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Why haven’t we cured cancer yet?

Why haven’t we cured cancer yet?

If we can put a man on the moon, why can’t we cure cancer?

If we can harness the atom, why can’t we cure cancer?

How many times have you heard these questions, or variants thereof? How many times have you asked this question yourself? Sometimes, I even ask this question myself. Saturday was the two year anniversary of the death of my mother-in-law from a particularly nasty form of breast cancer, and, even though I am a breast cancer surgeon, I still wonder why there was nothing in the armamentarium of science-based medicine that could save her from a several month decline followed by an unpleasant death. That’s why, to me at least, the timing of the publication of a study examining the genome of prostate cancer that was published in Nature and summarized in this Science Daily news story was particularly apt. Performed as part of the National Cancer Institute’s Cancer Genome Project, the study undertook complete genome sequencing of seven advanced and aggressive prostate cancers. The results, as ERV put it, revealed what can be describe as a “train wreck.”

Personally, I’d describe it as looking as though someone threw a miniature grenade into the nucleus of a prostate epithelial cell. You’ll see what I mean shortly.

Of course, although that image does give you an idea of the chromosomal chaos in the heart of prostate cancer cells, it is inaccurate in that it implies a sudden explosion, after which the damage is done, and if there’s one thing we know about cancer it’s that in most cases it takes many years for a normal cell to progress to a cancer cell fully capable of metastasizing and killing its host. I’ve written in detail about the complexity of cancer before, of course, and have even pointed out before that when President Nixon launched the “war on cancer” 40 years ago scientists had no idea how difficult it would be. Indeed, before I discuss the current study, it’s probably useful to reiterate a bit why, in order to put the study in context.

Cancer is not a single disease, and cancers are different

I’m sure that it probably becomes tiresome for readers to read this time and time again, and, believe me, sometimes I find it tiresome to keep repeating it, but it must be said: Cancer is not a single disease. It’s hundreds of diseases. Although there are many common themes in cancer, such as loss of responsiveness to growth signals with a resultant ability to grow unchecked. Other common capabilities of cancer cells include evasion of programmed cell death (apoptosis), inducing the surrounding tissue to provide a blood supply (angiogenesis), evading the immune system, and invading the blood or lymphatic systems to travel elsewhere in the body and take up shop in other organs, such as liver, lung, or bone. Although there are, again, common molecular themes by which cancers do this, individual cancers acquire these necessary (to the cancer) abilities by many different ways.

Even cancers arising from the same cell type can be quite different. For instance, the breast cancer that killed my mother-in-law was a rare spindle cell variant, which is quite different from the much more common invasive ductal carcinoma that is estrogen and progesterone receptor positive. Indeed, even within individual cancers, different populations of cells can be quite different. In many solid tumors, there are cells now referred to as “stem cells.” Personally, I consider this term a bit of a misnomer that I really don’t like because these cells are not really pluripotent, and the cell types into which they can differentiate are rather limited. Moreover, this nomenclature has also made the concept of the cancer stem cell more controversial scientifically than it really needs to be. What we are really talking about are a relatively small population of cells in many tumors that are endlessly self-renewing and, in general, resistant to chemotherapy. In mice, these are the only cells that can actually form a new tumor when transplanted into a new mouse, and these are the cells that appear to be responsible for relapse after chemotherapy and radiation therapy. Indeed, cancer progression can be viewed as being due to a case of evolution in which the tumor cells that survive selection to continue to grow are the ones that become best at doing all the things that tumor cells need to do to evade the body’s defenses and overcome its growth control signals.

One of my favorite examples of how cancer progression can be understood using evolutionary principles was a study of esophageal cancer by Carlo Maley, PhD, a researcher at The Wistar Institute, that was published nearly five years ago. In essence, Maley applied population biology principles, specifically the Shannon Diversity Index, to predict which cases of Barrett’s esophagus (a precancerous condition in which the cells lining the lower esophagus are changed by chronic inflammation such that they look more like the cells that line the inside of the stomach) are most likely to progress to invasive esophageal cancer.

Not only is cancer not a single disease, but individual cancers are made up of multiple different clones of cancer cells under selective pressure to become ever more invasive and deadly. Looking at it this way, it’s a wonder we don’t all die of cancer. We do, however, virtually all have small foci of cancer within us, as I’ve pointed out before. Yet most of us do not develop cancer, and fewer of us end up dying of cancer, even though cancer is currently duking it out with heart disease as the number one cause of death in industrialized societies. Fortunately, the steps required for cancer to become deadly are difficult and numerous, and the body’s defenses against cancer are formidable.

Mechanisms of carcinogenesis are not simple

Let’s take a trip in a time machine back to 40 years ago, around the time that Nixon signed the National Cancer Act of 1971. I was a child, and molecular biology was in its infancy. Few of the fancy tools that scientists take for granted these days when it comes to studying genes, proteins, and how they interact even existed. Heck, polymerase chain reaction (PCR)—at least, as we know it now—wasn’t even invented for another 12 years and didn’t become widespread until the late 1980s and early 1990s. (Nearly 20 years later, I still chuckle at the memory of the monster of a PCR machine, the only one in our department, that I occasionally tried to use in graduate school. The thing took up the better part of a benchtop.) In 1971, the very first oncogene discovered, src, had only been reported the previous year, and it hadn’t even been demonstrated that oncogenes were defective protooncogenes; i.e., genes involved in cell growth that were mutated in cancers. That discovery would not come until 1976. Tumor suppressor genes were not discovered until nearly 10 years later, when the retinoblastoma (Rb) gene was characterized in 1986. An even more famous tumor suppressor gene, p53 (or TP53), had been discovered in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, but had initially been thought to be an oncogene. Burt Vogelstein demonstrated its function as a tumor suppressor gene in 1989, and ultimately it was demonstrated to be a critical gene for responding to DNA damage. How that ten-year voyage from oncogene to tumor suppressor played out is described in detail here. It makes interesting reading how a scientific concept can change as new evidence comes in.

Thus, over the first 25 years or so after the National Cancer Act of 1971, it was all about the genes and mutations. The picture that began to emerge was that oncogenes drove tumor growth along with loss of tumor suppressor gene activity. This seemed to fit in nicely with Alfred G. Knudson’s “two-hit” hypothesis, which stated that not only were “hits” required in oncogenes to cause cancer but in tumor suppressors as well. Later, Burt Vogelstein developed a model of multi-stage carcinogenesis that required at least six mutations:

As you can see, things were getting pretty complicated. Even so, based on what we know now, even Vogelstein’s increasingly sophisticated models in retrospect turn out to have been fairly simplistic. We discovered this over the last decade or so, because, with the advent of expression array profiling (a.k.a. “gene chips” or “cDNA microarrays”) in the late 1990s, it became possible to measure the level of expression of thousands of genes at the same time. Before then, we did not have the computational power or the technology necessary to do this, but over the last decade or so, it’s become more apparent than ever before that it is not primarily individual genes that determine cancer, or even a handful of genes, but hundreds or even thousands of genes that form complex networks of interactions. Also, around 1998 it was discovered that there is a whole new class of RNA, known as microRNAs (miRNAs), which regulate gene expression. More recent evidence suggests that miRNA expression patterns might actually tell us more about how cancer develops than whole genome expression array profiling because individual miRNAs often regulate the expression of hundreds of genes.

And I’m not even getting into deep sequencing of whole genomes in cancer yet, or the metabolic derangements that characterize cancers and allow them to grow where normal cells cannot, derangements that are probably just as critical to the process of carcinogenesis as genetic alterations.

So, putting it all together as we understand it in 2011, cancer cells not only have mutations that result in dysregulated expression of oncogenes and tumor suppressors, but these changes result in the alteration of expression of hundreds of genes, and in different types of cancer it will be different batteries of genes and miRNAs that are messed up in different ways. In fact, in individual tumors, there will be different populations of cells with different sets of genes and miRNAs messed up in different ways. Even worse, as a tumor progresses, it tends to become more heterogeneous, meaning that the number of different populations of cells tends to increase. Looking at it this way, it’s amazing that we have been able to do as well as we have with various forms of “targeted” therapy directed at specific single molecular targets or a class of molecular targets in cancer cells. Gleevec®, for instance, has been amazingly successful as a targeted agent directed against several members of a class of enzyme known as a tyrosine kinases, and by that mechanism it has been phenomenally successful as a treatment for gastrointestinal stromal tumors and certain types of leukemia. Even hoary old Tamoxifen is a targeted therapy directed at the estrogen receptor, and it still remains a mainstay of treatment for estrogen receptor-positive cancers to this day, along with a newer class of drugs known as aromatase inhibitors.

Unfortunately, in the grand scheme of things relatively few tumors are responsive to the targeting of single agents.

The prostate cancer genome

So what does this study tell us? Basically, scientists working at the Broad Institute, Weill Cornell Medical College, the Weizmann Institute of Science, Yale University, and Harvard University completely sequenced the entire genome of seven different prostate cancers and catalogued the abnormalities found by comparing the genome in prostate cancer with that found in the white blood cells of each patient, which were used as the normal control. Of course, this is what’s known as a “hypothesis-generating” study (a.k.a. a “fishing expedition” to those more inclined to disparagement). Personally, I have no problems with “fishing expeditions,” because without them we would have a serious lack of hypotheses to test. Moreover, this sort of fishing expedition is one where, almost no matter what scientists found, they would learn something useful about prostate cancer. True, it may not be the sort of knowledge that can be translated into therapy quickly. In fact, going in I would have predicted that it almost certainly would not be the sort of understanding that would lead to rapid improvement in prostate cancer treatment, and the results of this study show that it is not. What it does show is just how messed up the genome of cancer cells tends to be.

So what did the investigators find? Rearrangements and translocations. Lots and lots of intrachromosomal rearrangements and interchromosomal translocations. In fact, they found a median of 90 rearrangements and translocations per cancer genome (range: 43–213). They even included a pretty picture to represent the rearrangements. Known as a Circos plot, this graph shows the genomic location in the outer ring and chromosomal copy number in the inner ring (red, copy gain; blue, copy loss). Interchromosomal translocations and intrachromosomal rearrangements are shown in purple and green, respectively. (click on the picture to go to the Nature website and see the full size version):

These rearrangements were, as noted above, both within chromosomes (intrachromosomal) and between chromosomes (interchromosomal). These are represented in the following figure (again, click on the figure to see the full-size version):

Panel a shows an idealized picture of how these translocations work, with chromosomal breaks and rejoining with pieces of other chromosomes. It’s not necessary for me to go into the details other than to point out that in panels b an c we see that the break points have a disturbing propensity to be located right smack dab in the middle of important genes, like tumor suppressors. For instance, in PR-2832, break points appear in the middle of TP53 and ABL1. In other tumors, investigators found recurrent rearrangements that involved CADM2 and PTEN. PTEN is a known tumor suppressor gene, but CADM2 (cell adhesion molecule 2). This result appears to be confirmatory of recent results implicating CADM2 as a tumor suppressor gene in prostate cancer. Overall, scientists observed some new rearrangements, and ones that had been detected before.

Or, to put it even more simply, as William Phelps, program director for Translational and Preclinical Cancer Research at the American Cancer Society, put it:

Here’s one way to conceptualize the alteration, Phelps said: “If the genome was a book, instead of just looking for out-of-place letters or misspelled words, whole genome sequencing looks for whole paragraphs that are in the wrong place.

“Because [the researchers] sequenced everything, they were able to map not only individual base changes but also how whole genes or segments of the chromosomes had moved around,” Phelps said. “By sequencing everything and comparing the normal DNA (in white blood cells), they could see that not only were there individual base changes in the genes, but the genes themselves had been reshuffled in the tumor as part of the process of becoming cancer,” he explained.

“If we could use those changes as a diagnostic tool that would be tremendously valuable,” he added.

Whole genome sequencing also enables scientists to look not only at “coding” genes, but also “noncoding” DNA around the genes that was once thought to be “junk” but is now known to play an important regulatory role within cells, Phelps said.

I’ll admit that when it was announced, I was skeptical of the utility of the cancer genome project. I still am, actually. Basically, it’s one massive fishing expedition. However, as the years have gone by, I’ve become less skeptical, although I can’t say that I’ve exactly embraced it. This study leads me to consider that perhaps I was wrong in my original assessment.

More interesting than whether I screwed up five years ago when I first heard of this project, these sorts of rearrangements have long been appreciated as being important in leukemias and lymphomas, but in solid tumors they had not—until relatively recently. One thing that is important to keep in mind is that these scientists focused on aggressive, advanced pancreatic cancer. Consequently, they were selecting for most “messed up” genomes. As more and more cancer genomes are sequenced, scientists will be able to make comparisons between aggressive and indolent tumors. It is possible that one day doctors will be able to sequence a patient’s tumor and use what is learned from this to tell whether the tumor is aggressive or not—or potentially whether it even needs treatment or not. I’ve written extensively about the problem of overtreatment and even about spontaneous regression. Wouldn’t it be great if we could identify patterns of rearrangements and mutations (or lack thereof) that are associated with slow growing, indolent tumors compared to patterns associated with fast-growing, deadly tumors like the one that killed my mother-in-law, and then be able to use that information to target therapy or to decide that a cancer patient can be safely treated with watchful waiting? Until the last few years, we really didn’t have the technology and computing power to make such a dream a possibility, but now we do.

So why haven’t we cured cancer, anyway?

I close with the same question with which I opened. Why haven’t we cured cancer yet, anyway? Yes, I know it’s a bit of a misleading question, given that we can actually cure quite a few cancers, including several leukemias and lymphomas, which are curable with chemotherapy and radiation, and solid tumors like breast and colorectal cancer which are curable with a combination of surgery, chemotherapy, and radiation. Unfortunately, although we do fairly well (and in some cases very well) against early stage cancer, we don’t do so well against stage IV metastatic disease, particularly solid tumors. The vast majority of these are not curable, and, very likely, the vast majority are much like the prostate cancer specimens studied by these researchers, full of chromosomal rearrangements and mutations leading to abnormalities in many different signaling pathways.

Last year, the tenth anniversary of the announcement of the results of the Human Genome Project provoked a veritable flood of “Why haven’t we cured cancer yet?” or “Why haven’t we cured this disease yet?” For example, Nicholas Wade wrote a painfully simplistic article last June entitled A Decade Later, Genetic Map Yields Few New Cures. It’s an article I should have blogged about; perhaps even eight months later it would be worth doing, although you could always read this perspective instead. Let’s put it this way: The technology, techniques, and knowledge developed during the Human Genome Project laid the groundwork that has made it possible to sequence the entire genome of prostate cancer tumors and compare them this way. Come to think of it, I’m really dreading December 23, 2011. That will mark the 40th anniversary of Richard Nixon’s signing of the National Cancer Act of 1971. I just know that the month of December will be filled with stories lamenting, “Why haven’t we cured cancer yet?” or proclaiming the “war on cancer” to have been a failure. Some will be from the mainstream media, and even more will come from places like NaturalNews.com and Dr. Mercola’s website. That’s one prediction you don’t have to be a psychic to make. I also predict a whole bunch of articles and blog posts trying to claim that we’d be able to cure cancer “if only,” as in “if only” we’d be less conservative in our research approach (never mind that there are lots of high-risk approaches, and the ones that work only appear obvious in hindsight), “if only” we’d educate our kids in science better, “if only” we’d get rid of the FDA (yes, this guy was serious, as silly as his argument is), or “if only” doctors didn’t make so much money treating cancer with drugs and wouldn’t make any money treating it with “natural” therapies.

In preparation for this landmark event, I’ll begin with a pre-emptive answer (which I’ll no doubt have to repeat in December). Why haven’t scientists cured cancer yet? Leaving aside the trite answer of “Which cancer?” I can say this: Because it’s hard. It’s very, very hard. It’s harder than going to the moon; it’s harder than building the nuclear bomb; it’s harder than wiping out smallpox. All of those were, of course, also very, very hard too, but cancer is a harder nut to crack still. It’s hundreds, perhaps thousands, of diseases. Each type of cancer can be many, even dozens, of different diseases in itself. Each tumor can be many diseases that are constantly evolving, both in response to the environment in which the cancer cells grow and to treatments that are thrown at them.

And most cancer cell genomes probably look like the prostate cancer genomes analyzed in this paper. There’s a less thorough study that suggests that the breast cancer genome does.

Does that mean I have no hope? Of course not! Otherwise, I wouldn’t keep doing what I’m doing. I am simply expressing humility in the face of a protean foe that has thus far withstood our best efforts to eradicate it. That does not mean that it will continue to do so. After all, never before have we had the tools that we have now to probe deeply into the biology of cancer at the whole genome level as we do today.

Still, it will be hard.

Posted in: Cancer, Science and Medicine

Leave a Comment (37) ↓

37 thoughts on “Why haven’t we cured cancer yet?

  1. Jan Willem Nienhuys says:

    even though cancer is currently duking it out with heart disease as the number one cause of death in industrialized societies

    The statistics for the Netherlands (2009) are:
    malign neoplasm … 41,322 (is 30.8% of all deaths, in 2000: 26.9%)
    heart disease ……… 22,674 (is 16.9% of all deaths, in 2000: 21.6%)

  2. WilliamOBLivion says:

    We’ve cured more people of cancer than we have put people on the moon.

    We’ve kill more people in space than we have landed on the moon.

    Harnass the atom? You mean like Nuclear Fusion, which we use to blow shit up, as we HAVEN’T (outside a lab) been able to harness it that way?

    Or as in fission, which creates lots of radiation, which, well, causes cancer. Except when used very precisely, which sometimes cures cancer.

    Oh, now I’ll read the article :)

  3. WilliamLawrenceUtridge says:

    ERV, one of my favourite bloggers, should always be referred to as “The inimitable ERV”. Admittedly an appellation that could be applied to many here, but still. I like her use of swears.

    “If only we’d educate our kids in science better” actually does seem like a reasonable goal to pursue, but I’m sure the Huffington Post spins it in a crazy way. “If only we’d educate our kids in the science of how homeopathy/acupuncture/naturopathy/herbs/crystals/dream interpretation/alkaline blood cures all disease better” would be my guess.

  4. Enkidu says:

    Dr. Gorski, I want to express my condolences on the loss of your mother-in-law. Also, thank you for making the eradication of these diseases your daily goal. It takes many many small steps and bits of information to move forward against a foe like cancer.

    My life has been altered by cancer, as I’m sure most people’s lives have. I have two dear friends who have recently “beaten” ovarian and stomach cancer, repsectively. Each trip to the doctor, we hope for good news that no sign of cancer remains. I have also recently suffered a loss: just last week we had to have our doggie euthanized. He was diagnosed with hemangiosarcoma in mid-December, and the cancer was so aggressive, here we are mid-February and he is gone. I know people will think, well, he was “only a dog,” but he was part of our family. Nine years with him just wasn’t enough.

  5. passionlessDrone says:

    Hi David Gorski –

    Very nicely written article. I am also in love with the graphics from the Nature paper. Thank you.

    BTW – I think you are missing a bit somewhere along the line:

    And I’m not even getting into deep sequencing of whole genomes in cancer yet, or the metabolic derangements that characterize cancers and allow them to grow where normal cells cannot, derangements that are probably just as critical to the process of carcinogenesis as

    - pD

  6. rork says:

    I’m optimistic about having new treatments, since some of the newly discovered mutations of ten years ago now have compounds in clinical trials. Folks like me can sometimes say “see, we were doing something that mattered after all”, when we were off fishing (examples: PPARG inhibitors in thyroid, IGF1R antibodies in adrenal). We are proud to be increasing the arsenal, standing right at the shoulder of your docs and nurses with extra rounds. However:

    One thing I’m worried about in a world where we have compounds for many of the mutations your tumor displays, is that doing clinical trials on custom-blends of several therapies will be hard, and very slow. In the most common tumor types it is a bit easier, but for others, the amount of time required to obtain convincing evidence for a particular drug combo against a particular mutation combo is going to be long. Just to have a grip on the toxicity profile of combinations is hard (e.g. erlotinib + irinotecan). Hell, your genotype at unmutated loci matter too (UGT1A1 for example). It’s so damned messy! Hundreds of diseases? It’s worse than that even.

  7. daedalus2u says:

    I think where this specific research will be most useful is in suggesting which research pathways are likely to not be fruitful.

    Even this research is just a snapshot of what is going on in the cells that were sequenced. Is every cell in the tumor identical to what was sequenced? Probably not.

    With such a messed up genome, likely it can’t replicate itself with good fidelity. That means the tumor cells are continuing to evolve and change.

  8. aeauooo says:

    Why haven’t we cured cancer yet?

    Isn’t that obvious?

    It’s in the best interest of the Unholy Cabal of Big Pharma, medical academia, and the American Cancer Society, AKA, The Cancer Industry, powerful men behind closed doors who are getting filthy-rich from keeping people sick, to suppress The Truth that cancer can and is being cured with baking soda, cannabis, alkaline water, bleach, and pixie dust.

    Sorry, someone had to say it.

    (I am speaking sarcastically, of course, )

    Question: Are conspiracy theories falsifiable?

  9. Alexie says:

    Just got back from today’s radiotherapy and read this.

    There’s only one thing to be said about this post.

    Thank you to everyone involved in the research and trialling of a drug called Rituximab/Mabthera, a monoclonal antibody, which has completely changed the prognosis of the once deadly Non-Hodgkins Lymphoma.

    Thank you to all the researchers and doctors who keep plugging away at this awful cluster of diseases called cancer, even though it mostly takes you down frustrating dead ends. There must be some of you who never see any positive results or cures come from your labs, but you keep on anyway.

    Thank you to all the patients who signed up for clinical trials, even when they didn’t help you and might have harmed you.

    Thank you to everyone who keeps working away, in the face of a ignorant group of people who are have the nerve to claim that you are hiding cures, because you make money from cancer, not to mention the hostile ignoramuses who honestly believe that eating raw vegetables can stop cells running crazy.

    Thanks for everything. I owe you my life.

  10. SarahAnn says:

    Dr. Gorski,

    Did you see the article about a new study that compared cancer cells as an ancient form of life in the universe, basically life a billion years ago behaves a lot like cancer:

    http://www.physorg.com/news/2011-02-cancer-cells-ancient-toolkit.html

    The best analogy I’ve read to illustrate is that cancer is like the ‘safe code’ of an operating system, an underlying rule of genetics that is normally kept in check when cells are doing their thing.

    I can’t pretend I understand a tenth of the complexity, but would love to know your thoughts.

  11. pmoran says:

    I add my appreciation of David forsparing the time to pre-digest such new and complex material for us.

    A thought– is ALL this disorder truly necessary for the cancerous state, as we assume at first sight, or may that state yet be found to be the result of glitches in a single, or a few, critical regularity mechanisms during mitosis? IOW, is this the DNA of the supposed “stem cells” or of a wide sampling of all their progeny?

    The severe disorder could merely be the genetic basis for the macroscopically obvious heterogeneity of the cells in a cancer –pleomorphism, polyploidy, etc)?

    This reflects on the “stem cell” characterisation of cancer growth, which I am not yet enthusiastic about in the sense that the words evoke. It always was obvious on macroscopic appearances that many of the cells in a cancer cells are likely to be so stuffed up as to not be able to reproduce themselves.

    Also, I wonder why it should matter what chromosome a gene is on?

  12. Forgive the possibly trite comment, but…

    What’s wrong with fishing expeditions? One has to drop a line in the water to even know if there’s fish there in the first place.

    Fish away, boffins. Let us know when you pull in the big score, and I’ll wait patiently until then.

  13. overshoot says:

    There is no easy way to do a hard thing.

  14. overshoot says:

    Also, I wonder why it should matter what chromosome a gene is on?

    Because the mechanism isn’t fussy about where it snipped on the way out or where it inserted on the way in. Given the relative length of genes, a multi-gene transposition is pretty much guaranteed to screw up four different genes.

    If the patient is lucky, they all stop doing anything, good or otherwise.

  15. Draal says:

    “What’s wrong with fishing expeditions? One has to drop a line in the water to even know if there’s fish there in the first place.”

    ‘Anomaly hunting’ is another way of putting it.

    I’m curious as to what the mechanism(s) are for gene translocation. Transposons come to mind but they require transposon elements flanking the gene. Viral infections is another means (e.g. HPV). Are there types of tissues that are resistant to cancer, like muscle and brain tissue? B/c they do not replicate rapidly?

  16. Josie says:

    I am printing this entry and posting it above my desk.

    While I don’t work in cancer I do work with stem cells and potential therapies derived from them.

    Biology IS hard, it’s frustrating to the researchers and to the folks who want us scientists to give them something tangible for their tax dollars.

    I think it’s a sign of coming scientific maturity when we can step back and say, this is difficult and this is why —an advance in my view from the noble yet naive statement of “we will cure this disease”

  17. JMB says:

    Thanks for a great article Dr Gorski. Maybe in your spare time, you should write a textbook on the subject.

    I would suggest a term to replace evolution in the quote,

    Indeed, cancer progression can be viewed as being due to a case of evolution in which the tumor cells that survive selection to continue to grow are the ones that become best at doing all the things that tumor cells need to do to evade the body’s defenses and overcome its growth control signals.

    How about de-evolution? I would argue that evolution has a direction. That direction is to decrease entropy. Genetic changes that result in death of an organism are increasing entropy, therefore de-evolution. The cancer cells are losing the evolutionary development of cooperation with the organism, and acting on basic instinct. This kinda relates to the article SarahAnn was quoting. It is sort of the “ontogeny recapitulates phylogeny” concept, but on the level of the genome and cell differentiation, rather than the organism and embryonic development.

    Why doesn’t someone compare the collective genome of adjacent non-cancerous tissue to the cancerous tissue in the same individual? With some special mathematical techniques, you could derive an estimate of the number of translocations/mutation steps required to produce a malignant tumor. It would also be interesting to compare the genome of the patients’ germ cells, to see how well they have been protected from translocation/mutation.

    It is an interesting idea that translocations are more likely to result in a functional gene that has lost it’s response to regulation, than a mutation of a base pair. So perhaps random mutations are less efficient in producing a functional cancer cell than a translocation. Maybe that explains why asbestos is so efficient at producing cancer, it does not directly produce mutations, but does result in rapid turnover of cells, and has a nano-structure that might disrupt orderly cell division.

  18. JMB says:

    One basic argument that we have made significant progress in the war against cancer is that we are seeing a lower cancer mortality rate in younger age groups. As the population distribution shifts to higher ages, we will see a higher incidence of cancer.

  19. David Gorski says:

    How about de-evolution? I would argue that evolution has a direction. That direction is to decrease entropy. Genetic changes that result in death of an organism are increasing entropy, therefore de-evolution

    I said evolution, and I meant evolution. Your terminology is incorrect, I’m afraid. Evolution does not have a “direction.”

  20. passionlessDrone says:

    Hello friends –

    Serendipitously, today at In the Pipeline there was a very neat post that touches on a different take on the same problem; the ineherent complexity of developing drugs to cure disease. It is entitled, ‘New Cures! Faster! Faster’

    http://pipeline.corante.com/archives/2011/02/14/new_cures_faster_faster.php

    This is a cool, cool blog that I’d recommend to anyone interested in learning.

    - pD

  21. windriven says:

    @aeauooo

    “Question: Are conspiracy theories falsifiable?”

    Yes. Unfortunately, conspiracy theorists are not ignorable. Ignorable. Ignorant. So close.

  22. gippgig says:

    I recently made this point on another blog, but I think much more effort should be directed at preventing cancer. It should be much easier to block (or at least slow) the development of cancer than to cure it once it has occurred. Look for ways to induce DNA repair proteins, detoxification pathways, & stress resistance proteins, as well as vaccines.

  23. dedicated lurker says:

    I would also point out that with some cancers, the children diagnosed survive at a greater rate than the adults do. A six year old with ALL is probably going to be cured. A sixty year old, much less so. While I haven’t studied oncology extensively, I’d assume this was due to the fact children are undergoing quite a bit of modification of cells due to growth.

  24. Jan Willem Nienhuys says:

    JMB has a point. How many translocations and mutations are there actually in ordinary cells? After all, evolution of species is not only by point mutations, but also by gene doubling and translocations. And the huge variety of immune globulins is produced by randomly reshuffling of parts of genes, I thought.

  25. Paddy says:

    @Draal,

    > I’m curious as to what the mechanism(s) are for gene
    > translocation. Transposons come to mind but they require
    > transposon elements flanking the gene. Viral infections is
    > another means (e.g. HPV).

    You can also get a translocation occurring by accident if an accidental break in the chromosomes is repaired by sewing the bits of the wrong chromosomes together (a bit of a simplification, but it’s along those lines). Sometimes such an event can also lead to DNA loss (in a robertsonian translocation) and these events are particularly implicated in various forms of myelogenous leukaemia (cancer of the bone marrow).

    > Are there types of tissues that are resistant to cancer, like
    > muscle and brain tissue? B/c they do not replicate rapidly?

    Yes. I’d be willing to bet, for instance, that you’ll never have heard of “heart cancer”, for instance, because it’s just that rare. Pretty much the only way cancer can show up in the heart is if it metastasises there from somewhere else; the heart has only an extremely limited regenerative capacity, and thus a very limited potential for that capacity to go wrong. Whereas skeletal muscle and smooth muscle have greater regenerative capacity but more commonly turn cancerous.

  26. Artour says:

    Official medicine continue to ignore clinical evidence regarding unphysiological respiratory parameters in advanced cancer patients. I am talking about heavy and fast breathing (chronic hyperventilation) that reduces tissue oxygenation due to CO2 effects (suppressed vasodilation and the Bohr effect). For medical evidence on breathing in advanced cancer, visit:
    http://www.normalbreathing.com/diseases-cancer-breathing.php

    Tissue hypoxia leads to over expression of hypoxia-inducible factor-1, chronic inflammation, generation of free radicals due to anaerobic cellular respiration, and a cascade of other pathological effects.
    It is not a surprise that in one trial on metastasized breast cancer, breathing retraining group had 5 fold decreased mortality:
    http://www.normalbreathing.com/diseases-cancer-1-clinical-trial.php

    Should cancer patients preserve their normal breathing parameters, they would never get tumors in the first place.

  27. JMB says:

    One more idea about testing adjacent non neoplastic tissue for tissue damage, it may be a factor in predicting local recurrence. As thousands of errors accumulate, the likelihood of damage to the 5 to 10 critical genes or gene regulators producing a cancer increases.

  28. Zuvrick says:

    If we can put a man on the moon, why can’t we cure for cancer?

    We can, sir [pun intended]

    We did. More than once. Royal Raymond Rife not only developed a super optical microscope that optical experts and physicist said was impossible, he used it to see and positively identify a cancer bacillus, then used the principle of resonance to destroy the virus. He also found the resonant frequencies for most other diseases. Researchers and pathologists from leading universities and medical schools supported his work and proved that what he discovered worked. A clinical trial under the observation by leading doctors from University of Southern California supplied 16 patients who were all hopeless Stadium IV cases, and with the resonant therapy administered for 3-5 minutes once every three days, within six to eight weeks 14 of the 16 cases were totally cured, as pronounced by the doctors. (the others took a bit longer, but were cured.) That happened nearly 70 years ago.

    However, Rife’s work was viciously attacked by the AMA under Morris Fishbein. Apparently Fishbein initially wanted to buy the rights to the Rife equipment (allegedly to prevent it from being produced by anyone), but when Rife declined, Fishbein saw to it that the FDA declared the equipment worthless and most units were confiscated and destroyed. Doctors were harassed. His supporters were attacked and they withdrew their support. Two brave MDs continued to use their units secretly for 22 years, and kept accurate records on the treatment results. One doctor reported that 60% of the cancer cases referred to him were hopeless cases that other MDs had given up on, yet his success rate for total remission that included follow-up checking for up to 10 years was a clean 100%. The machine also cured cataracts without surgery, among other things.

    So we can find a cure. It has probably happened multiple times. But nobody wants to cure cancer. Too many researchers earn a living seeking a cure by remaining inside a narrow, restricted channel of dogma. Their institutions get grant money and survive from the funding. Big Pharma makes big bucks selling chemotherapy drugs, surgeons remove tumors and various radiation devices employ radiologists and firms making these machines. MRI and CT scans would not be needed for cancer if Rife technology were available today.

    Monique and Mirko Beljanski, French cancer researchers, wrote, “A cancerology “big boss” told us quite recently, “Watch out! You’re straying from the main track. If you get too far outside the system, the products you’ve developed, as good as they are or might be, will never have a chance. ” (“Health Confiscated”).

    I might also cite the work of Gaston Naessens in Canada, but I’ll naturally be attacked because he is a well-known mountebank and fraud who has no degree [sic], yet his research spanning more than 60 years should qualify him for a Nobel prize since he is a true scientist of the highest order. If you were to objectively research his discoveries, as a number of doctors and researchers have, you would have to agree. But slanderous statements continue to be repeated about this dedicated genius, who has successfully treated thousands of carcinomas with his 714-X. Naessens proved pleomorphism and that cancer begins from within the body. His painstaking somatid research, spanning decades, will take a long time to be accepted because it shakes the core of biology and medicine, and most textbooks on cellular biology would become quite obsolete.

    The cure exists and it is too simple to accept. If it were accepted and permitted a vast number of highly respected and highly paid individuals would be forced to seek other work.

    That’s all for now.
    Zu.

  29. Mojo says:

    “Royal Raymond Rife not only developed a super optical microscope that optical experts and physicist said was impossible, he used it to see and positively identify a cancer bacillus, then used the principle of resonance to destroy the virus.”

    What virus?

  30. hat_eater says:

    A virus that begins inside the body. And where does it end? Einstein was sure it’s infinite.

  31. TsuDhoNimh says:

    Zuvrick – If Naessens has, as he claims, invented an incredible microscope which “breaks the laws of physics to show you living organisms at 30,000X magnification and 150 Angstrom resolution ”

    He should skip medicine and head straight to semiconductor manufacturers. They would love to see it in action, because it would make them BILLIONS in profits and revolutionize their manufacturing processes.

  32. Khym Chanur says:

    Royal Raymond Rife not only developed a super optical microscope that optical experts and physicist said was impossible, he used it to see and positively identify a cancer bacillus, then used the principle of resonance to destroy the virus.

    Not only is the Conspiracy so big that it can prevent the medical field from using Rife’s discoveries, it’s also so big that it can prevent opticians and physicists from re-discovering how the microscope worked. Amazing!

  33. Zuvrick says:

    You have to understand where Rife was in the timeline and what else was happening in a troubled world. Concerning the microscope, at the time all of the major optical advances were smugly in the hands of the Germans, who were quite distracted gearing up for a large war. In the USA there wasn’t much interest in optics, but the electronics giant RCA had just developed the electron microscope and were pouring a lot into promoting it as the final breakthrough to make optical microscopy obsolete. Unfortunately in medical research it doesn’t work at all for live specimens. You get a stunningly high resolution snapshot of what remains after vacuum and metallic bombardment of the specimen has been done. Rife and Naessens both watched living things for hours upon hours. Naessens 16-stage somatid cycle takes 30-60 hours, and required addition of video to record the cycle.

    Rife’s microscope was lost in the shuffle of his resonance “beam ray” device that was attacked. The conspiracy was probably not huge, but was led by the head of the AMA, Dr. Morris Fishbein, who eventually had to resign in disgrace over other cases. He allegedly never practices medicine and failed his anatomy class, but he was wealthy and this powerful.

    Mojo asked about the bacillus, which Rife called BX. I think by that time Rife was quite aware of the futility of the Koch idea of naming each species since he had found and proved pleomorphism. In his 1953 book, he wrote:

    “We have classified the entire category of pathogenic bacteria into 10 individual groups. Any organism within its group can be readily changed to any other organism within the ten groups depending upon the media with which it is fed and grown. For example, with a pure culture of bacillus coli, by altering the media as little as two parts per million by volume, we can change that micro-organism in 36 hours to a bacillus typhosis showing every known laboratory test even to the Widal reaction. Further controlled alterations of the media will end up with the virus of poliomyelitis or tuberculosis or cancer as desired, and then, if you please, alter the media again and change the micro-organism back to bacillus coli.”

    He isolated and proved that the BX cancer virus existed repeating the experiment over 400 times. He wasn’t working alone, he had one of the best multistory labs in the country, with a large staff, optical fabrication equipment, room for around 1000 animals used in tests, the best sterilizing equipment, million-volt xray equipment, and so on. This operated for about 15-20 years, bankrolled by millionaire Henry Timken, but near the end it was raided by the FDA goons and later mysteriously burned down in a fire. The many outstanding doctors and scientists that supported him withdrew and a number of them died mysteriously. Some others went into early retirement in Mexico. Some of supporters who verified many of his discoveries, included:

    Dr. Milbank Johnson, M.D. [Chief Medical Director of Pacific Mutual Life Insurance Company]
    Dr. Alvin G. Foord, M.D. [director of pathology, Pasadena Hospital]
    Prof. Dr. Arthur I. Kendall, Ph.D. [Northwestern University Medical School]
    Dr. E.C. Rosenow, M.D. [Mayo Foundation & Children's Hospital of New York]
    Dr. C. Fischer, M.D. [Children's Hospital of New York]
    Dr. George Dock, M.D. [Professor of Medicine, Tulane University]
    Dr. Karl Meyer, M.D. [Director of Hooper Foundation for Medical Research]
    Dr. O.C. Grunner, M.D. [Archibald Cancer Research Committee, McGill University]
    Dr. Waylen Morrison, M.D., [Chief Surgeon, Santa Fe Railroad Hospital]

    Of those, the big named were Rosenow, Kendall and Milbank Johnson. The two doctors who used his “beam ray” unit for up to 22 years to treat (“cure”) cancer successfully were Dr James B. Couche, M.D. dan Dr. Arthur
    Yale, M.D.

    By the time that Rife had become an emotional wreck from the various attacks the United States was busy in WW II and fears were focused to other threats.

    –Zu

  34. Zuvrick,

    Writing in a book that you can change a bacterium into a virus and back again is not a proof of anything except that you have no understanding of the difference between a bacterium and a virus, and is consistent with writing before Watson and Crick published the structure of DNA.

    To “prove” pleomorphism as described you would have to perform detailed experiments and publish them in peer-reviewed journals in such a way that other teams could follow your process and repeat your results even if they were trying to prove you wrong.

    Once everyone else had replicatec your results and had excluded all the more-probable explanations, then you would have proved something.

    If just saying you did something counted as proving, well this morning I turned my dog into an okra seed and back again by changing her food. Now that I have proved pleomorphism in multicellular organisms, where do I go to collect my Nobel?

  35. Badly Shaved Monkey says:

    We seem to have headed off into La-La land on the trail of Royal Rife, but can I return us to a real-world problem?

    Yesterday’s UK media gave a lot of coverage to advice about limiting red meat intake to 70g per day to reduce the number of bowel cancers.  This advice was coupled with the information that bowel Ca kills 16,000 people per year in the UK. 

    It always seems to me that the way these stories are presented implies that if we take all the best advice then then incidence of the particular cancer can be reduced to zero. By extension, if we took all the best advice then the incidence of all cancer would be reduced to zero.

    An ability to prevent all cancer is one of the Big Lies sold to us by SCAM. 

    My point is that simplistic public reporting opens the door for SCAM to make these claims. 

    However, as Dave Gorski points out, nests of precancerous and cancerous cells are present in all of us and are, effectively, a fact of the ageing process. I have definitely heard it said of prostatitic cancer, given its high prevalence in old men, that the issue is not whether a man will get prostate cancer but when and whether, by the product of its age of onset and intrinsic aggressiveness, it will be the eventual cause of death. 

    And so, discussion of absolute numbers of cancer cancers per year in the population is misleading. What we are actually trying to do is postpone the onset of cancer and/or reduce its rate of progression. Might it be that the incidence is self-correcting over the long-haul?

    Use some made-up numbers to illustrate my point. I’ve not sat down to make the arithmetic work, so please don’t go and check it. 

    Population 70million. 16,000 bowel Ca per year. Life expectancy 75. 
    Apply successful harm-reduction strategy
    Population 71million. 16,000 bowel Ca per year. Life expectancy 77. 

    Obviously one can quibble with the numbers but the point is that reducing cancer now may simply postpone the appearance of cancer in people only to reappear later on in that same group. So, absolute numbers of cases and cases per year may homeostatically return to their prior levels. BUT, incidence of disease at a specific age and life-expectancy will have increased. 

    So, the conclusion at last, should medical authorities advising the public talk not in terms of absolute cases per year, but in one of several possible metrics: life expectancy, cases per year for a specific age cohort, additional cancer-free years of life, additional years to death from cancer?

    Adopting this more subtle approach would cut the ground from under the cancer-cure quacks and show the question “Why haven’t we cured cancer yet?” to be based on a falsely simplistic premise. 

    I accept this may be all very familiar to cancer epidemiologists but from my outsider’s perspective it is certainly not being applied to inform public policy and the presentation of public policy.

    This approach also places an umbrella over a problem on which Dave has commented previously- early diagnosis of cancer and the question of whether increased life-expectancy post-diagnosis is genuinely increased overall life-expectancy or merely an artefact of starting the cancer survival clock running at an earlier point rather than showing a genuine benefit from treatment. 

  36. Badly Shaved Monkey says:

    As illustration of my opening point here’s a link to the BBC’s coverage of yesterday’s story;

    http://www.bbc.co.uk/news/health-12571576

    “Experts say thousands of bowel cancer deaths could be prevented every year if people kept to the new limits.”

    It’s that unqualified word “prevented” that is at the heart of the problem.

  37. Steve Packard says:

    Given the complexity of cancer and the fact that it’s really not one condition but a variety of conditions that exist in numerous systems and organs in the body, I don’t see how we can reasonably expect a single compound or therapy to ever be a general purpose “cure” for cancer.

    The only way that I could see that happening – a day where you could take a pill and it will cure your cancer, regardless of what stage or variety it is, would be if we got to the point where we could introduce some type of entity, either in the form of nano-robots or synthetic microbes that are pre-programed to go through every cell in the body and systematically assess the health of every cell and then destroy cancerous cells and rearrange tissue to repair all injuries.

    Of course this is totally science fiction now and we’re not going to be to the point of introducing nanoscopic robots to sweep the body of cancer cells today tomorrow or in ten years.

    But in one hundred years? Who knows, it may happen. Then again, it may not. That’s the only way I could ever imagine a true general purpose “cure” for cancer.

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