Respectful Insolence

The complexity of cancer

About a week ago, there appeared a story in the New York Times about recent discoveries in cancer research written by George Johnson and entitled Cancer’s Secrets Come Into Sharper Focus. Overall, it was a better-than-average article for the lay press about recent discoveries in cancer research that go beyond just the cancer cell and just oncogenes. I must admit, however, that certain aspects of it irritated me, not the least of which is that it appeared to buy into one of the most cliched of tropes about medicine and science in spinning the story along the lines of “everything you know about cancer is wrong.” More pettily, the author couldn’t resist a dig at the scientists and physicians at the meeting described as “fueled by the free espresso offered by pharmaceutical companies hawking their wares.” In retrospect, I regret not having blogged the article at the time it was released, because it didn’t take long for purveyors of quackery to leap at it and use its contents to try to argue that scientists don’t understand cancer. While it may be true that we have a long way to go before we truly “understand” cancer, it is even more true that quacks don’t understand cancer at all; indeed, many of them cling to a false understanding of cancer.

Unfortunately, Johnson’s article has been used as the basis of an argument that, because our understanding of cancer has changed significantly over the last decade, “conventional” scientists don’t understand cancer, the implication being that the quacks do. Today, in part I of what will be a two-part post, I’ll discuss the NYT article, its good, its bad, and its indifferent, hopefully in the process illuminating how complex cancer is. Tomorrow or Thursday, I’ll lay some not-so-Respectful Insolence on a quack who uses this article as a jumping off point to argue for cancer quackery, particularly his hilarious criticisms of the article’s “shortcomings.”

I’ll begin by showing you a bit why the NYT article leaves itself open to that such unfortunate uses:

For the last decade cancer research has been guided by a common vision of how a single cell, outcompeting its neighbors, evolves into a malignant tumor.

Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline.

With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.

These basic principles — laid out 11 years ago in a landmark paper, “The Hallmarks of Cancer,” by Douglas Hanahan and Robert A. Weinberg, and revisited in a follow-up article this year — still serve as the reigning paradigm, a kind of Big Bang theory for the field.

But recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be even more willful and calculating than previously imagined.

This is, unfortunately, a massive straw man. Yes, it is true that in the past science focused almost exclusively on the cancer cell and the mutations that drove it to become cancerous. However, contrary to what is portrayed in Johnson’s article, the understanding that cancer is about more than just the cancer cell began long before ten years ago. In fact, you can see evidence of that in the classic article (published, intentionally no doubt, at the turn of the millennia) that is mentioned in the passage above. Right there in the article is a figure that I personally have used in many talks to point out that cancer is not just about the cancer cells. Here is Figure 3:

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Notice something? On the left is the “old” view of cancer (the “old view” eleven years ago). This old view considers mainly the cancer cells and views tumors as primarily collection of cancer cells. This is contrasted to the figure on the right, which portrays a tumor as a complex tissue containing many cell types. To emphasize how little Johnson apparently understood Hanahan and Weinberg’s classic paper, here’s what the caption to this figure in Hanahan and Weinberg’s classic paper says:

The field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them (left panel)–a focus that has produced an extraordinary body of knowledge. Looking forward in time, we believe that important new inroads will come from regarding tumors as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda (right panel). The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.

In other words, the paper that Johnson cites as evidence of how scientists clung to a simplistic model of how cancer operates eleven years ago is anything but that. Rather, it pointed out that the discoveries of the decade before (i.e., the 1990s) had complicated our previous seemingly neat understanding of cancer. Well, it wasn’t that our understanding of cancer was so “neat”; rather, it was that our understanding back then was indeed primarily focused on the cancer cell. However, contrary to what Johnson implies, that hasn’t been the case in over 10 years. It is, however, a convenient narrative to make it seem as though the discoveries described in Johnson’s article are so utterly novel that they were not the active topic of study far longer than ten years ago. Indeed, when I was in graduate school, I studied the tumor microevironment, specifically tumor angiogenesis, starting in 1996, five years before. When Johnson says that “research is increasingly focused on the fact that a tumor is not a homogeneous mass of cancer cells” but “also contains healthy cells that have been conscripted into the cause,” he should look at the eleven year old article that he cites, which says more or less the same thing. In other words, this is not new news, nor is it new for tumors to be compared to “renegade organs sprouting inside the body.” The tumor microevironment has been a fertile area for cancer research at least as long as I can remember, which in terms of my interest in cancer biology is at least 20 years.

In all fairness I’ll point out that Johnson isn’t wrong about some things. Rather, it’s the emphasis that irritates me because it makes discoveries that are not particularly new seem new. One exception is a discovery whose consequences Hanahan and Weinberg could scarcely have envisioned in 2000, namely the discovery of microRNAs. microRNAs are small RNA molecules that are able to bind to messenger RNA and prevent its translation into protein or induce its degradation, a process known as gene silencing. Given that microRNAs were only discovered in 1998, the importance of microRNAs in cancer biology is truly a new discovery that has emerged out of the last decade or so. In doing so, our increasing understanding of micrRNAs has rocked our understanding of cancer and many other cellular processes. Ten years ago, no one could have suspected how important microRNAs are in regulating gene expression. Indeed, a single micrRNA (miRNA for short) can regulate hundreds, even thousands of messenger RNAS (mRNAs), which are the RNAs that are used as the template that translates the information in the genome into protein. So ubiquitous have miRNAs become in cancer research that yours truly has even gotten into the act, having found one miR that might be important in indirectly silencing the expression of the tumor suppressor gene TP53. More recently, it turns out that miRNAs can be detected in the serum and that serum miRNA profiles might actually serve as biomarkers for cancer and other diseases.

But it goes beyond even that. There’s more to other genomic contributions to cancer than miRNAs. Indeed, we now refer to a whole class of RNAs as “noncoding” RNAs (ncRNAs) with regulatory functions that we haven’t yet figured out. However, next generation sequencing techniques, coupled with huge increases in computational power and the development of new algorithms that allow the analysis of petabytes of data, have led to this new knowledge, even to the ability to sequence the genome of individual cancers at a cost that is falling to ranges that are not astronomical. Remember, all of this has discovered over the last twelve years or so. The last decade in cancer research has been truly amazing. The next decade will be even more exciting, as scientists try to sift through this incredible mass fo data and as rapid declines in the cost of next generation sequencing techniques make sequencing the genomes of individual cancers feasible.

I just wish Johnson hadn’t fallen for the “junk DNA” trap:

Most DNA, for example, was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. Only about 2 percent of the human genome carries the code for making enzymes and other proteins, the cogs and scaffolding of the machinery that a cancer cell turns to its own devices.

These days “junk” DNA is referred to more respectfully as “noncoding” DNA, and researchers are finding clues that “pseudogenes” lurking within this dark region may play a role in cancer.

Of course, the issue of “junk DNA” is a lot more complicated than that, and Johnson’s passage sounds uncomfortably like creationists gloating every time scientists find some ncRNA or other that has a previously unsuspected function. As Larry Moran points out, “noncoding” has traditionally meant “does not make protein” and has never meant “has no function.” Indeed, even in 1972, it was known that there were forms of RNA with functions other than making protein, such as transfer RNAs (tRNAs transfer amino acids to the ribosomal complex as protein is being translated), ribosomal RNA (rRNA), and regulatory regions in promoters. In brief, “junk DNA is not the same thing as “noncoding DNA” and never has been. Moreover, even the discovery of miRNAs and other forms of ncRNAs with gene regulatory functions does not imply that cancer scientists ignored “junk DNA” all these years. But it makes a great hook to portray scientists in the past as having been “obsessively focusing their attention on 2% of the genome.”

Don’t get me wrong. There is much to like in Johnson’s article, such as the discussion of how microbes might contribute to the development and growth of cancer and the explanation of how miRNAs have become major players in understanding cancer. Johnson also gives a great summary of the complexity of cancer in his final paragraph:

With so many phenomena in search of a biological explanation, “Hallmarks of Cancer: The Next Generation” may conceivably be followed by a second sequel — with twists as unexpected as those in the old “Star Trek” shows. The enemy inside us is every bit as formidable as imagined invaders from beyond. Learning to outwit it is leading science deep into the universe of the living cell.

As I’ve pointed out before, cancer is really, really, really complex. I wrote about this at length six months ago and still recommend that, if you haven’t already, you go back and read that post. It’s one of my better ones, if I do say so myself, and it makes an incredibly important point, although in retrospect I realize that I actually did concentrate mainly on the cancer cell and its genetic derangements. In actuality, the complexity of cancer goes far beyond the genome. There are metabolic derangements (for example, the Warburg effect); complex interactions between cancer cells and the tumor microenvironment, between cancer cells and the tumor vasculature, and between cancer cells and the immune system; there are levels upon levels of genetic derangements, ranging from chromosomal rearrangements, to single mutations, to alterations in microRNA expression; and lots and lots of abnormal intracellular signaling. Although we’ve made great strides in starting to understand the the abnormal “wiring” of the cell and how abnormal interactions of cancer cells with their surrounding “normal” tissue environment contribute to its malignant behavior, we do not as yet have a good handle on what determines how this process proceeds and, more importantly, how to intervene effectively in such as way that doesn’t cause significant “collateral damage,” as chemotherapy, radiation therapy, and surgery can. Add to that the fact that cancer is not a single disease, but rather hundreds of different diseases in which normal cells lose their normal checks and balances and in essence parasitize the body, each with potentially different biology (sometimes radically so) and requiring different approaches to treatment, and it is more understandable that even forty years of the “war on cancer” is only enough to begin to scratch the surface.

Unfortunately, that doesn’t stop the quacks from using gaps in the scientific understanding of cancer as openings to sell their quackery.

Comments

  1. #1 Denice Walter
    August 23, 2011

    The very complexity of cancer ( like many other issues in medicine and psychology) facilitates speculation by woo-meisters because the general public *doesn’t* understand the research and is vulnerable to tales spun from the complacent ignorance of pseudo-scientists. The fact that woo-meisters would even present the “acid/base” nonsense, the “fungus” meme, or “nutritional” solutions illustrates how deficient they themselves are in even rudimentary comprehension. There’s this thing called “cognitive complexity”: you won’t find it on NaturalNews.

    However, people who are seeking information tend to gravitate to where there is “clarity”- even if it’s spurious. Like the person who searches for his or her lost car keys near the street light because “that’s where the light is “( i.e. not the most likely place where they were lost), a flashlight that focuses on small *important* areas at a time is necessary.

    Quacks often portray themselves as revolutionaries who have simple answers to complex problems- somehow their great insight will reveal a hitherto uninvestigated connection that *no one else has ever cpnsidered* and shift paradigms faster than a speeding bullet, bringing fame, fortune, and a better wardrobe in its wake. And followers perhaps enjoy riding the rising tide and being cooly “in on it” ( it reads like a bad screenplay because that’s most likely where these ideas originate). Both take easy paths to gratification not the long haul. As one of my profs always said,”If you have no toleration of ambiguity, what the f–k are you doing here?”

    Being an educator has to involve showing the degree of complexity in a salient fashion- one step at a time- and explaining why short-cuts don’t work. Can we make ambiguity and complexity more palatable? Wish I knew but I think that diagramming with lots of arrows always helps.

  2. #2 Poodle Stomper
    August 23, 2011

    While it may be true that we have a long way to go before we truly “understand” cancer, it is even more true that quacks don’t understand cancer at all; indeed, many of them cling to a false understanding of cancer.

    You just won the internet. That statement sums up my biggest beef about the anti-science crowds. Yes, science does not know everything about everything (if we did we wouldn’t have to do research anymore) but that doesn’t mean that the quacks can insert their fairy tales in the grey/unknown areas without some damn good evidence to back them up.

  3. #3 DaveD
    August 23, 2011

    Midway through the article, there is a paragraph that ends rather abruptly as follows:

    “More recently, it turns out that miRNAs can be detected in the serum and that miR profiles might actually ”

    This sounds fairly ominous, so I’m wondering what it is that they might actually do.

  4. #4 Jeff Read
    August 23, 2011

    The fact that woo-meisters would even present the “acid/base” nonsense, the “fungus” meme, or “nutritional” solutions illustrates how deficient they themselves are in even rudimentary comprehension.

    Bob Lustig’s work on fructose toxicity and its implication in the development of type II diabetes, heart disease, and various forms of cancer indicate that the “woo-meisters” were right in that nutrition plays an even greater role than we thought in health and disease.

    The thing about being fuzzy-minded like many hippies, mystics and other promoters of woo are, is that sometimes you’re kinda-sorta right.

  5. #5 cervantes
    August 23, 2011

    But recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be even more willful and calculating than previously imagined.

    I really detest this metaphor — hopefully it’s intended as metaphor and the writer doesn’t actually believe this. Cancer, obviously, is neither willful nor calculating. People also say this about HIV — that it’s “intelligent” and it can “figure out how to get around the drugs.” There are so many things wrong with this I don’t know where to begin. It’s the same sort of teleological fallacy people apply to the evolution of species, and indeed in the case of both cancer and HIV drug resistance we are talking about evolution, or evolution-like processes if you prefer. The appearance of intention or design is created by mutation and selection; there is no intelligence involved. But the idea of a canny and willful enemy underlies the heroic, martial metaphors often applied to medicine — the “war” on cancer, the therapeutic “armamentarium,” etc. This is mysticism, we should eschew it.

  6. #6 Krebiozen
    August 23, 2011

    Jeff Read,
    I think Robert Lustig’s claims about fructose are overstated. All the nutritional research I have read in recent years seems to confirm that excessive calorific intake and a sedentary lifestyle are the main problems, and that blaming fructose in isolation is as foolish as blaming fats in isolation.

  7. #7 lilady
    August 23, 2011

    Robert H. Lustig, M.D. has published extensively in peer reviewed journals (82 citations (1992-2011)…author search…Pubmed). He is Professor of Clinical Pediatrics, Division of Endocrinology U.C.S.F. with a sub-specialty in Neuro-Endocrinology and a practicing clinician. He has written extensively about childhood obesity-Type II Diabetes and the role of highly concentrated fructose syrup sweeteners in high caloric “snack foods” (i.e. junk food).

    However the vegans, macrobiotic diet “specialists” and self styled “nutritionists” might frame his research…the fact remains that he has researched childhood obesity/Type II diabetes extensively and the use of high fructose syrups manufactured from corn syrups is implicated in the alarming increase of childhood obesity:

    High-fructose corn syrup (HFCS) — also called glucose-fructose syrup[1][2] in the UK, glucose/fructose[3] in Canada, and high-fructose maize syrup in other countries — comprises any of a group of corn syrups that has undergone enzymatic processing to convert some of its glucose into fructose to produce a desired sweetness. In the United States, consumer foods and products typically use high-fructose corn syrup as a sweetener. It has become very common in processed foods and beverages in the U.S., including breads, cereals, breakfast bars, lunch meats, yogurts, soups and condiments. (Wikipedia)

    (Not meaning to discount the role of lack of exercise and the culture of “indoor” leisure activities as a major role in obesity/Type II diabetes in childhood and in adults)

  8. #8 cervantes
    August 23, 2011

    The issue with corn syrup is not that its calories are any more pernicious than others (although it does have a high glycemic index, which is causative of diabetes), but rather that it is extremely cheap — partly because of the distortions created by federal agricultural subsidies. That in turn makes sweetened products cheap and there you go.

  9. #9 Krebiozen
    August 23, 2011

    Lilady,
    Lustig is certainly a respectable researcher but I don’t buy his hypothesis that fructose is the root of all evil. There’s a good skeptical look at his ideas here.

  10. #10 Roadstergal
    August 23, 2011

    Being an educator has to involve showing the degree of complexity in a salient fashion- one step at a time

    I remember this most vividly in college – learning simple paradigms in Biol 202 that became increasingly complex as I made my way up the course catalog (after senior year, I had adapted to the ambiguity, as mentioned, and now it’s just a fact of life).

    It was often couched as ‘everything you knew was wrong,’ but it wasn’t wrong, it was merely simplified – and I think that’s what gets lost in the ‘scientists thought x, but it’s actually y’ meme. We refine existing knowledge, and that involves shifting paradigms now and then. But that’s science’s strength – it keeps looking, and refining, and happily shifting if that’s where the evidence leads.

    ‘The earth is round’ is technically wrong, but it’s a good starting generalization to further refine.

  11. #11 daedalus4u
    August 23, 2011

    It is very unfortunate that the complexity of cancer is not appreciated.

    What is even more unfortunate is that the complexity of normal physiology is not appreciated. Cancer is due (mostly) to the loss of various control DNA. Thus, cancer in all its complexity is still simpler than normal cells which retain all of their various coding and non-coding DNA bits and still in fully functional operation.

    It is only because normal physiology seems so normal that there is the default assumption that physiology must be simple because it just works.

  12. #12 lilady
    August 23, 2011

    @ Krebiozen: I confess I haven’t viewed the video on the website you provided…one and one-half hours is about one hour and twenty minutes too long for me. If you state that the thrust of Dr. Lustig’s presentation was on “fructose”…not HFCS…then I believe you; it belies all the research the Dr. Lustig has done on childhood obesity/Type II diabetes that appear on his PubMed citations that prominently include the use of HFCS in food.

    Remember that Dr. Lustig’s specialty is pediatric endocrinology and that he treats kids with *metabolic syndrome* (insulin resistance/type II diabetes), obesity and elevated triglycerides/lowered HDL cholesterol)…he is not a fitness trainer.

    There is an excellent article on SBM:

    High Fructose Corn Syrup: Tasty Toxin or Slandered Sweetener (Jim Laidler August 23, 2010) (apologies for not “linking”…my deficient skill-set)

    * Thanks to poor diet and deplorable lack of exercise we now have childhood metabolic syndrome at an alarming rate.

  13. #13 Beamup
    August 24, 2011

    I think Dara O’Brian responded very well to this.

    “Science knows it doesn’t know everything. Otherwise, it’d stop. … But that doesn’t mean you can fill in the gaps with whatever fairy tale most appeals to you!”

  14. #14 nsib
    August 24, 2011

    lilady,

    I confess I haven’t viewed the video on the website you provided…one and one-half hours is about one hour and twenty minutes too long for me. If you state that the thrust of Dr. Lustig’s presentation was on “fructose”…not HFCS…then I believe you; it belies all the research the Dr. Lustig has done on childhood obesity/Type II diabetes that appear on his PubMed citations that prominently include the use of HFCS in food.

    The video is simply a presentation by Dr. Lustig, used by Alan Aragon as an example of the claims made by Dr. Lustig. So there’s no need to watch it to understand the refutation that follows.

    And yes, Dr. Lustig’s focus is certainly on fructose. HFCS is just a mixture of glucose and fructose after all, and I don’t see Dr. Lustig or anyone else leading a crusade against glucose!

    I’ll check out that article you referenced.

  15. #15 Krebiozen
    August 25, 2011

    lilady,

    As nsib states, Lustig does focus mainly on fructose. I don’t doubt that there is a lot of truth to Lustig’s theories. He is a very engaging speaker, and I enjoyed his lecture. It was only after I did a bit more reading on the subject, including the SBM post that you mention, that I began to think he has taken it a bit too far, and found the skeptical look at his ideas I linked to.

    BTW I think it’s interesting that US per capita consumption of calorific sweeteners peaked around 1999 and has been heading downwards ever since. HFCS consumption has been slowly falling since 2001 while sugar consumption has been slowly rising, perhaps because of the demonization of HFCS. The graph here is accurate – I went to the USDA site and checked.

  16. #16 mo
    August 25, 2011

    So ubiquitous have miRNAs become in cancer research that yours truly has even gotten into the act, having found one miR that might be important in indirectly silencing the expression of the tumor suppressor gene TP53.

    Nature paper?

    it turns out that miRNAs can be detected in the serum and that serum miRNA profiles might actually serve as biomarkers for cancer and other diseases.

    Can you give a reference for that? I’m interested in possible cell-cell transmission mechanisms of RNAs.

  17. #17 Kemist
    August 26, 2011

    HFCS is just a mixture of glucose and fructose after all

    Indeed. And so is ordinary cane sugar, aka sucrose.

    Sucrose is simply one fructose and one glucose molecule linked together via the glycoside bond. This bond will become undone quite easily even in the absence of any enzyme. Acidic conditions, for instance (such as those that exist in the healthy stomach), will easily convert sucrose to its component fructose and glucose – what is called inverted sugar.

    HFSC is simply inverted sugar that comes from corn. It’s called “high fructose” because it contains a bit more fructose than inverted sugar made from sugarcane (55% compared to 50%). That’s about the same composition as typical honey, which is hawked everywhere as a healthier sweetener. For truly frightful fructose/glucose ratios, some fruits are really the worst thing you can eat : an apple contains 70% of its sugar as fructose.

    The problem here is not one of quality of sweeteners but one of quantity, of ubiquitous and excessive use. Whatever you will use will have its own set of problems.

    Fructose has a very low glycemic index. Indeed, it was sold in pure powdered form as a health food product not so long ago, and strongly recommended to diabetics, until it was found out that it promotes insulin resistance.

    Glucose has a relatively high glycemic index which promotes insulin release via the classical sugar regulation mecanism.

    Most known non-caloric sweeteners are now suspected of promoting insulin release via a non-classical neurological mecanism, inducing hunger and excessive food consumption, thus promoting obesity.

  18. #18 DLC
    August 26, 2011

    Krebiozen: High Fructose Corn Syrup is not much different from honey. Of course, any sugar is going to be bad for you when consumed in excess, but HFCS is not chemically any worse than other sugars.
    As for the cancer discovery — news of any scientific discovery is going to be blown out of proportion by the media, and used by some kind of quacks or cranks. I recall seeing papers on subatomic particle research cited by woo-miesters as proof of their quackery.