Dean's World

Had a visit with my family physician today. Best doctor I ever had. And I mean that without reservation: she's the best doc ever ever. She really listens, she's respectful, she cares, and she's not a wimp. She really knows her sh*t, she can disagree with me but respect my disagreement, and she really cares. God I love her.

She's also maybe ten years my senior. And I caught her today in a "senior moment." We were sitting there after the office visit and she was talking to her staff, and she said, "OK so check me on this, tomorrow is July 31, right?"

I immediately said, "Uh, no."

"OK, tomorrow is September 1?"

"Uh, no?"

Now, see, a really stupid person would say "wow, this doctor is totally addled and can't find up from down." But the intelligent person says, "This is my very intelligent doc, who just made a fencepost error."

If you think you're above a fencepost error, you're an idiot.

And you know how I know she is one of the best family physicians ever? When she asked that question, I said, "Do you know what year it is? Do you know who is the President of the United States? Can you follow my finger?" as I waved it in front of her face.

See, now, you think I was being sarcastic and snotty. But this is the moment in which I knew I loved her:

She busted out laughing and said, "Hahahaa, you got me!"

That, my friend, is a family physician you want forever.

I wouldn't just trust my life with this woman. I'd trust my wife and children with this woman. Not that she's perfect (she ain't, no one is) but she knows her calling.

This doesn't include Japan or France, but is still pretty powerful evidence our healthcare system is the best in the world.



This data says the oft-publicized plight of the uninsured is not dragging U.S. cancer survivability down even to European levels -- and cancer is expensive to treat. So either the insured are getting incredibly good care, so good it outweighs the alleged 50 million uninsured who would supposedly die from lack of treatment if they got cancer, or the uninsured are in fact getting treated.

It's not just that U.S. hospitals treat everyone who shows up needing care, or that states have their own systems of funding medical care for the poor; there are also all kinds of medical charities, formal and informal, a product of American-style capitalism's enormous private wealth. These are not hard to come by; in a rural area where I lived in for a while, there was a family or ne'er-do-wells notorious for fundraising almost every year for supposedly desperately-needed kidneys or livers.

It seems very unlikely a significant enough number of U.S. citizens are involuntarily going without medical care in the U.S. to the extent that the toll exceeds, per-capita, the excess deaths of citizens being forced to wait for medical care or given substandard care in socialized systems.

M Simon at Power and Control has the scoop, as usual. There is apparently confirmation from Dr. Bussard that the Navy is going to pick up his original contract and re-fund his efforts to produce a WB-7 demo model — and if the results are as expected, a full-scale power plant (approx $100-$200M), which is more than we'd dared hope. Confirmation and further details should follow shortly.

Tom Ligon says Bussard credits the grassroots campaign among bloggers, so thanks to everyone who followed this.

So now the race with Tri-Alpha to a working net-power IEC fusion machine (and perhaps a new era for humanity) begins. Should be a very exciting next few years.

I found this story of an embattled sex researcher fascinating. I honestly take no opinion on his theories, except to note that I've been saying for, oh, at least 10 or 15 years now that gay people who insist that homosexuality is genetic were going to face certain arguments that they didn't like sooner or later, and that this sort of argument was long-term damaging to the community.

I also note that it's just sort of assumed in the story in passing that people who associate with this researcher are afraid they'll lose their ability to get research grants. Which goes with something I've raised so many times, which is the complete charade that is our "anonymous peer review funding" system to dole out taxpayer funds in an opaque, croney-filled system. More people should be upset about it since it's so obviously a flawed and irresponsible way of spending public funds.

*Update*: The Wikipedia entry is indeed interesting.

When you're working to advance science, the appropriate response when someone finds an error in your data or calculations is contrition (best expressed by an openness to further scrutiny and re-evaluation), and perhaps gratitude that truth has been served. James Hansen, on the other hand... well, read for yourself:

The contrarians will be remembered as court jesters. There is no point to joust with court jesters. They will always be present. They will continue to entertain even if the Titanic begins to take on water. Their role and consequence is only as a diversion from what is important.

The real deal is this: the ‘royalty’ controlling the court, the ones with the power, the ones with the ability to make a difference, with the ability to change our course, the ones who will live in infamy if we pass the tipping points, are the captains of industry, CEOs in fossil fuel companies such as EXXON/Mobil, automobile manufacturers, utilities, all of the leaders who have placed short-term profit above the fate of the planet and the well-being of our children. The court jesters are their jesters, occasionally paid for services, and more substantively supported by the captains’ disinformation campaigns.

Court jesters serve as a distraction, a distraction from usufruct. Usufruct is the matter that the captains wish to deny, the matter that they do not want their children to know about. They realize that if there is no ‘gorilla’, then usufruct is not an important issue for them. So, with the help of jesters, they deny the existence of the gorilla. There is no danger of melting the Arctic, of destabilizing the West Antarctic ice sheet, of increasing hydrologic extremes, more droughts and stronger forest fires on one hand and heavier downpours and floods on the other, threats to the fresh water supplies of huge numbers of people in different parts of the globe. “Whew! It is lucky that, as our jesters show, these are just imaginary concerns. We captains of industry can continue with business-as-usual, we do not need to face the tough problem of how to maintain profits without destroying our legacy in our children’s eyes.”

Hardly the model of dispassionate reason and logic; this is as polemic as anything written by Ann Coulter. I mean, really, calling your critics "jesters?"

I didn't know much about Hansen before this incident, but this does not inspire confidence in his work.

As has been noted before, if Hansen really cares about global warming as much as he claims, he needs to release all the GISS data and algorithms for public scrutiny. Someone reverse-engineered GISS' work to find this error, which as a programmer I can tell you is a very troubling harbinger, as it means it was fairly obvious. Maybe the rest of the GISS data is perfect, but sunlight is the best disinfectant.

Again, if global warming really matters to Hansen, he should be doing everything possible to ensure the integrity of the data and calculations his apocalyptic rhetoric is based on; that's the scientific method to dispel doubt, not calling your critics names when they find flaws in your work. As Glenn says, we'll believe this is a crisis when the people claiming it's a crisis start acting like it's a crisis.

in. your. face!

The Germans confused group velocity for velocity.

In the wake of the news that German physicists claim to have broken the speed of light, Glenn asks "Does quantum tunneling really violate special relativity?" I think the answer is yes. QM and relativity just don't get along very well.

There's an esoteric effect in relativity that demonstrates the problem with FTL information transfer. In Fabric of the Cosmos, Brian Greene notes that according to relativity, a person ten billion light-years away can move centuries into your past or future simply by walking toward you or away from you, because the effect accumulates over distance. This isn't a problem for relativity, where nothing travels faster than light and no information can pass between the two that might violate causality. But enter quantum nonlocality, and now you have a problem. Your 10B-LY-distant friend could travel into your future by walking toward you, get some stock/lottery picks from your grandkids instantly via a nonlocality effect, walk away from you and give them to your grandparents.

I think eventually we will find relativity's treatment of time must be lacking in some respects, or that Warren Buffet has been doing this for years.

UPDATE: Okay, I found the passage I referenced above from Fabric of the Cosmos. It's on pages 134-139, and it says more or less exactly what I remembered: an observer at rest relative to us, 10 billion LY away, can travel into our past and future by walking towards and away from us. Brian gives the example of a Presidential election rather than stock picks, but it's the same concept. This means that if you can communicate with him instantaneously, as the Germans claim to have in their experiment, you can learn about your future and violate causality.

I don't believe causality can be violated, so as I said above I think this means relativity must be incomplete.

Since it seems to be Global Warming Day here at DW, I'll join the party and chime in as well.

There are essentially three assertions that warmenists need to prove to make the case that huge amounts of money need to be spent to prevent global warming (it's important to keep in mind that in the scientific method the bar for heretics/denialists is much lower; the null hypothesis does not bear the burden of proof).

1. Global temperatures are rising.

2. This global temperature rise is caused primarily by human activity.

3. Global warming will have profoundly negative consequences in a meaningful time frame (say, 100 years).

Even with the recent GISS embarassment and weak underlying data, the first is almost certainly true. The second is believed to be true by most scientists, though there are vocal dissenters who point to solar irradiance, other natural variability, and warmer periods in the Earth's past prior to homo sapiens' industrialization. The third assertion is the one that really doesn't prove out very well: sea levels are not expected to rise enough to seriously affect humanity (and recent ice core samples from Greenland indicate catastrophic flooding is even less likely than previously thought), and other putative negative consequences are offset by probable positive consequences (generally speaking, in human history warming has been overwhelmingly beneficial, allowing longer growing seasons, better hunting/foraging, less need for heating fuel, reduced misery, and more biodiversity).

The third assertion is also the focus of an increasing number of claims based on little or no scientific evidence, from the notion that global warming has created a plague of feral cats to the idea earthquakes and tsunamis or increased hurricane frequency are caused by climate change. This kind of alarmism distorts the debate and tends to discredit even the valid scientific arguments by assocation; warmenists need to be more careful in this regard and police their own if they want climate change to be taken seriously.

Finally, it has to be kept in mind that there exists both a large economic incentive and an ideological imperative for warmenists to prove their case, which should make any independent oberver wary of their claims. Money and politics rarely make for good science.

I am a skeptic.

For people who truly understand, a "skeptic" does not say "I think X is not true." A skeptic says, "I am not convinced about X, and I have some tough questions." Which, to me, has always been where science truly starts.

I'm often astonished how some people, especially some with college degrees in science, can't distinguish the difference.

Many of my friends and teachers who have been working scientists have told me a certain dirty fact: there are an awful lot of "scientists" who are nothing but bureaucrats and self-serving suckups and administrative button-counters and bottle-washers-- just like every other honest and admirable profession in the world.

(Repeat: Just like every other honest and admirable profession in the world.)

On global warming, my position has been the same for years:

1) It is undeniable that there is Climate Change.
2) It is virtually 100% certain that human beings are contributing to Climate Change.
3) It appears highly likely that there is a general warming trend in the world at the moment.
4) CO2 levels have clearly been increasing globally for decades.

So, given that I agree to all of that, what exactly am I "doubting" or "denying" or expressing "heresy" or whatever on? I await a succinct answer upon that.

In the meantime, what is not clear to me, and has not been clear to me for some time is:

1) The increase in CO2 levels is the primary cause of whatever warming trend we've seen recently. How sure are you? It's okay if you have some doubt. But how high is that doubt? 10%? 20%? 30%? What's your confidence interval?

2) Regardless of how certain you are, a separate question: is this truly the most important ecological question we face as a species and as a planet? Should this truly be our #1 priority, ecologically and in terms of our nation, our race, our species, or our planet?

I've been saying most of this pretty consistently for quite some years now. Indeed, I'm pretty sure that (aside from maybe a sarcastic or flip comment now and then) that I haven't changed my view on that in a decade.

For the record, I have read Al Gore's Earth in the Balance cover-to-cover, including all footnotes, and checked many of his references. Have you?

I've also read Rarchel Carson's Silent Spring, by the way. Have you read it, Mr. Self-righteous Liberal or Ms. All-Knowing Conservative? I even have the special edition where Al Gore wrote his own introduction to it somewhere in my library. I remember being as unimpressed with it as I was with Al Gore's incredibly self-serving, messianic political campaign movie, An Inconvenient Truth, which he quite transparently hoped would transport him to the Presidency in 2008 and still hopes will make him a viable candidate in 2012. (Which is just fine by the way, but let's not kid ourselves that this man is in any way smarter or more noble than, say, George Bush or Bill Clinton, because he isn't. Although he's still a way more honest and intelligent pseudo-documentarian propagandist than, say, a hatemonger like Michael Moore).

Indeed, for some time now I've been saying that if Al Gore and their supporters would just drop their destructive opposition to nuclear power, I would be willing to compromise and support some of their other proposals which I found dubious. All they have to do is stop demonizing nuclear power, which is the most environmentally friendly, greenhouse-gas-free form of power generation ever invented by humanity. Unfortunately, Al Gore still publicly refuses to do so.

And by the way, my own personal financial or personal stake in the nuclear power industry? 0.0%. It's just the most environmentally friendly and economically viable form of power generation humanity has ever created, and I still feel betrayed by "environmentalists" who demonize it.

Anyway, since you can't make this simple politics-free concession, Al & Co, I'm not on your side, and will instead continue to do my best to (A) educate people on why we appear to have been snookered by the ridiculous luddites who oppose nuclear power, and (B) continue to point out why everyday people should be skeptical of global warming scaremongers, especially those scaremongers who clearly derive their entire incomes and personal prestige from spreading that scaremongering.

And by the way, to you scientists who do this research? For pay? As part of your full-time jobs? From money that comes from taxpayers like me? You don't get to whine like wounded puppies when someone says, "uh, so, that money we gave you, did you do something valid with it? Or are you just rationalizing?"

As for me: "Denier?" "Heretic?" "Doubter?" Hey, pick whatever convenient label helps you ignore the substantive arguments raised here (and elsewhere, not just by me but by many others).

*Update*: By the way, as I've said many times before, I pretty much consider it a given that anyone reduced to using the word "denier" or "denialist" or "conspiracy" or claiming that only money drives skepticism automatically proves themselves intellectual lightweights not worthy of answering.

Weird but apparently true — and bad timing for some. When we called global warming "anthropogenic," I don't think we meant it was caused by programmers.

Of ccourse, this mostly just means the problem isn't as bad as thought; it doesn't affect the global averages by more than a few percent. But it does raise troubling questions about the accuracy of the underlying data, especially since people like James Hansen, who heads GISS, have a huge financial and career interest in having the numbers trend upward. A conflict of interest coupled with a lack of transparency is a recipe for abuse.

I hadn't realized the GISS temperature data underlying so many GW models was based on secret computer code and undisclosed correction methods. If they're serious about global warming as anything more than a vehicle for funding, they need to release all of this for public scrutiny. Now.

UPDATE: This is even worse than I thought. There's been a volunteer project to check out the network of temperature monitoring stations, to determine how reliable their measurements are. When problems like nearby air conditioner exhaust and lightbulbs next to thermometers were found, the response from the National Climatic Data Center was... to hide information about the stations locations so no one could check them. They later relented, but cancelled a project to validate the network.

This is so not how science is done.

I just got off the phone with Dr. Miklos down under. For some stupid reason, after over 2 years of correspondence, I'd somehow assumed he was Spaniard by descent, but it turns out he's a Hungarian. Silly me.

Still, he's semi-retired, and paid as a genetics consultant. He has no book to sell, no treatment plan to offer, no patent to sell, and no profit motive. I already knew all of that except the Hungarian part. I've always loved Hungarians since I met my first Hungarian, whose name was Atilla Nanay. I told George that if he was named Atilla Gabor rather that George Gabor, everybody would be afraid of him. He laughed heartily and said "Atilla Genghis would be even better, eh?"

George's list of peer-reviewed publications is longer than your right arm, stretching over the last 30 years. Just go ahead and check if you don't believe it. He's just in a position right now where he owes no allegiance to anyone, financially or otherwise. Indeed, as his recent email stated:

I am semi-retired, financially independent and enjoying a lifestyle that allows me to think, interact with whomsoever I wish, travel internationally and write without any pressures from academia, government or the corporate world.

I set up Secure Genetics nearly 10 years ago as a private consulting company so that I could think about data in my retirement and draw upon the expertise of people whose clinical and scientific expertise I valued.

It transpired that a number of firms, large and small, wished to, and continue to, use my insights into various problems with which they are faced, precisely because I have no axe to grind. I just evaluate data; scientific, clinical, statistical and corporate.

Secure Genetics has never applied for any grants, government or private, nor does it intend to do so. It is not a front for, nor does it endorse, any particular technologies, imaging or otherwise.

The article:

When one looks at the completed Miklos-Baird article and it's references, the only reference to an imaging technology for human cancer is reference 98 which is to Magnetic Resonance Imaging of lymph nodes of patients from the Massachusetts General Hospital and the Harvard Medical School. I do not know any of the people involved. This is the type of imaging technology which the article highlights for metastatic cancer.

As far as BioTraces is concerned, it's a company whose technology I have been aware of for over a decade. It is a radioactive technology and cannot be used in cancer patients for in vivo imaging because of the properties of the multi photon detection characteristics. A look at the picture will reveal an image of a 2 dimensional format which any scientist or clinician would recognize. My current intellectual interests are in evaluating 2D protein gel data in the adult stem cell field in terms of cutting edge technologies. The Biotraces radioactive methodology is particularly suitable for this, hence the picture.

I have not received any payments from Biotraces, nor do I consult for them, nor do I help them apply for grants. I interact with them as I do with all my affiliates when I need advice in areas in which I am deficient.

The data I have evaluated for recent international clients have involved the diverse areas of renal dialysis; chemical fractionation technologies for immunoglobulins; single nucleotide polymorphisms potentially predisposing to myocardial infarction, stroke and atherosclerosis and finally, trade mark disputes involving pesticides.

I became interested in the cancer area as one that was a complete mess in terms of therapies that seemed to be doing little for patients and so I have slowly evaluated it over the last 5 years as a personal intellectual challenge, in combination with my friend Dr Phillip Baird who is both a physician and a pathologist of decades standing.

If the cynics wish to fly over to the northern beaches of Sydney to enjoy the idyllic surroundings and genuinely discuss cutting edge scientific and clinical aspects of cancer that may be of therapeutic benefit to patients, or any other of the diverse areas in which I have an interest, then they are most welcome to do so. Attached is a picture from my home office. They would then realize that the last thing one would wish to do is to bother interacting with granting agencies, private or governmental, or setting up imaging companies. Life's too short for that.

After talking to George, I made a single invitation: he and Dr. Baird should review all the comments left so far on Dean's World on this particular series, and respond on the front page to any comments they find particularly interesting or worthy of challenge. For example, commenter Elizabeth Reid left a couple of comments regarding a couple of their citations that deserve an answer. I am otherwise proud to have presented this series, and to have presented a simple question to American (and non-American) taxpayers and medical consumers:

Are we getting our money's worth out of what we've spent these last 30+ years?

by George L Gabor Miklos, PhD and Phillip John Baird, MD PhD

To understand how cancer begins, it is useful to examine readily accessible tissues for the earliest stages. One such place is the cervix where billions of PAP smears and other gynecological examinations have been conducted. Here the first microscopically recognizable changes reveal that some cells have four copies of their DNA instead of two (66-68). Why is this finding so important?

Once four DNA copies are attained, all Hell breaks loose

The two-copy to four-copy event is rare but can occur spontaneously in any normal cell population. Two normal cells may fuse, or a normal cell may replicate its DNA but then not divide. Such events can also be caused by viral infection (69).

Once attained, a four-copy DNA state is 1000-fold more unstable than a two copy state (70-72). These cells with their doubled-up DNA begin to jettison the excess DNA or to silence their genes by mutation or chemical modifications. Systems fail, errors increase enormously and deletions, additions, rearrangements and mutations devastate the DNA.

Thus every-day cell biological processes, once started, wreak havoc. A population of cells is generated with massively disrupted DNA contents leading to modifications in metabolism and further accumulation of changes including single letter mutations (65,73-76). The flexibility of this population far exceeds anything that can be achieved by mutations alone in a two-copy DNA system. It is this flexibility which drives the spread of cancer and subsequent drug resistance.

The Mutationists

The theory of the mutational basis of cancer in humans is predicated on the progressive accumulation of mutations in “cancer” genes in two-copy DNA systems. This interpretation received a boost when three specific genes were experimentally introduced into a cell line and those human cells formed tumors when transplanted into mice (77,78). Mutations then became the drivers of cancer and the massively altered DNA contents of the metastatic cells in patients, (which are crucial to drug resistance), were quietly ignored.

The results from this artificial three gene system, however, turned to dust. Reexamination of the original cells not only revealed them to have massively altered DNA contents, but other investigators could not repeat these findings using exactly the same three genes (79,80,81,82,83).

These inconvenient truths, however, were ignored and investigators began a frenzied search for mutated “cancer” genes in every tumor source. Having found mutations, however, few investigators attempted to determine their clinical significance. It is axiomatic that if a mutation in a gene causes cancer, then reintroducing a good copy of that gene into a cancerous cell should restore the cell to normalcy. When this simple test was conducted, however, the cells did not revert to normalcy(80). The basic premise of causality failed the most elementary test.

Worse follows. Recent population-based data on two famous breast “cancer” genes calls into question the clinical significance of the extensively studied mutations in these genes, for which many women are tested (84).

The BRCA1 and BRCA2 breast cancer genes

Most women are aware of these two genes and dread that they may carry mutations within them. After decades of detailed examination of mutations in these genes, however, definitive clinical data now reveal that breast cancer specific rates of death among women who are carriers of BRCA1 or BRCA2 mutations, are no different to those of women without these mutations (84). Clinical data have thus rendered irrelevant a decade or more of mutation-based research data.

Despite all the clinical and experimental data to the contrary, leading cancer figures regard the mutational basis of cancer as some sort of Final Truth which is not to be questioned; only the details need to be filled out. Cancer researchers ferociously defend any genes on which they work as being absolutely crucial to some aspect of cancer, no matter how tenuous, distant or vaguely relevant the clinical connection may be. This is hardly surprising; finding “cancer” genes is now a prerequisite for fundraising and for Big Science enterprises.

(Next up, and the finale: Cancergate, The Hope, and Failure vs. Crime. To be published Monday August 6.--Dean)

I saw yesterday morning that a rather famous newscaster named Robin Roberts has breast cancer. I find this somewhat ironic since we're featuring the series on the cancer industry this week, and because a male acquaintance who's very close to me is currently undergoing a breast cancer scare---for himself.

These days I can't get online as much as I used to, but a comment to the Miklos/Baird series that was left the other day deserves a public answer:

Dean, I worked in the cancer field...Your mind is as closed on this as you accuse the medical research industry of being. You think we are all ghouls motivated by our paychecks alone and that we would gladly suffer the ill to die rather than cure them because otherwise we are out of jobs. Or maybe you don't believe that, but you are still giving Miklos the time of day and front page access to your blog to endorse his views of same.

This is over-the-top. It's certainly not what I believe. I'll give Miklos and Baird the opportunity to respond for themselves. But let me tell you what I think:

Few if any Oncologists (cancer doctors) can be blamed for failures of the research industry. They can only go by what the research establishment tells them. Indeed, going against that research establishment would open them up to lawsuits and other serious professional problems. Nurses and other cancer caretakers are even less to blame. The only people who can be accused of failure are professional cancer researchers, and even their blame is limited. Especially young researchers.

Still: failure is failure, and it's our money and our lives that are on the line.

by George L Gabor Miklos PhD and Phillip John Baird MD PhD

DRUG RESISTANCE AND THE RETURN OF CANCER

Normal cells are inflexible in a crisis

When normal cells are subjected to chemotherapeutic drugs, the cells have a limited capacity to either inactivate the drug or to expel it using various pumps that are found at the cell surface (42,43). Some cells respond better than others, since they have more efficient versions of these pumps and/or more efficient drug inactivating systems. As the level of the drug increases, however, the inactivation and pump systems are overwhelmed and normal cells die from drug toxicity. They lack operational flexibility, even in times of crisis, because they can only implement the fixed instructions in their two-book operating manuals.

Cancer cells have additional flexibility in a crisis

By contrast, when cancer cells encounter a chemotherapeutic drug, the diversity within the cell population is so great that some cells always have a novel combination of instructions courtesy of their massively disrupted DNA contents. Some cells survive and grow back even in the face of different drug combinations. Thus the return of cancer is understandable when viewed from the perspective of cancer cell populations, the members of which have diverse and flexible operating systems. These attributes have yet to be recognized by most cancer researchers who are generally unfamiliar with classical manipulations of large chunks of DNA and the consequences of the additive effects of genes that are slightly sensitive to abnormal dosage (44).

The flexibility inherent within a massively disrupted DNA cell population was clearly demonstrated by the experimental removal of the main drug pumps from cells (45-48). With their frontline multidrug defences completely missing, such cells were nevertheless rapidly able to become drug resistant because of their massively disrupted DNA contents.

How different is drug resistance in each person?

Every human being (except for identical twins) is unique at the DNA level. Hence each cancer cell population follows a unique trajectory as the cells leave the primary tumor. Each woman with breast cancer will not only differ in terms of drug resistance, but also in her intrinsic ability to control the growth of any particular cancer. For example, breast cancers in African-American women are more aggressive and less responsive to treatment than breast tumors in Caucasian women (49). Some women will have cancers that return quickly, others more slowly. The majority of women who respond to Herceptin will develop drug resistance within a year (50), but others take longer. Some cancers will even remain dormant for years.

Handling the truth

The earlier statements of Dina Rabinovitch, “My cancer keeps recurring. Nobody can tell me why”, are now less mysterious when viewed in the context of the differences in flexibility between normal and cancer cells.

Most cancers rapidly become drug resistant because each population of cancer cells is different in terms of its massively altered DNA contents. Each cancer reacts to drugs in its own way leading to the selection of those cells with novel genetic operating systems that resist drug effects. It is the ability of any cancer population to continuously adapt that makes it so dangerous.

NEW FRONTIER OR YET ANOTHER UNFULFILLED PROMISE?

Personalized treatment for the individual patient

Examining a person’s DNA profile has been popularized by forensic medicine and is now being applied to cancer patients. Dr Victor Velculescu of John Hopkins University explains personalized cancer treatment (51).

A cancer patient comes into a clinic and has her tumor analyzed. Then she is treated based on a spectrum of her mutations with a cocktail of drugs. It doesn’t mean a new drug for each person, just a different combination of drugs.

The above seems like a dream come true and is being heavily promoted as the new frontier in cancer, with billions of taxpayers dollars due to be spent in this new area (52-55). Pharmaceutical companies have recognized the potential of increased sales and are designing new drugs to target cancer-based gene products in order to obtain the biggest slice of this upcoming $60-$70 billion market.

DNA profiling

Current DNA profiling technology of single letter DNA mutations is straightforward, but how relevant is a drug combination prescribed on the basis of profiling a primary tumor to shutting down metastatic growths?

Single letter mutations

When fully sampled, a primary breast tumor will harbor millions of mutations (6,32,56). In addition, each breast and colorectal patient analyzed to date (6) has been found to have a unique combination of mutations (15). This huge number of mutations, plus the unique combination of them in an individual, poses enormous challenges in demonstrating the clinical relevance of mutations. Clinical relevance cannot be sufficiently emphasized.

Since only about 1 in 50,000 of the cells in a primary tumor has the potential to become metastatic (34-38), which of the millions of mutations are in the dangerous cells that leave? It is not possible to determine this without first isolating these maverick cells from the bulk of the solid tumor. Since this is not done, DNA profiling reflects the sum total of all the mutations in the primary tumor. Any clinically relevant mutations remain diluted by millions of clinically irrelevant mutations. A DNA profile from a primary tumor consists almost entirely of noise.

Drug combinations

Future personalized drug combinations will require clinical trials and separate FDA approval. There are currently only five FDA-approved combination regimens for one of the most intensely trialled major cancers, colorectal cancer (57), but the number of possibilities for new drug targets generated by the millions of mutations in a primary tumor is astronomical. The mere thought of developing new drugs each specific to one of the millions of potential new targets, given the current ten year time frame for the development and testing of each new drug, is delusory.

Drug combinations can be dangerous. As Dr Steven Hirschfeld of the FDA points out; “These are all myths having to do with anticancer drugs…that they’re very targeted, when in fact all these drugs have multiple targets. That they’re nontoxic, when in fact the latest ones have their own set of side effects. And that they’re cures, when they are not.” (58). There are no anticancer drugs that are specific for a single target; all bind to several (59,60).

The data show that each cancer cell population is unique, each anticancer drug is nonspecific and each patient differs with respect to drug resistance. Personalized cancer medicine in its currently practiced form of determining the extensive DNA profile of a primary tumor via single letter changes and then prescribing drug combinations is simply another promotional exercise (52,53,61-65). The glib statement that, “it doesn’t mean a new drug for each person, just a different combination of drugs”(51), is completely out of touch with the reality of clinical, pharmaceutical and FDA implementations.

The reality of massively disrupted DNA contents

Current personalized cancer medicine focuses on single letter mutations rather than the massively disrupted DNA component of cancer. Half a century of genetics, however, shows that the effects of massive changes involving many genes dwarf the effects of single letter mutations. Analyses of additions and deletions of DNA in experimentally manipulable organisms reveal that varying the dosage of large chunks of DNA has far more important biological effects on the flexibility of genetic operating systems than the small scale mutational changes that can be induced in normal cells (44).

So how have we reached this preoccupation with personalized DNA profiling of mutations when our answer lies not in the bulk of the tumor, but in the tiny population of maverick cells with their massively disrupted DNA contents? The answers lie in the fashions that dictate cancer research.

(Next up: The Earliest Stages of Cancer, The Mutationists, and Breast Cancer.--Dean)

Interesting news:

UCI biologist Dominik Wodarz has shown for the first time that the development of AIDS might require HIV to evolve within a patient into a state where it spreads less efficiently from cell to cell. This counters the current belief that AIDS develops when the virus evolves over time to spread more efficiently within a patient, ultimately leading to the collapse of the immune system.

The study also finds that multiple HIV particles must team up to infect individual cells, called co-infection, in order for deadly strains to emerge and to turn the infection into AIDS. If just one virus particle infects a cell, the deadliest strains may not be able to evolve, stopping HIV from progressing to AIDS. By keeping more than one HIV particle from infecting a cell, scientists might be able to ward off AIDS, the study suggests. AIDS killed more than 17,000 people in the United States in 2005.
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This theory could explain why certain monkeys that are naturally infected with the monkey version of HIV never develop AIDS. According to Wodarz's model, multiple virus particles may infect cells at reduced levels or not at all. Wodarz says this theory also could be tested experimentally.

This, combined with the difficulty in properly diagnosing AIDS (particularly in Africa) probably explains why the connection has been as tenuous as it has, which has even led some to totally discount any link between HIV and AIDS (which is going a bit too far, imho).

It's also interesting that we have two articles involving in vivo evolution of deadly diseases on DW today. Apparently the concept is catching on with medical researchers, if not in Kansas or Karachi.

by George L Gabor Miklos PhD and Phillip John Baird MD PhD

The cells that leave the primary tumor have different DNA characteristics to those that remain. It is their altered properties that enable these emigrants to leave in the first place and for their descendants to infiltrate and destroy vital organs. (20, 21, 22, 30, 31)

Normal cells

All normal cells have two copies of their DNA, one set from the mother and one set from the father. There are thus two DNA code books (instructions-for-cell-survival) in every normal cell. If one book is damaged, there is always a good copy from which to make repairs in an emergency. Normal cells carefully follow the instructions encoded in their DNA and execute them in a particular order and at specified times. Normal cells are tightly constrained by their two-book genetic operating manuals.

Cancer cells

By contrast, cancer cells that have left the primary tumor and are in transit or have arrived at their final destinations, have massively disrupted DNA contents. Their instructions-for-cell-survival books have been copied and they have more than two of them, but with profound differences. Enormous errors have occurred during the copying process so their books now contain some extra chapters, sentences and paragraphs, while some other chapters, paragraphs and sentences have been completely deleted. Furthermore, differing amounts of text have been shifted from one place to another and at the most basic level, single letters have been changed. These single letter changes are commonly referred to as mutations (6,32).

The extent of these massive alterations in DNA is aptly described by Dr Garth Anderson, of the Roswell Park Cancer Institute in Buffalo, NY; "in most adult solid tumors the genome is shot to hell by the time the tumor is found..." and ...a mutation will not be in every cell in the tumor." (33)

The danger lies in the diversity within a cancer cell population

The mistake-prone process of DNA copying, cutting and pasting that goes on in cancer cells produces remarkable outcomes. Cancer cells no longer have to obey instructions. They have been liberated from the rigidity of conventional two-book genetic operating manuals. The ongoing process of massive alterations in DNA provides a cancer cell population with novel instructions on how to cope with various emergencies. Thus when chemotherapeutic drugs are encountered, some cancer cells in the population have different ways of dealing with drugs. No matter what defenses the body may deploy, some cancer cells in a population always have a new combination of instructions ready to face a crisis.

The cancer cells that leave home have increased informational diversity

The cancer cells that leave a primary tumor are often first found in the nearest lymph node draining the tumor and later in more distant places such as the bone marrow. A comparison of the DNA contents of individual cancer cells from the lymph nodes and bone marrow of the same patient to those of individual cells in the primary tumor reveals that cancer cells at these different locations have accumulated their own specific changes in their DNA contents. (22)

The cancer cells that leave the primary tumor represent a diverse population upon which selection will act. Some cancer cells are destroyed by the immune system, others reach the lymph nodes and progress no further, whereas still others reach an organ but are held in check by the local resident cell population and cannot proliferate. Finally, some cancer cells survive all these hazards, grow at their new sites and ultimately destroy a vital organ. In a nutshell, this is metastatic cancer.

Most cells in a primary tumor never leave

Only a small number of the cells in a primary tumor ever develop the DNA alterations to emigrate (21,34,35). If all cells had the capacity to leave, no primary tumor would be left (21). When the cells of a primary tumor are tested both clinically and experimentally for their ability to form a new tumor, only approximately 1 in 50,000 cells has the capacity to do so (34-38). Only cells that have sufficiently altered genetic operating systems or stem cell-like properties (39-41) break free of the local constraints and depart. Normal cells always remain in their local neighborhood.

(Next up: Drug Resistance and the Return of Cancer, and, New Frontier or Yet Another Unfulfilled Promise?--Dean)