chromosomes are scrambled. Mr. Duesberg suggests these chromosomal disruptions unbalance the way thousands of genes regulate cell function and reproduction, eventually leading to cancerous cells.

The chromosome hypothesis avoids some difficulties with the gene theory of cancer, Mr. Duesberg says. Some of the most potent carcinogens, like asbestos or tar, don’t cause genetic mutations. But the chromosomes of cells treated with cancer-causing doses of carcinogens become unstable. Few children get cancer, but Mr. Duesberg notes that the rare cases of those who do also suffer from or are susceptible to chromosomal abnormalities. — Robin Moroney
Permalink | Trackback URL: http://blogs.wsj.com/informedreader/2007/04/16/a-cancer-theory-from-a-controversial-scientist/trackback/

For additional understanding of the value of Duesberg’s approach – and the scientific weakness of the oncogene paradigm which has ruled for nearly three decades in cancer research – see Harvey Bialy’s book, “Oncogenes, Aneuploidy and AIDS: A Scientific Life and Times of Peter H. Duesberg” (North Atlantic Book, 2004).

Then you can have fun reading and dissecting the blog critique, which task Dr Bialy, Duesberg’s sharp witted champion in this as well as in the soggy science of HIV∫AIDS, says is beneath him, according to a recent communication referring to “gibberish read only by pod people”. It is hard not to agree with him.

It is also hard to stomach the demons of illwill and disrespect let loose by the witchcraft of the Web and attached to every comment by “Adele” and other witless riders of Orac’s self-confessedly “insolent” coat tails, or those of epidemiologist Tara Smith, the svelte bathing beauty and blogging genius also at Science Blogs to whom Duesberg’s errors are also transparent at first glance. It is amazing that knowledgeable posters such as Ky Sanderson are prepared to punt in this verbal sewer, where they have as little effect trying to correct the prejudices of the lynch mob as pouring a single bottle of Listerine into the subterranean tunnels of waste disposal under Manhattan.

Here is the self-description of the blogger:

Who (or what) is Orac?

Orac is the nom de blog of a humble pseudonymous surgeon/scientist with an ego just big enough to delude himself that someone, somewhere might actually give a rodent’s posterior about his miscellaneous verbal meanderings, but just barely small enough to admit to himself that few will. (Continued here)
…I’m not only a cancer surgeon (which in and of itself is not enough to qualify me to comment on this topic) but rather because I’m also a cancer researcher and a molecular biologist (which, I submit, does make me qualified to comment on this topic).

This is the well qualified fellow who now has the effrontery to decorate his text in his long post with the following prejudicial statements (errors in bold) about Duesberg’s incorrectness (as he sees it) on HIV∫AIDS”, reminding us that one of the many crosses the distinguished Berkeley professor has had to bear in trying to enlighten the elite as to the scientific three card monte shuffle perpetrated upon them for 22 years by Robert Gallo, Anthony Fauci and now John Moore is the smug prejudice of the lay defenders of the faith, who intuitively know that he is wrong even though his many hostile peer reviewers were by definition unable to show it:

Peter Duesberg, as you may know, is the controversial scientist who is perhaps the foremost advocate of the discredited hypothesis that HIV does not cause AIDS.

(A rhetorical statement) “The one that first comes to mind as particularly relevant to Peter and AIDS is that it does seem impossible that a man who is clearly so utterly wrong concerning something as now scientifically straightforward as whether AIDS is caused by HIV could actually be correct about something as complex as the genetic basis of malignancy.”

Yet they 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

I do not plan on discussing why Duesberg’s ideas regarding HIV are wrong, even though the results of such HIV/AIDS denialism leads to quackery and has serious real-world consequences for real people. Tara and Nick have done far more than my minor efforts to critically examine such wingnuttery.

I think Duesberg’s an utter crank and pseudoscientist when it comes to his HIV/AIDS denialism,

Clearly, this is a man in whose brain the AIDS meme has taken up residence and cuckoo-like, has kicked out any semblance of openmindedness on that score, and so probably one who appoaches Duesberg’s new ideas with equal lack of self assessment.

That characteristic is always the most amazing attribute of the host of otherwise intelligent, combative and self promoting bloggers that have mushroomed with the advent of the Web. Why is it that they never turn their critical eye on themselves and their own thinking? Self-editing is not the greatest talent of Orac, that’s for sure. Does he not consider that if in his view Duesberg’s hypothesis is “argued poorly”, it may be his own understanding which is lacking? After all, it has been Duesberg’s career interest and project for many years, and if it has made headway against so much prejudice against him it must make very good sense.

But Orac is such a clogged thinker himself that it may be he is simply confused. For example, he says “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. ” Here he seems unable to grasp the point, which is not that the two fields are closely related but that Duesberg is a very good mind in science, one of the best in the business. who has initiated two fashionable fields of research.

Similarly, he writes that

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.

without seeming to think of the possibility that without Duesberg’s pathbreaking efforts over many years the dominant paradigm (cancer through individual gene mutation) would reign on undisturbed, and that he has every reason to take credit that it is now a hot topic.

It is by now abundantly clear that Orac’s research methods lean heavily on the “Ask John” approach.

However, he begins with a nice enough statement of the core idea of aneuploidy – excess chromosomes in the cell – and its history starting with Boveri and sea urchins.

It has been known for many many decades that most cancer cells are aneuploid. This means that, instead of having the correct number of chromosomes (in the human, 46 chromosomes, two matched sets of 22, plus the sex chromosomes, either XX or XY). In some diseases, such as Down syndrome (known as trisomy-21), there are either missing or extra chromosomes. In the case of Down syndrome, there is a third copy of chromosome 21. Such abnormal chromosomal numbers come about when, during meisosis (cell division that produce germ cells), the newly copied chromosomes don’t segregate properly to the two daughter cells, one to each. Instead, both go to one or the other cell. In cancer cells, the situation is much worse; such missegregation during mitosis can lead to aneuploidy that is much more severe, to the point where some cancer cells can have 70 chromosomes or more. Because certain genetic mutations, for example in DNA damage repair genes, can lead to chromosomal instability that can in turn lead to aneuploidy, the basic argument has been over the relative importance of the roles of aneuploidy and the accumulation of genetic mutations as leading to cancer. 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.

This is an introduction to a post which in theme is presumably the product of Orac’s “Ask John” research, where he has checked with anyone around in the hospital who might know to find out what the current paradigm’s cancer research is all about. Anyone who has read “Oncogenes, Aneuploidy and AIDS” knows what kind of briefing he has received. Leading scientists in the field are desperate to make sure that even if aneuploidy continues to prove out as a productive field it won’t replace the oncogenes paradigm they have invested in for three decades.

Now master blogger Orac sounds the same theme: aneuploidy is “intriguing” and may even be “primary” but let’s allow oncogenes to keep their place on the stage also. Never mind that Duesberg – who founded the field of oncogenes, no less, when he discovered the first example of a cancer causing gene in the Rous sarcoma virus – has always rejected that paradigm as well the HIV∫AIDS story as unsound, and Orac doesn’t seem to know why.

The concept that aneuploidy may play a major and, in some cases, primary role in carcinogenesis is a legitimate scientific idea with scientific evidence to support it. It doesn’t need to be defended or argued using such bad arguments, but Duesberg can’t seem to help himself. The problem is, Duesberg’s thinking is black-and-white, all-or-nothing. He can’t seem to fathom the concept that both aneuploidy and genetic mutations might feed upon each other. In addition, he also almost totally neglects other evidence implicating other causes or important factors in the progression of cancer, such as cancer stem cells, tumor angiogenesis, or even the metabolic hypothesis ( i.e., the Warburg effect), which, like the chromosomal hypothesis, is also enjoying a resurgence. Cancer is a complex set of diseases, likely with multiple causes contributing to the development of different cancers in different proportions, which is why my skeptical antennae start twitching whenever I hear someone like Duesberg (or anyone else, for that matter) postulate in essence a single cause for all cancer.

Still, he is obviously persuaded persuaded that Duesberg’s approach is productive, even if he spends much time emphasizing that Duesberg didn’t think of it first:

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

All in all, not too disrespectful a treatment, and a useful collection of possible objections to aneuploidy that will come from the blog world. There are endless jabs at the supposed idiocy of one of the world’s great scientists for flouting the assumption of the blogger that HIV∫AIDS must be as valid as its global support indicates. But these don’t erase the new if split respect that Orac seems to have for Duesberg now that the Scientific American has endorsed aneuploidy and him in this fashion.

The Comments that follow include a priceless articulation of the hostile prejudice against Duesberg that now sprinkles the floor of the Web forest like toadstools:

I agree with you, this almost seems to be a presage to even more crankery from Duesberg. I can just see that as time goes on and this hypothesis is balanced out by other findings that show every cancer can’t simply be housed under the umbrella of aneuploidy if he’ll once again just dig in and refuse to accept evolving facts. When Duesberg suggested that HIV causing AIDS was based on mostly correlative evidence in 1987 (and Science published it), he kind of had a point. It wasn’t a particularly good, or useful point, but within the year there was excellent evidence from studies of AZT, as well as responses to Duesberg’s criticisms that really should have had those ideas tossed, and certainly by about 1993 or so the science was settled. These days given what we know about the HIV proteins, mechanisms of latency and entry in CD4 cells, it’s frankly just embarrassing he didn’t give up decades ago, I wonder if he’ll do the same here if things don’t turn out his way.

I will continue to disagree, however, that this wasn’t a mistake for Sci Am. I believe in the scientific death sentence – that is, if you are proven untrustworthy, you shouldn’t be allowed to contribute to the literature anymore. So what if he’s changed fields, he demonstrated himself to be a dishonest crank so badly and for so long why should we risk the literature with contributions from this guy? I don’t find his so-called dissident status cute or funny, it results in bad science, bad policy and ultimately death as these bizarre ideas take hold in Africa (especially S. Africa) and even in the United States as with the HARM people. I’m all for the black list for cranks too because I believe cranks are fundamentally deceptive and untrustworthy contributors to scientific debate, and all of his subsequent (thankfully rejected) internet publications on HIV/AIDS are really just a pack of lies.

I simply wouldn’t trust this guy again, ever.

Posted by: Mark | April 25, 2007 03:50 PM

Established publications used to keep this kind of rant out of the letters column, but now we see it given permanent form on the servers of the Web, rather like a madman used to have to work very hard to get hold of a weapon, but now a Mr Cho can kill 32 people with a Glock bought at a sports store.

One always wonders what the writer – Mark, in this case – will feel when he is older, and Duesberg is vindicated, but his juvenile post is still cached by Google for all his grandchildren to see,

(Orac’s post)

Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly

Category: Cancer • Medicine • Science • Skepticism/critical thinking
Posted on: April 25, 2007 9:01 AM, by Orac

A lot of readers (well, a couple, anyway) have been asking me about the recent article by Peter Duesberg in the most recent issue of Scientific American entitled Chromosomal Chaos and Cancer. I suppose it’s because I’m not only a cancer surgeon (which in and of itself is not enough to qualify me to comment on this topic) but rather because I’m also a cancer researcher and a molecular biologist (which, I submit, does make me qualified to comment on this topic). Peter Duesberg, as you may know, is the controversial scientist who is perhaps the foremost advocate of the discredited hypothesis that HIV does not cause AIDS. I had been tempted to comment on Dueseberg’s hypothesis based on the orgasmic reaction of Duesberg’s sycophants in the HIV/AIDS “dissident” community to the recent publication of an article on it by Duesberg in Scientific American. One such booster, even went so far as to say:

The one that first comes to mind as particularly relevant to Peter and AIDS is that it does seem impossible that a man who might just be correct concerning something as complicated as the genetic basis of malignancy could be so totally wrong about something as straightforward as whether HIV kills T-cells.

This is perhaps the dumbest thing I’ve heard said about evaluating Duesberg’s aneuploidy hypothesis of cancer. To demonstrate why, let me recast the question a bit to: “The one that first comes to mind as particularly relevant to Peter and AIDS is that it does seem impossible that a man who is clearly so utterly wrong concerning something as now scientifically straightforward as whether AIDS is caused by HIV could actually be correct about something as complex as the genetic basis of malignancy.”

HIV/AIDS denialists would be screaming bloody murder about such a question were I to pose it as anything other than a rhetorical device, and they would have a point to some extent. Yet they 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. That is why I do not plan on discussing why Duesberg’s ideas regarding HIV are wrong, even though the results of such HIV/AIDS denialism leads to quackery and has serious real-world consequences for real people. Tara and Nick have done far more than my minor efforts to critically examine such wingnuttery. Instead, I decided simply to ask the question about Duesberg’s chromosomal chaos hypothesis as the cause of cancer and ask: Is there any “there” there? It’s a question I’ve asked myself before but never written about, and this seemed like an opportune time to discuss the issue.

The first thing that struck me about the Scientific American article is that it looked very much like a popular version of two very similar recent review/opinion articles that Duesberg published in 2005 and 2006. I’m mainly going to discuss the Scientific American article because it’s basically the same message in a form more palatable to the educated lay reader. But, before I begin, I’d like to point out a couple of things. 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.

It has been known for many many decades that most cancer cells are aneuploid. This means that, instead of having the correct number of chromosomes (in the human, 46 chromosomes, two matched sets of 22, plus the sex chromosomes, either XX or XY). In some diseases, such as Down syndrome (known as trisomy-21), there are either missing or extra chromosomes. In the case of Down syndrome, there is a third copy of chromosome 21. Such abnormal chromosomal numbers come about when, during meisosis (cell division that produce germ cells), the newly copied chromosomes don’t segregate properly to the two daughter cells, one to each. Instead, both go to one or the other cell. In cancer cells, the situation is much worse; such missegregation during mitosis can lead to aneuploidy that is much more severe, to the point where some cancer cells can have 70 chromosomes or more. Because certain genetic mutations, for example in DNA damage repair genes, can lead to chromosomal instability that can in turn lead to aneuploidy, the basic argument has been over the relative importance of the roles of aneuploidy and the accumulation of genetic mutations as leading to cancer. 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?

Unfortunately, although he describes how tumors evolve under the selective pressures of the organs in which they arise, acquiring the ability to proliferate, evade apoptosis, become insensitive to normal growth arrest signals, and metastasize, Duesberg seems unable to restrain himself from overselling his case and lapsing into straw men arguments about rival hypotheses. He’s very frustrating that way. The concept that aneuploidy may play a major and, in some cases, primary role in carcinogenesis is a legitimate scientific idea with scientific evidence to support it. It doesn’t need to be defended or argued using such bad arguments, but Duesberg can’t seem to help himself. The problem is, Duesberg’s thinking is black-and-white, all-or-nothing. He can’t seem to fathom the concept that both aneuploidy and genetic mutations might feed upon each other. In addition, he also almost totally neglects other evidence implicating other causes or important factors in the progression of cancer, such as cancer stem cells, tumor angiogenesis, or even the metabolic hypothesis ( i.e., the Warburg effect), which, like the chromosomal hypothesis, is also enjoying a resurgence. Cancer is a complex set of diseases, likely with multiple causes contributing to the development of different cancers in different proportions, which is why my skeptical antennae start twitching whenever I hear someone like Duesberg (or anyone else, for that matter) postulate in essence a single cause for all cancer.

Let’s look at what Duesberg argues. 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.
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Grrlscientist has posted a concise summary of Duesberg’s arguments here, and Hank Barnes has a copy here. (I’m guessing that Duesberg or Harvey Bialy gave him the PDF.)

So, here we have a scientific hypothesis with a moderate degree of plausibility based on what we know. What arguments can Duesberg marshal in its favor? Disappointingly, most of his arguments leave much to be desired. Let’s start with Duesberg’s first argument, which is so bad that it needs to be quoted extensively to be appreciated:

Cancer risk grows 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. If, as that hypothesis holds, about half a dozen mutations to critical genes were necessary to ignite malignancy, certainly some of those mutations would accumulate like SNPs over the course of generations in the genomes of many individuals. A baby could thus inherit three of six hypothetical colon cancer mutations from her mother, for example, and two from her father and be at extremely high risk of cancer from picking up the missing sixth mutation in any one of her billions of colon cells. Some babies might even be born with colon cancer from inheriting all six hypothetical colon cancer mutations from their parents. But colon cancer is never seen in children. Indeed, even laboratory mice intentionally engineered to carry an assortment of ostensibly carcinogenic mutations from birth can live and propagate happily, with no higher risk of developing tumors than normal lab mice.

[…]

Interestingly, among the rare exceptions to cancer’s age bias are children with congenital aneuploidy, as in Down syndrome, or with inherited chromosome instability syndromes, such as the disease known as mosaic variegated aneuploidy (MVA), which also causes severe mental retardation. Defects of mitotic spindle assembly in the cells of children with MVA produce random aneuploidies throughout their bodies, and nearly one third develop leukemia or unusual solid cancers.

Being born aneuploid, or prone to aneuploidy, clearly accelerates processes that lead to cancer. Indeed, the inherent instability of aneuploid cells would explain why most aneuploid embryos, as Boveri observed 100 years ago, would not be viable at all and thus why newborns are cancer-free and cancer is not heritable.

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. Quite frankly, I don’t know what Duesberg was smoking when he wrote that and don’t see his rationale for arguing that. For one thing, it’s not true that colon cancer is never seen in children. It’s quite rare, to be sure, but in families with genetic mutations that predispose to colon cancer, the disease can appear in children as young as 5 or 6. I presume that Duesberg picked colon cancer because the genetic sequence of mutations that occur as the lining of the colon goes from dysplasia, to polyps, to noninvasive cancer, to invasive cancer was worked out so elegantly by Burt Vogelstein back in the early 1990’s. In addition, it is true that patients with Down syndrome are more susceptible to certain cancers, specifically hematopoietic (blood) cancers, but it also turns out that they are less susceptible to solid tumors, thanks to high levels of the antiangiogenic factor endostatin, the gene for the precursor of which happens to reside on chromosome 21 and is expressed at a higher level because there are three copies rather than two. Second, Duesberg neglects to notice that oncogenes and tumor suppressors cause dysregulated growth and morphogenesis, the sine qua non of cancer. Although it is true that deleting some tumor suppressors results in viable mice who appear normal other than a predisposition to cancer, such potent growth dysregulation could cause embryonic lethality just as easily as aneuploidy could, depending on the specific gene.

Indeed, although it’s not as obvious, Duesberg’s making in essence the same mistake as Dr. Egnor: confusing selective mechanisms in germ line cells with those in somatic cells. A basic consideration of evolutionary theory makes it obvious that there would be major selective pressure against mutations that result in cancer in babies and children, because the cancer would kill the child before reproductive age. In contrast, cancer-predisposing genes that are either neutral before reproductive age or confer some advantage (as has been postulated, for example, for some mutations in the BRCA1 gene, which predisposes to breast cancer), may not be selected against and could remain in the germline at a high frequency in the population. Thus, from a strictly evolutionary perspective, it is not at all surprising that inherited cancers are rare in newborns and young children, even if we postulate, for the sake of this argument, that aneuploidy has nothing to do with cancer and the “genetic mutation theory” of cancer is 100% correct. Duesberg should know this, given his invocation of selective pressures leading to increased aneuploidy in cancer.

Finally, Duesberg tries to argue that mutations don’t occur at a sufficient frequency under normal conditions to account for the increasing rate of cancer with age, but does not address the shortening of telomeres or that it may only take one or two mutations in key genes, such as those involved in DNA damage repair, to make the a single cell deficient in repairing its own DNA, which can then lead to an increased mutation rate, leading both to mutations and increased aneuploidy. Indeed, it has been postulated that the prerequisite for some cancers is what is termed a “mutator phenotype,” in which a much higher rate of mutation is observed. In any case, aneuploidy is easier to detect than mutations, assays for which can only look at a small fraction of the genome at one time and are not sensitive enough to detect mutated cells in a background of normal cells. In contrast, small numbers of aneuploid cells can be detected in a normal background. The bottom line is that chromosomal instability is a feature of virtually all cancers but the evidence that it is driven by primarily aneuploidy is conflicting and nowhere near the slam dunk that Duesberg seems to think; in essence, it’s unclear whether it is primarily aneuploidy that drives mutation or primarily mutation that leads to aneuploidy.

Here’s the next bad argument:

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. A gene mutation scenario therefore does not explain why cells exposed to carcinogenic agents become cancer cells…

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. It may ultimately be shown experimentally to be true that aneuploidy is a better explanation for the long latency period of human cancers, but there is nothing in the mutation theory that demands that there must be a short latency period after a tumor cell is exposed to a carcinogenic agent, especially since it is now understood that “multiple hits” are usually required occurring in a single cell to result in cancer.

Here’s the next Duesberg argument:

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. In all cases, however, the chromosomes of cells treated with cancer-causing doses of carcinogens were unstable–that is, displaying higher than usual rates of breakage and disruption.

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. For example, part of the mechanism by which asbestos is thought to cause cancer is by causing chronic inflammation, which chronically stimulates nearby cells to divide, while at the same time exposing them to a milieu containing numerous inflammatory cytokines secreted by white blood cells that invade the area. In the case of dioxin, for example, there appears to be a receptor to which dioxin binds that stimulates cell survival pathways. Either of these mechanisms, and others, could be at play in the carcinogenesis due compounds that do not cause extensive DNA damage and could account for the long latency period between exposure to carcinogen and cancer.

The rest of Duesberg’s arguments range from the “so what?” to the more intriguing. For example, he points out that different patterns of aneuploidy are seen in different tumors. Given the known genetic heterogeneity of cancers, this is not at all surprising and doesn’t necessarily mean that aneuploidy is the primary cause of cancer. For example, the Philadelphia chromosome, the result of a reciprocal translocation, an exchange of genetic material, between chromosomes 9 and 22. It is very common, virtually pathognomonic for chronic myelogenous leukemia. This is associated with the excessive production of an oncogene (Bcr-Abl), which activates cell cycle genes and induces genomic instability. Certainly, there must be some sort of aspect to the structure of these two chromosomes that make this particular translocation as common as it is, but the end result that drives CML is a mutation that results in the excessive production of an oncogene. Indeed, molecularly targeting this oncogene has resulted in a very effective drug against CML called Gleevec. In fact, targeting single gene abnormalities, although it hasn’t resulted in a cure for cancer, has resulted in several very effective treatments, such as Herceptin, which is directed against the Her-2/neu oncogene. Finally, lots of single gene mutations in transcription factors, DNA repair enzymes, or cell signaling molecules can alter the expression of dozens or hundreds of downstream (or even thousands) of genes in predictable ways. Large scale chromosomal breaks are not necessary to account for such globally deranged gene expression.

Duesberg next argues that “gratuitous traits do not contribute to cancer survival,” referring specifically to genes for metastasis and drug resistance, oddly enough. The problem with this argument is that a subset of the genes for carcinogenesis are not infrequently also genes involved in metastasis. Similarly, genes involved in drug resistance often have other functions than just drug resistance. For example, the mdr1 multidrug resistance gene product is an ATP-dependent channel that extrudes a variety of substances, not just chemotherapeutic agents, from a cell, an excellent example of how evolution can coopt the function of an existing protein to do another function. Finally, Duesberg appeals to the ability of cancer cells to change their phenotype rapidly, supposedly much faster than genes can mutate. This may indeed be true, and it may indeed be possible that aneuploidy contributes to this, given its ability to cause wholesale rearrangements of chromosomes and hundreds (or even thousands) of genes in one fell swoop. However, all it takes is selection by drug for tumor cells that express ever-increasing amounts of mdr1; chromosomal rearrangements, although they certainly may contribute to drug resistance, do not appear to be strictly necessary for it. Moreover, once again, Duesberg cannot resist overselling his case:

Once this vicious cycle is under way, the fact that every cell would be randomly generating its own new phenotypes could explain an observation made decades ago by Leslie Foulds of the Royal Cancer Hospital in London that “no two tumors are exactly alike … even when they originate from the same tissue … and have been induced experimentally in the same way.” Such individuality is yet another hallmark of cancer that cannot be explained by the activity or inactivity of specific genes, which would be expected to have consistent effects each time and in each cell.

The problem with this argument is that it’s only partially correct. Using the “gene chip,” which now allows scientists to assay the levels of every gene in the human genome at the same time, we now know that tumors often have a surprisingly similar pattern of expression of thousands of genes. Indeed, one of the most startling findings early in the use of such gene chips was that nearly all breast cancer could be divided on the basis of gene chip experiments into a small number of distinct subtypes, the main ones of which include the “basal” (more aggressive) or “luminal” (less aggressive) phenotype. Moreover, the expression of the Her-2/neu oncogene leads to a distinct, identifiable, reproducible gene expression pattern, in direct contradiction to Duesberg’s claims above. Indeed, tests based on such gene chips are already making their way into the clinic to estimate a patient’s risk of recurrence and guide chemotherapy decisions.

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. However, contrary to how Duesberg’s sycophants like to portray the chromosomal hypothesis of cancer as an epic battle that’s all about Duesberg, who is portrayed as the lone voice arguing for the hypothesis that aneuploidy is the cause of cancer, in reality it’s nothing more than yet another scientific controversy that is, fortunately, no more nasty than a lot of other controversies in science, such as, for example, the hypothesis that changes in cell metabolism are the cause of, not a consequence of, carcinogenesis. It’s also nowhere near as clear as Duesberg claims whether aneuploidy is a cause or a consequence of carcinogenesis. For one thing, there are at least two examples that I’m aware of (which means there are probably more than that) of groups generating tumor cells that do not have significant or widespread aneuploidy, demonstrating that aneuploidy may not be a prerequisite for carcinogenesis, in direct conflict with Duesberg’s hypothesis. In addition, there’s a very interesting article from Don Cleveland’s lab in the January Cancer Cell that suggests that aneuploidy can promote carcinogenesis under some circumstances (an observation that seems supportive of Duesberg’s hypothesis) and act as a tumor suppressor under others (an observation that is arguably not).

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.

Duesberg’s supporters may look at the relative neglect of chromosomal structure as a controller of gene expression and a potential cause of cancer and wonder why it was neglected for so long. The analogy I like to make is to politics. It is said that politics is the art of the possible. To me, science is the study of what it is possible to study. Two to three decades ago, we figured out how to study individual genes; so that’s what we studied, even though we soon realized that such reductionist techniques did not give the complete picture of cancer. Less than 10 years ago, gene chips, coupled with improvements in statistical analysis and increases in computing power that made it possible to analyze the data produced from such huge experiments, allowed us to look at the expression of the entire genome at once, leading to a richer understanding of the changes in gene expression that occur during cancer. The more sophisticated techniques and understanding did not invalidate what we had learned before; it complemented and extended it. Similarly, we now have the tools to probe chromatin structure at a level of detail never before possible; consequently we are now looking at chromatin structure in cancer. Our increasing ability to probe the detailed structure of chromosomes will likely now complement and extend what we have learned about cancer through the study of mutations in individual genes. Walter Giaretti asks:

…I would like to pose the question if the “aneuploidy theory” of cancer in relationship with the “mutation theory” still remains as controversial as in the near past. Don’t we have now enough experimental evidence that cancer originates and progresses with the contribution of both gene mutations and aneuploidy?

Duesberg’s failure is that he doesn’t seem willing to accept that the answer to this question is almost certainly “yes.” As Giaretti puts it:

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.

There are indeed deficiencies in our current understanding of cancer initiation and progression, but there’s no reason that gene mutations and aneuploidy couldn’t both contribute to these processes. Indeed, I’d be surprised if it were otherwise. Duesberg seems too dogmatic and wedded to his hypothesis to see the big picture.

(TrackBack URL for this entry: http://scienceblogs.com/mt/pings/38968)
* Ky Sanderson on Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
* Kristjan Wager on Wiley & Sons: When “fair use” equals “no use”
* Mustafa Mond, FCD on “Woo-omics” at NCCAM
* Dale on Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
* TheProbe on Wiley & Sons: When “fair use” equals “no use”
* Ky Sanderson on Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
* Orac on Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
* Adele on Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
* ordinarygirl on Ever wonder what happened to Roger Ebert?
* Luna_the_cat on Who perpetrated the “Holohoax”? Tell us!

Comments

Just how central is Duesberg to the latest research in aneuploidy and cancer. I read Bialy whining somewhere that Duesberg was not cited in a recent review of aneuploidy and cancer. I get the impression that Duesberg (or at least Bialy) is overselling his role. Certainly Duesberg’s sycophants seem to believe that Duesberg is the centre of the world.

The one thing that Duesberg is doing that others aren’t is taking an extreme position.

Posted by: Chris Noble | April 25, 2007 10:43 AM

Gene mutations, aneuploidy, epigenetic processes, tumor environment and anything else that alters gene expression. Duesberg is far too dogmatic.

The cynic in me thinks that flogging Duesberg’s role in popularizing interest in the role of aneuploidy in cancer may just be a way of drumming up business for this company that he, Bialy and Rasnick are associated with that is marketing or attempting to market this Anucyte cancer detection system? http://www.primenewswire.com/newsroom/news.html?d=112649

Posted by: Dale | April 25, 2007 11:10 AM

Isn’t Down syndrome due to a non-disjunction event in the second meiotic division, not mitosis? In that sense, it’s different than aneuploid cancer lineages which arise due to mitotic non-disjunction.

I may have missed this, but is the main chromosomal abnormality in Duesberg’s article aneuploidy? What about other aberrations (fusions, translocations, inversions, duplications, deletions, etc)? Aren’t there a lot of cancers associated with chromosomal defects other than aneuploidy?

Posted by: RPM | April 25, 2007 12:50 PM

Retinoblastoma.

Posted by: mark | April 25, 2007 01:16 PM

Not to be too cryptic, but as far as kids not getting cancer? Nope.

As far as chromosomal defects yes. In particular, it’s not the aneuploidy of a huge number of translocations seen in leukemias and lymphomas but the creation of fusion genes and inappropriately expressed genes from the transformation (a promiscuous promoter driving an oncogene for instance) that results in specific types of cancer.

Orac is right. Duesberg is being to simplistic and rigid.

Posted by: mark | April 25, 2007 01:22 PM

Acute promyelocytic leukemia.

The majority of cases of acute myelogenous leukemia.

Posted by: Abel Pharmboy | April 25, 2007 01:34 PM

sn’t Down syndrome due to a non-disjunction event in the second meiotic division, not mitosis? In that sense, it’s different than aneuploid cancer lineages which arise due to mitotic non-disjunction.

Fixed.

In these epic posts, the occasional screwup does occur. Mea culpa. It’s kind of like the scene in Animal House:

Bluto: Over? Did you say “over”? Nothing is over until we decide it is! Was it over when the Germans bombed Pearl Harbor? Hell no!

Otter: Germans?

Boon: Forget it, he’s on a roll.

I was on a roll.

Posted by: Orac | April 25, 2007 01:47 PM

Orac,

Thanks for a typically smart and insightful criticism of Duesberg’s article, not to mention an admirably reasonable reaction to the fact of Duesberg’s authorship.

At the risk of seeming unappreciative: Scientific American’s lawyers do usually frown on the use of its graphics without permission–strictly speaking, it isn’t a violation of our rights so much as it is of the artist’s. I don’t think she’d mind in this case, but can I offer a shout of appreciation to the terrific Jen Christiansen, who drew that illustration?

Posted by: John Rennie | April 25, 2007 03:18 PM

Finally got to read the whole thing, it was a bit epic.

I agree with you, this almost seems to be a presage to even more crankery from Duesberg. I can just see that as time goes on and this hypothesis is balanced out by other findings that show every cancer can’t simply be housed under the umbrella of aneuploidy if he’ll once again just dig in and refuse to accept evolving facts. When Duesberg suggested that HIV causing AIDS was based on mostly correlative evidence in 1987 (and Science published it), he kind of had a point. It wasn’t a particularly good, or useful point, but within the year there was excellent evidence from studies of AZT, as well as responses to Duesberg’s criticisms that really should have had those ideas tossed, and certainly by about 1993 or so the science was settled. These days given what we know about the HIV proteins, mechanisms of latency and entry in CD4 cells, it’s frankly just embarrassing he didn’t give up decades ago, I wonder if he’ll do the same here if things don’t turn out his way.

I will continue to disagree, however, that this wasn’t a mistake for Sci Am. I believe in the scientific death sentence – that is, if you are proven untrustworthy, you shouldn’t be allowed to contribute to the literature anymore. So what if he’s changed fields, he demonstrated himself to be a dishonest crank so badly and for so long why should we risk the literature with contributions from this guy? I don’t find his so-called dissident status cute or funny, it results in bad science, bad policy and ultimately death as these bizarre ideas take hold in Africa (especially S. Africa) and even in the United States as with the HARM people. I’m all for the black list for cranks too because I believe cranks are fundamentally deceptive and untrustworthy contributors to scientific debate, and all of his subsequent (thankfully rejected) internet publications on HIV/AIDS are really just a pack of lies.

I simply wouldn’t trust this guy again, ever.

Posted by: Mark | April 25, 2007 03:50 PM

John Rennie,

I salute you, Sir, for publishing the article by Dr. Peter Duesberg on aneuploidy and cancer. His hypothesis is clearly testable: produce a diploid tumor, somewhere, somehow.

I disagree, though, that Orac’s criticism is “smart” or “insightful.” Rather, it is a mess. It could never be published anywhere — he intersperses irrelevant issues (Egnor and creationism), spends half the time talking about Duesberg and his supporters, carping on strawman HIV issues, and in typical verbose fashion misses the import of the issue.

Cancer kills over 500,000 Americans each year. Most families have lost a loved one to cancer. Aside from the success in lung cancer (smoking reduction) and some leukemias (a few new drugs), cancer prevalence rates haven’t budged since the 1950s.

So, what clinical benefits or societal benefits has the “oncogene” theory of cancer produced in nearly 40 years? I submit –zero.

That’s why the Duesberg article is important — old wine in a new bottle as Nature Biotechnology once wrote.

Let’s not lose sight of the objective — to cure cancer. To cure something, one has to properly determine its cause. Since aneuploidy, apparently, is found in every solid tumor, it certainly must be explained — not explained away as Orac in typical smarmy fashion seeks to do.

Posted by: Ky Sanderson | April 25, 2007 04:10 PM

Sanderson, you nut-job, why not read what Orac wrote before you piss on it? Then you would know that Orac doesn’t explain away aneuploidy at all. He actually supports Duesberg on this one.
You might also learn something about cancer. Like about Herceptin and Gleevec, drugs that wouldn’t work at all if there weren’t some truth to the oncogene hypothesis.
Why don’t you go and hang out with your three denialist friends. Maybe you can teach each other how to read.

Posted by: Adele | April 25, 2007 04:43 PM

In my opinion, what has driven interest in the role of genomic instability and aneuploidy in cancer isn’t Duesberg but the technological advances of the early 90s (like fluorescent in situ hybridization) that have enabled investigators to examine ploidy in tumors in far more detail than was possible prior to the 90s. Also my opinion – aneuploidy and mutations both contribute to cancer but aneuploidy is more obvious in tumors than mutations are because it’s easier to detect.

Posted by: Dale | April 25, 2007 05:10 PM

I’m not sure what the fine print of the “fair use” law says, but I really feel that Orac is ripping SciAm off a bit here. From my vantage point, I’d fully support a recommendation from SciAm that Orac remove the pictures in this blog. They go beyond fair use, unless Orac’s post was along the lines of “SciAm used artwork which gives a misleading impression…” (that is, the pictures were a cornerstone of the point Orac was making).

I think that a more appropriate treatement from Orac would be a summary of the article with perhaps a selected quote or two, and a comment along the lines of “the ideas are very elegantly presented in artwork accompanying the SciAm article” (with a link to the paid-for article).

Posted by: Kevin | April 25, 2007 05:16 PM

Sadly typical of Duesberg. Can’t accept that the concept isn’t exactly novel, can’t accept that other theories have validity, can’t accept supporting role instead of leading man.

Posted by: Robster, FCD | April 25, 2007 06:06 PM

Dear Dr.

For a different view of cancer, you might want to see the article shown on the cover of The American Journal of Pathology in this month’s MAY issue. (http://ajp.amjpathol.org/) (Tone Sandal, Klara Valyi-Nagy, Virginia A. Spencer, Robert Folberg, Mina J. Bissell, and Andrew J. Maniotis.

Epigenetic Reversion of Breast Carcinoma Phenotype Is Accompanied by Changes in DNA Sequestration as Measured by AluI Restriction Enzyme. Am J Pathol 2007 170: 1739-1749.) I’ll send you the entire PDF if you send me an address where I can email it.

I read your assessment of Peter’s SCi Am. article on aneuploidy, and agree with you about the excitement regarding the renaissance of global changes in higher order structure, and cancer, that similar to aneuploidy, involve entire genomic structural changes. You might want to look at what others as well as I have written regarding this issue of “mechanogenomics,” as I called it.

Stein GS.Am J Pathol. Mechanogenomic control of DNA exposure and sequestration. 2005 Apr;166(4):959-62.

Maniotis AJ, Valyi-Nagy K, Karavitis J, Moses J, Boddipali V, Wang Y, Nuñez R, Setty S, Arbieva Z, Bissell MJ, and Folberg R: Chromatin organization measured by Alu I restriction enzyme changes with malignancy and is regulated by the extracellular matrix and the cytoskeleton. Am J Pathol 166: No. 4 April 2005.

Folberg R, Arbieva Z, Moses J, Hayee A, Sandal T, Kadkol S, Lin AY, Valyi-Nagy K, Setty S, Leach L, Chevez-Barrios P, Larsen P, Majumdar D, Pe’er J, Maniotis AJ.
Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns. Am J Pathol. Oct;169(4):1376-89, 2006.

Valyi-Nagy K., Folberg R., Valyi-Nagy T. Andrew Maniotis. Role of tumor invasiveness, the extracellular matrix, and chromatin sequestration in the susceptibility of uveal melanoma to herpes simplex virus type 1. Experimental Eye Research 84 (2007) 991-1000.

Mechnogenomic control of DNA exposure and sequestration.

Drawings from 100 years ago of Galeoti’s, Hertwig’s, and Hanseman’s comparisons of cancer cell and normal cell chromosomes illustrated gross differences in chromatin structure and chromosome numbers in human tissue harboring a tumor (1). But how higher order chromatin structure is controlled and maintained by the cancer cell and its microenvironment has remained beyond our reach. The work presented by Maniotis et al. in this issue presents new data that shows there are striking differences in restriction enzyme sensitivity between tumor cell and normal cell genomes. The work shows in addition, that these differences depend upon chromatin-associated proteins rich in disulfide bonds, specific molecules present in the extracellular matrix (ECM) environment, and the cytoskeleton, whose organization permits or impedes sequestration and exposure of specific sites along DNA. The work advances the idea that the mechanical contiguity of these components may work in concert to form a cytoarchitectural resistance mechanism that may constitute a basis for a paradigm shift in both the contexts of normal cellular physiology, and in cancer.

It had been established by a previous generation of tumor biologists using DNase digestions and nick-end labeling techniques, that in order for a gene to become expressed, it had to be “exposed.” Moreover, Puck et al., (2) had shown that transformed tumor cells that were “reverse transformed” to a normal phenotype with various chemical compounds exhibited a shift in their nuclei’s sensitivity to DNAase I, and also exhibited changes in cell shape and cytoskeletal organization.

Maniotis et al. in this issue show data that compared the extent of exposure or sequestration of a well-characterized collection of highly invasive, poorly invasive, and normal human cell genomes to specific restriction enzymes. Restriction enzyme digests on intact genomes untreated with other chemical agents showed that Alu I and Msp I both could distinguish normal cells from tumor cells of different degrees of invasiveness. Highly invasive cell nuclei always resisted digestion with these enzymes compared to poorly invasive or normal cells. Also, through comparisons of mitotic chromosomes microsurgically extracted as complete genomes (3,4), with interphase nuclei from the same cell types, differences in chromatin digestibility were shown to be independent of the cell cycle, and localized to chromosomes, without the possibility of enzyme access contributing to the differential digestive effects observed in different cell types. The different relative sensitivities of chromatin or chromosomes to restriction enzymes was also demonstrated to be independent of ploidy, but sensitive to oncogene insertions on the same genetic background. Moreover, the differences in chromatin and chromosome stability in comparisons of highly invasive, poorly invasive, and normal cells was also found to involve proteins rich in disulfide bonds. This phenomenon was demonstrated by adding DTT or ß-mercaptoethanol to the digestion reactions and rendering the highly invasive cell genomes sensitive to Alu I.

In the second part of the work, a systematic search was initiated to test if growth factors, or soluble and polymerized ECM molecules also induce cells to alter their sequestration or exposure of DNA, and to test if there was any specificity to the influence of different ECM molecule types on Alu site exposure or sequestration. These experiments showed that soluble laminin and RGD-C were both capable of rapidly and profoundly causing all cell types that were tested to sequester their DNA from the digestive effects of Alu I. However, sequestration induced by these ECM molecules was always more intense among increasing grades of cellular invasiveness. Serum, fibronectin, bFGF, EGF, and type I collagen exerted no effect on the seqestration of Alu I sensitive sites. The same results were obtained with polymerized extracellular matrix conditions. In addition, when polymerized ECM preparations were prepared such that ECM molecules were deposited in specific regions of a surface, the contrast in chromatin sensitivity could be easily observed between cells touching the extracellular matrix compared to the same cells that did not touch ECM deposits.

These studies suggest several novel biological concepts: through comparisons of the sensitivities of chromosomes derived from a chromatin extraction method that preserves the native structure of chromatin with digestion of specific Alu I and Msp I sites with digestions of interphase cells of the same type that are exposed or not exposed to defined matrices, a more accurate picture is provided as to how global chromatin structure exists and is controlled under physiological ion conditions, and how the organization, mechanics, and function of different types of genomes are linked to DNA sequestration, and exposure, and how these processes might occur at the level of tissue.

These findings have special relevance in tumor biology. It is now known that laminin is a principal component of extravascular matrix-rich vasculogenic mimicry patterns, or fluid-conducting meshworks that conduct plasma within tumors that probably arises from leaky vessels disturbed by invasive tumor cells (5-11), and whose presence designates how patients harboring melanomas and other tumors will progress (see Ref. 12). The fact that laminin and RGD-C sequester the Alu sites in both normal and tumor cells in only 30 minutes is remarkable because it suggests that specific ECM moieties present in the environments of malignant tumors can rapidly and profoundly induce a complete reorganization of the higher order structure of the genome to sequester Alu sites. However, these observations also suggest that perfusion itself, by whatever route (eg. tumor angiogenesis, vasculogenic mimicry, vessel cooption, etc.) may be a small part of the story regarding how factors get into cells of highly invasive tumors. These data would suggest that the highly invasive cells themselves, owing to their abnormal organizational characteristics, may be the principal directors for both nutrient access, and many of the nucleic acid-disrupting drugs used in cancer chemotherapy.

Furthermore, it is clear that conceptual frameworks advanced to explain how prokaryotic genomes are controlled cannot explain how the regulatory machinery controlling higher order chromatin structure coordinates large regions of the eukaryotic genome along with its batteries of hundreds, or perhaps thousands of genes and gene networks. For instance, it has been established that even among single cell eukaryotes such as yeast, the majority (>95%) of single-gene mutations in yeast affect not only the expression of the mutant gene, but also the expression of many other genes (13).

In multicellular organisms, in addition, the cytoskeleton and extracellular matrix (ECM) are known to play a fundamental role in determining cellular behaviors. To test if different cytoskeletal fiber systems influenced the sequestration or exposed the Alu I sites, a variety of cytoskeleton-disrupting drugs were then employed to determine if the higher order structure of chromatin was controlled by actin, microtubules, or intermediate filaments. It had been previously established that a tug to an integrin receptor could alter the molecular alignment of intranuclear molecules in 1 second, and each cytoskeletal system had been shown to exert different stabilizing effects on both nuclear structure, and force transduction (14). The results of these experiments showed that indeed, as with the force-transduction experiments on integrin receptors, each cytoskeletal fiber system contributed profoundly to the sequestration or exposure effect, such that actin disruption decreased sequestration, while microtubule or intermediate filament disruption increased sequestration.

These findings raise and experimentally address new questions regarding the fundamental way genetic information is controlled by proteins containing disulfide-rich bonds, by the extracellular matrix microenvironment, and by the cytoskeleton. The work also has contributed several new approaches that can be used as diagnostic tools that use the differences in the sensitivities of DNA to distinguish differing degrees of malignancy that do not depend on molecular markers which have been shown to be highly variable in the context of vasculogenic mimicry, and which manifests as molecular mimicry in tissue sections of the most invasive types of tumors (5,15,16). These factors working separately, or in concert, may have relevance to the “resistance” of malignant cells, and have implications regarding how drug resistance of the most malignant types of tumor cells may be induced by the presence of specific types of extracellular matrix moieties. It appears the architecture of cytoplasm and nuclei themselves, induced by the extracellular matrix, dictates how DNA is sequestered or exposed. Models of higher order chromatin structure and gene control in higher eukaryotic cells must be considered contextual and hierarchical with respect to the ECM environment and the cytoskeleton (17). In this context, and as suggested by the authors, tensional integrity (tensegrity) may be a useful conceptual framework to account for how molecules can function collectively as components of integrated, hierarchical systems, in the physical context of living cells and tissues (18).

References
1. Wilson EB. The Cell in Development and Inheritance. Pathological mitosis in cancer cells, pps. 68,69. Reprinted from the New York Edition of 1896. The sources of Science # 30, Johnson Reprint Corporation, New York and London, 1966.

2. Puck TT, Krystosek A, Chan DC. Genome regulation in mammalian cells. Somat Cell Mol Genet 1990 16: 257-265.

3. Maniotis, A., Bojanowski, K., Ingber, D. Mechanical continuity and reversible chromosome disassembly within intact genomes removed from living cells. J. Cellular Biochem. Vol 65: 114-130, 1997.
4. Bojanowski, K., Maniotis, A., Ingber, D. DNA toposiomerase ll can control chromatin topology and drive chromosome condensation without enzymatically modifying DNA. J. Cellular Biochem. Vol. 69:127-142, 1998.
5. Maniotis A., Folberg R., Hess A., Seftor E., Gardner L., Pe’er J., Trent J., Meltzer P., Hendrix M. Vascular channel formation by human uveal melanoma cells in vivo and in vitro: Vasculogenic mimicry. Amer. J. Path. Vol. I55, No 3, pps. 739-752, September,1999.

6. Andrew Maniotis, Xue Chen, Christopher Garcia, Phillip J. DeChristopher, Ding Wu, Jacob Pe’er, Robert Folberg. Control of Melanoma Morphogenesis Endothelial Survival, and Perfusion By Extracellular Matrix. Lab Investigation. Vol. 82 No. 8 p.1083-1092, 2002.

7. Shirakawa K, Tsuda H, Heike Y, Kato K, Asada R, Inomata M, Sasaki H, Kasumi F, Yoshimoto M, Iwanaga T, Konishi F, Terada M, and Wakasugi H. Absence of Endothelial Cells, Central Necrosis, and Fibrosis Are Associated with Aggressive Inflammatory Breast Cancer. Cancer Research 61, 445-451, January 15, 2001.

8. Shirakawa K, Kobayashi H, Heike Y, Kawamoto S, Brechbiel M, Kasumi F, Iwanaga T, Konishi F, Terada M, Wakasugi H. Hemodynamics in Vasculogenic Mimicry and Angiogenesis of Inflammatory Breast Cancer Xenograft. Cancer Research 62, 560-
566, January 15, 2002.

9. Kobayashi H, Shirakawa K, Kawamoto S, Saga T, Sato N, Hiraga A, Watanabe I, Heike Y, Togashi K, Konishi J, Brechbiel MW, Wakasugi H. Rapid accumulation and internalization of radiolabeled herceptin in an inflammatory breast cancer xenograft with vasculogenic mimicry predicted by the contrast-enhanced dynamic MRI with the macromolecular contrast agent G6-(1B4M-Gd)(256). Cancer Res. 2002 Feb 1;62(3):860-6.

10. Shirakawa K, Kobayashi H, Sobajima J, Hashimoto D, Shimizu A, Wakasugi H. Inflammatory breast cancer: vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model. Breast Cancer Res. 2003;5(3):136-9. Mar 06, 2003.

11. Clarijs R. Otte-Holler I, Ruiter, de Waal MW. Presence of a fluid-conduting meshwork in xenografted cutaneous and primary human uveal melanoma. Investigative Ophthalmology and Visual Science: Vol. 43 No 4 2002.

12. Folberg R, Maniotis AJ. Vasculogenic mimicry. Acta Pathologica, Microbiologica, et Immunologica, Scandinavica. Jul;112 (7-8):508-525,. 2004.

13. Featherstone DE, Broadie K. Wrestling with pleiotropy: genomic and topological analysis of the yeast gene expression network. Bioessays. Mar;24(3):267-74, 2002.
14. Maniotis, A., Chen, C., Ingber, D. Demonstration of mechanical interconnections between integrins, cytoskeletal filaments, and nuclear scaffolds that stabilize nuclear structure. Proc. Nat. Acad. Sci . Vol. 94 pp.849-854, 1997.

15. Chen X, Maniotis AJ, Majumdar D, Pe’er J, Folberg R: Uveal melanoma cell staining for CD34 and the assessment of tumor vascularity. Invest Ophthalmol Vis Sci. Aug; 43(8): 2533-9. 2002.

16. Seftor EA, Meltzer PS, Kirschmann DA, Pe’er J, Maniotis AJ, Trent JM, Folberg R, Hendrix MJ. Molecular determinants of human uveal melanoma invasion and m
metastasis. Clin Exp Metastasis. 2002;19(3):233-46.

17. Roskelley CD, Srebrow A, and Bissell MJ: A hierarchy of ECM-mediated signaling regulates tissue-specific gene expression. Curr Opin Cell Biol 7: 736-747, 1995.

18. Ingber DE. The Architecture of Life. Scientific American, January, pp 48-57, 1998: see also Ingber DE. Tensegrity II. How structural networks influence cellular information processing networks. Journal of Cell Science 116, 1397-1408, 2003.

Posted by: Andrew Maniotis | April 26, 2007 05:22 AM

Trying to blow your own trumpet again, Andrew? Perhaps more people might read what you write if you presented it in smaller digestible chunks, and more might listen to what you have to say if you dropped the dogmatic and anti-scientific approach that you share with Duesberg in refusing to be open to alternative hypotheses and willing to accept when you have been shown to be wrong (as you both have in relation to your AIDS denial).

Posted by: DT | April 26, 2007 09:53 AM

Wow, Dr. Maniotis, nice work! I just have to wonder how you justify your work with “Alu I”. Because I personally don’t believe it exists.

Do you have electron micrographs of Alu I in the act, cutting DNA? Have you confirmed this with crystal structures? Are your Alu I preps 100% pure? Are you sure the DNA isn’t just being cut by endogenous restriction enzymes activated by oxidative stress when you add your inevitably impure “Alu I”? Did you check the redox environment of the cells? Isn’t it possible that the DNA in cancer cells is more sensitive to “Alu I” digestion because of their different redox state?
Another thing I notice is you use the T4-2 breast cancer cell line. You know better than anyone, “to culture is to alter.” So what’s the relevance? Why didn’t you do this work in situ in patients? Cancer has been around forever, and there’s still no work on Alu I sensitivity directly in patients? Unbelievable.

Obviously, AluI doesn’t exist. And now I’m not even sure about cancer.

Posted by: Adele | April 26, 2007 10:57 AM

Methinks Dr. Maniotis would like me to blog his latest article. A little bit excessively self-promoting, but what the heck? I might even be willing to oblige him as long as it’s not a Wiley & Sons publisher, where I might have to worry about being sued if I were to do a selective quotation or two or appropriate a smaller version of one of his figures for “fair use.” I’m always happy to talk science, as opposed to pseudoscience like HIV/AIDS denialism, and I’m equally happy that Dr. Maniotis refrained from mentioning his views on HIV/AIDS, given that he is a signatory to a letter by the Perth Group stating that HIV doesn’t cause AIDS.

As long as we stick to cancer, I don’t see why we couldn’t have a fruitful discussion, and I don’t see why I couldn’t have a fruitful discussion even with Duesberg himself. For one thing, I’d be interested in knowing Dr. Maniotis’ thoughts on Dr. Duesberg’s arguments, as presented in the SciAm article and a couple of recent scientific reviews, particularly bad arguments such as “babies don’t get cancer.”

Posted by: Orac | April 26, 2007 11:57 AM

I would like to see a fruitful discussion on cancer between Orac and Dr. Maniotis. However, could you shorten it a bit? Not every scientific argument has to be “War and Peace”

Posted by: Ky Sanderson | April 26, 2007 12:14 PM

Adele, As you are no doubt aware there are still ethical questions about the circumstances under which Watson and Crick obtained Rosalind Franklin’s crystallographic data of DNA structure. I think to be on the safe side you should add DNA to your list of things whose existence must be questioned.

Posted by: Dale | April 26, 2007 12:33 PM

Orac:

You state that would like to address “particularly bad arguments such as “babies don’t get cancer.” But, Dr. Duesberg didn’t write that and you know it.

He wrote:

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.

How can anyone dispute this? He then wrote:

But colon cancer is never seen in children., which you deliberately misinterpreted this narrow quote to include cancer in general.

So, back to the properly framed issue:

If you can produce babies with colon cancer, then your point is well-taken and Dr. Duesberg is in error. If not, then your point is not well-taken, and you are in error.

Here’s a paper from the NCI on colon cancer.

It’s pretty good, but doesn’t mention any babies getting colon cancer, so it doesn’t quite answer the question.

Here’s a SEER Fact Sheet, also from the NCI. It states:

From 2000-2004, the median age at diagnosis for cancer of the colon and rectum was 71 years of age. Approximately 0.0% were diagnosed under age 20.

So, according to these authorities, Duesberg is right: babies don’t get colon cancer. At least from 2000 – 2004. Do you have any comment on these facts?

Posted by: Ky Sanderson | April 26, 2007 01:29 PM

2 Responses to “Potshot at Duesberg”

  1. Michael Says:

    Orac shows all his true colors with his statement:

    “What really irks me about Duesberg with respect to his ideas about cancer is that he may be on to something”,

  2. MacDonald Says:

    Orac shows all his true colors with his statement…

    Not all of them Michael. Orac shows the rest by his summary of Duesberg’s HIV/AIDS critique:

    …the hypothesis that HIV doesn’t cause AIDS

    This is the equivalent to a theologian summarizing Darwin’s “The Origin of Species” as ‘the book that contradicts the first chapter in the Bible’.

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