But I’m obviously in the minority.  Seafood is big business, and our growing ability to use technology to harvest vastly higher quantities of fish than were possible historically has put entire oceanic ecosystem at risk.  Fortunately, the U.S. is finally taking the lead on the attempt to impose catch limits (see the pdf fact sheet about the new rules) in order to at least slow this process down.  There is now another piece of good news as well:  Some fish stocks are showing signs of recovery (based on a pdf NOAA report), which means our policies are headed in the right direction.

Pretty much all resource extraction industries are about making as much money as possible, with no thought or care about the future.  The mentality is, “if I don’t get it first, someone else will anyway.”  Conservatives use this “tragedy of the commons” argument to support private vs. public ownership of resources — even though there is plenty of evidence that people are often no more protective of resources they own than those they don’t, because the short term is always weighted economically much higher than the long term. But even if that argument actually held, there is no real way to allocate ownership of oceanic resources.  Even when countries maintain sovereignty of their coastal waters, these “borders” are impossible to defend.  There is no way to prevent overfishing other than by government-mandated catch limits, because there is no way for this system — like nearly all extractive industries, I would argue — to self-regulate for sustainability.

We can’t control the rules other countries make, but there’s no doubt that when the U.S. fails to weigh in on an environmental issue, or actively spurns an international effort to deal with one (such as the Kyoto climate change agreement), that significantly reduces the likelihood that other countries will continue to do the right thing.  Although containing just 5 percent of the world’s population, the U.S. consumes roughly a quarter of the world’s resources, and so any claims about why we should not be held to the same standards as the rest of the world ring hollow.  So U.S. policy positions on world ecological problems carry a lot of weight, whether we like it or not, and we may already be seeing the fruits of this in the 2011 fisheries report, which classifies six fish species now as “rebuilt.”  This contributes to a promising trend of higher sustainability in the way we are fishing (details on how the FSSI index is calculated can be found in another pdf):

This comes with caveats, of course.  First of all, the definition of “rebuilt” has nothing to do with historical levels, but rather is calculated as current biomass divided by the maximum sustainable yield (which also must be determined for every species).  Any number above 80% is assumed to be within “normal” fluctuations.  So “rebuilt” is not truly “rebuilt” in ecological terms, just in economic terms. According to Lee Crockett, director of federal fisheries policy for the Pew Environmental Group, this corresponds to 40% of historical levels (although that number must be different for different species, so one assumes he means on average). There’s no understanding (let alone consideration) of what levels are sustainable ecologically.  All creatures exist as part of the greater food web, not as separate, distinct populations, and in the longer term, economic sustainability is dependent on ecological sustainability.

The second problem is that inevitably, labeling a stock as “rebuilt” will cause political pressure to increase catch limits again, pretty much the opposite of what you want to do in the case of a recovering species.  Politics is injected into nearly all resource decisions, even when the government tries to rely on science, so any gains should be considered fragile, and the constant pressure short-term economic gain makes long-term planning difficult.  But you can follow yourself how this story progresses at the NOAA site.

But as it turns out, indiscriminate use of ineffective chemotherapy may actually be eliminating other treatment options, in more than one way.  A big new area of research is on how to convince our immune system to attack and destroy cancer cells without them attacking healthy cells.  From one perspective, invasive cancer can be considered an immune system failure, because somehow immune cells are diverted from doing what should be their job and clearing out these defective cells.  Of course, it’s asking a lot of our immune system to recognize cells originating from our own body as foreign, especially given that cancer cells are very good at manipulating our natural immune response (Whiteside 2006).  Immune function is also very complicated.  But recently, some studies are helping scientists to manipulate the immune system in a way that shows very promising preliminary results that could significantly impact the way we treat cancer.

One trick is to train our immune system in a very similar way that we do with any regular vaccine against a disease.  Of course it’s a lot more difficult to train our immune cells to selectively attack our own cancer cells while leaving healthy cells intact, because our immune cells work by targeting specific proteins on cell surfaces.  One you have been exposed to an invader such as a virus or bacterial pathogen, your immune system “learns” what those cells look like based on their surface proteins, and produces a whole line of special cells designed to attack and kill any cells in the body with that specific protein signature.  We never get sick from the same cold virus twice, because each time we develop immune cells ready to attack a previously experienced viral strain, before it multiplies enough to cause symptoms (unfortunately, in the case of cold viruses, there are hundreds of strains, and so there is always a new one we can catch).  In the case of serious foreign pathogens such as those causing flu, measles, polio, hepatitis, and other life-threatening diseases, we can often pre-train our immune system by introducing a small amount of the pathogen into our bodies — usually it’s a killed version of the pathogen that cannot harm us but which still retains the identifying surface proteins.

The hard part of enlisting our immune systems to attack cancer cells is identifying surface proteins that are unique to the cancer cells.  Willingham et al. (2012) have found that some cancer cells overexpress a protein (called CD47) that sends a “don’t eat me!” message to white blood cells (immune cells) that are phagocytic, or cell-eating.  In fact, the higher the level of expression, the lower the survival rate for someone with that cancer.  The researchers exposed tumors in mice to a CD47 antibody, which enabled the mouse’s immune system to destroy the tumor cells.  They also transplanted human tumor cells into mice and got the same effect — in several cases the tumors completely disappeared, making the mice cancer-free.  They tried it with several types of cancer.  When they gave mice tumor cells known to aggressively metastasize, the CD47 antibodies also prevented metastasis compared with controls.

Another step in this problem was alluded to earlier: researchers had to establish that the antibody attacking this protein, which is also expressed in some normal cells (to a lesser degree than in tumor cells) would not work as a toxin by causing the destruction of healthy cells (as most chemotherapeutic compounds do).   They found that the primary side effect was anemia and neutropenia — a temporary killing off of red and white blood cells.  And, they have reason to believe that the doses of antibody that they used in the mice were much higher than might be necessary, which reduces the probability that toxicity would be a problem in a therapeutic setting.  (And let’s not forget that the neutropenia associated with commonly used chemotherapy regimens at this time has been deemed acceptable despite its danger, partly because we have drugs such as neulasta which mitigate the problem by stimulating overproduction of white blood cells.)  A cancer treatment that could be applicable across a wide range of different cancers has truly been the holy grail of the “war on cancer.” Now it seems possible that the grail could exist.

Also interesting are the studies going on looking the anti-cancer effects of recombinant pox virus vaccines (Mohebtash et al., 2011).  These work by the addition of genes into a pox virus that stimulate the immune system to attack other proteins associated with cancer cells, such as MUC-1.  This treatment also has essentially no side effects because it targets cancer cells. Their preliminary data from a human trial shows promise, with the interesting effect so far that the treatment worked better in patients who had not undergone previous chemotherapy.  Given the damage that chemotherapy causes to immune systems, these therapies certainly wouldn’t work in conjunction with chemotherapy, but results raise questions about whether or not chemotherapy is causing longer term immune damage that we may be ignoring. At the same time, muddying the waters are results showing that chemotherapy and immunotherapy can actually be synergistic, though it is still unclear why (Ramakrishnan and Gabrilovich, 2011).

What few people realize is ideas relating the immune system to anti-cancer effects are hardly new, having existed for well over a hundred years.  Infections themselves have been demonstrated to halt cancer progression, perhaps partly due to the fever response (Hobohm, 2009) but until recently, this avenue of research has been essentially ignored in favor of a focus on chemotherapy.  It’s hard not to think that the profit motive that has a huge influence on biomedical research has a lot to do with this.

There’s still a way to go to develop this work into therapeutic drugs, but that work is finally on its way. There are hopeful signs that medical scientists are finally seeing the routine and usually useless poisoning of millions of people every year for the therapeutic dead end that it clearly is.

References

Hobohm, U., 2009. Healing Heat: Harnessing Infection to Fight Cancer. American Scientist, 97(1):34-40.

Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL., 2011. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clinical Cancer Research 17(22):7164-73.

Ramakrishnan R, Gabrilovich DI., 2011. Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer. Cancer Immunol Immunother. 60(3):419-23.

Whiteside T.L., 2006. Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Seminars in Cancer Biology 16(1):3-15.

Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL, 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Science USA. Mar 26. [Epub ahead of print]

It has been 35 years since the FDA acknowledged the risk of treating healthy livestock with antibiotics.  Yet, they have made little progress on regulating this practice, in part because of pressure from the livestock industry claiming that there was no evidence of the practice causing resistant human pathogens, even while some scientists argue that the danger of resistance spread may be greatly underestimated.

Fast-forward to the era of methicillin-resistant Staphylococcus arueus (MRSA), which at its peak resulted in over a quarter million hospitalizations and 20,000 deaths in the U.S. (though thankfully, the trend of hospital-acquired MRSA infection is currently being reversed, probably due to better hygiene practices).  So far, the FDA has taken only the small step of banning one class of antibiotics, (a rule that was delayed and watered-down over three years by industry opposition) even as studies from other countries showed years ago that stopping usage of routine antibiotics in livestock reduces resistance to related antibiotics used in humans.

A new study has now clearly demonstrated that we are playing with fire when it comes to overuse of antibiotics in animals (Price et al., 2012). Researchers studied the evolutionary origin of the MRSA strain clonal complex 398 (CC398), which occurs in livestock. Their phylogenetic analysis of this strain revealed that it originated from a methicillin-susceptible S. arueus (MSSA) strain occurring in humans. This means that an antibiotic-susceptible strain in humans jumped to livestock, acquired resistance to antibiotics commonly used in both animals and humans, and is now jumping back to humans in its less-treatable form. The diversity of the 89 isolates of CC398 from four continents that they collected and analyzed “is suggestive of strong and diverse antimicrobial selection associated with food animal production.”

Their conclusion follows:

In this study, we provide strong evidence that CC398 originated in humans as MSSA and then spread to livestock, where it acquired resistance to methicillin and tetracycline. Genomic analyses presented here, in conjunction with previous epidemiological data, suggest that the jump from humans to animals was followed by a decreased capacity for human colonization, transmission, and virulence, yet livestock-associated CC398 has been linked to an increase in MRSA infections in northern Europe. Further research is required to characterize the full scope of the genetic changes associated with the shift from humans to livestock.

Sure, the bright side is that the MRSA that evolved in livestock appears to have reduced virulence in humans compared to the MSSA it came from.  Further research on this process should indeed be done (Rosengren et al., 2010). What would be even better would be to do the research after a complete ban on non-therapeutic hormone use in livestock is in place (which many scientists support), so that disaster doesn’t happen before we’ve actually understood the mechanism by which it will happen.

Would a ban increase the price of meat and reduce the profits of agribusiness? Almost certainly somewhat (although according to the World Health Organization which studied the issue in Danish pig production, not much). But even if the rise in cost of meat is significant, it all works out for the best, because with Americans’ meat consumption per capita over 200 lbs per year, and its attendant heart disease and cancer risks which we are all paying for (whether we individually eat meat or not) through our health insurance premiums, more expensive, humanely treated, unmedicated meat would be a win-win for everyone. Fortunately, the trend in meat (especially beef) production is going down, but until the U.S. finally stops this insane practice, try buying local, free range, unmedicated meat for awhile, and see what you think. Eat less of it, enjoy it more, be healthier, and as an added bonus exert some consumer pressure away from risky and unhealthy agriculture.

Feel free to tell me I can peel your cheap, factory-farmed meat from your cold, dead fingers — right after you stop making me pay the medical bills you racked up before that last heart attack finally did you in.

References:

Price LB, Stegger M, Hasman H, Aziz M, Larsen J, Andersen PS, Pearson T, Waters AE, Foster JT, Schupp J, Gillece J, Driebe E, Liu CM, Springer B, Zdovc I,Battisti A, Franco A, Zmudzki J, Schwarz S, Butaye P, Jouy E, Pomba C, Porrero MC, Ruimy R, Smith TC, Robinson DA, Weese JS, Arriola CS, Yu F, Laurent F,Keim P, Skov R, Aarestrup FM., 2012. Staphylococcus aureus CC398: Host adaptation and emergence of methicillin resistance in livestock. MBio 3(1).

Rosengren LB, Gow SP, Weese JS., 2010. Antimicrobial use and resistance in pigs and chickens: A review of the science, policy and control practices from farm to slaughter — executive summary. Can J Infect Dis Med Microbiol. 21(3):123-7.

If you go looking for cancer, you will find it more often than if you don’t.

First of all is the continuing promotion of mammography for early breast cancer detection, despite data that have not convincingly showed that it saves lives (Welch, 2004). This is not really surprising when radiologists who benefit financially from mammography do it, but it is unconscionable that the ACS has actively chosen to denigrate and ignore the science used to change the recommendations of the U.S. Preventative Services Task Force task force over two years ago, based on data that the risks of routine screening for women in their 40s probably outweigh the benefits:

Early detection: Mammography can often detect breast cancer at an early stage, when treatment is more effective and a cure is more likely. Numerous studies have shown that early detection saves lives and increases treatment options. Steady declines in breast cancer mortality among women since 1990 have been attributed to a combination of early detection and improvements in treatment.

There are layers of misconceptions in these sentences, which reflect dogma more than actual data. This is at best unbecoming for an organization which as one of the main sources of information for cancer patients should to be on the forefront of scientific and medical progress in cancer.

What is the risk of death from cancer?

One of the main misunderstandings about cancer rates and risk of death is that the trends in these can be objectively produced in order to support the idea that we are doing a better job of early detection and treatment:

The 5-year relative survival rate for all cancers diagnosed between 2001 and 2007 is 67%, up from 49% in 1975-1977. The improvement in survival reflects both progress in diagnosing certain cancers at an earlier stage and improvements in treatment.

However, anyone with any understanding of probability can see that as imaging detects smaller and smaller cancerous masses, many of which will never become life-threatening (or indeed present any symptoms at all), then a smaller and smaller percentage of cancer diagnoses will ultimately result in death, without treatment playing any role whatsoever. The fact is that data of cancer incidence from 2011 are simply not comparable to data from 1977, and what “progress in diagnosing” really means is we now have the ability to find lots of little cancers that we never would have known about.

New York: Federal Art Project, between 1936 and 1938, from Wikimedia Commons

For example, “63,300 new cases of in situ [noninvasive] breast cancer are expected to occur among women in 2012. Of these, approximately 85% will be ductal carcinoma in situ (DCIS).” The report does not mention that in many cases, DCIS will never become invasive. And yet, all the positive screens which result in risky and painful treatment for many women are always spun as a success story, because the cancers were “caught early.”

Even worse is that the term “cancer deaths” continues to be poorly defined; in fact, the ACS report doesn’t bother to define it at all. To be fair, this is probably because in general the reporting of exact cause of death is so poor, and it is likely nearly impossible for the ACS to gather accurate data. The problem is that they do not state this caveat explicitly, but instead give the impression that these are good, solid, real data.

Why is it difficult to define “cancer death”?

Cancer certainly kills many people; if it did not, we would not spend the money and time we do trying to treat it. But what often goes undiscussed is the degree to which medical treatment for cancer hastens death, or even worse, causes deaths that might have been avoided without treatment.

It should be noted that the way that cancer deaths are counted is both underestimated and overestimated, but it is not clear whether or not these biases cancel each other out. The underestimation of cancer deaths happens when patients receive a treatment (usually surgical) that causes a secondary complication resulting in death that is not immediate (Welch and Black 2002). Welch and Black argue that these deaths should be included in cancer death statistics, but often are not.

But this can also be looked at from another point of view. Many people who develop complications from chemotherapy or surgery and die from them quickly are classified as having died from cancer, even when, as in the above case, they died of treatment rather than disease. A recent example of this is the experience of Joe Paterno, who clearly died from the effects of chemotherapy sooner than he would have of his cancer itself.

It is certainly true that many of the people who die from cancer treatment would have died from the cancer had they not been treated. But what remains undiscussed is that there are also certainly people who die from treatment who would not have died from their cancer. Especially for common cancers such as early stage breast and prostate cancer, patients often go into treatment perfectly healthy, with no symptoms at all. (Although this can also be true when cancer has metastasized [has reached stage IV], the probability that one will die from stage IV cancer is obviously considerably higher than from stage I-II cancer.) Some of those patients will end up dying of surgical and chemotherapeutic complications. Some of those deaths will be classified as cancer deaths, which is not quite right, and some of them will be classified as death from another cause, which is not quite right either.

The worst kind of cancer-treatment death is from complications due to diagnosis and staging. For example, lung biopsies are notoriously risky, but only now are researchers attempting to quantify that risk (Wiener et. al, 2011). Although on the surface most of the risks are sublethal, the chance of a collapsed lung was found to be 15 percent. Treatment for a collapsed lung is an incredibly painful procedure that adds to the risk of infection, respiratory failure and/or death. Other types of biopsies carry risks that are routinely disregarded in our blinding quest to wage our endless war on cancer.

So, we are left with a hodge-podge in defining cancer deaths, and this is important given how statistics are used to lobby for more research funds, for insurance coverage, etc. It is bordering on ridiculous that a country with the resources of the U.S. has not made an effort to increase the accuracy of our data collection on our second-largest cause of death. We need to be identifying more precisely causes of death that occur during medical treatment, and categorizing them for what they really are when we talk about cancer statistics. This will not only give us better information about the true trajectory of cancer deaths, but more broadly will allow epidemiologists and other researchers to identify areas in which deaths could be prevented, not to mention money saved from the treatment of unnecessary complications. Resistance from doctors to this would seem inevitable, in that this would undoubtedly cause more doctors to have to take more responsibility for treatment deaths But just like weaning doctors off of profits from using their fancy machines, this it is one more necessary piece of the puzzle to counter the spiraling trajectory of health care costs which will inevitably result in fewer and fewer Americans being able to afford insurance at all. And some of those left behind really do die from their cancer, because they can’t afford any treatment at all, let alone the spurious kind.

References

Welch, HG, and Black, WC, 2002. Are deaths within 1 month of cancer-directed surgery attributed to cancer? J Natl Cancer Inst. 94(14):1066-70.

Welch, H.G., 2004. Should I Be Tested for Cancer?: Maybe Not and Here’s Why University of California Press, Berkeley, CA.

Wiener RS, Schwartz LM, Woloshin S, and Welch HG. 2011. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med. 155(3):137-44.

It has been apparent for the last few decades that if overfishing continued at the rates it has reached with mechanized and technological fishing, fish would soon become a scarce commodity.  Indeed, the skyrocketing prices that bluefin tuna have recently fetched in Japan are an example demonstrating that eating any tasty fish species could become a luxury to be experienced only by the 1% if steps are not taken to preserve stocks for the long term.

Bluefin tuna, Courtesy Jon Hanson and Wikimedia Commons

The best part of the new rules is that they were developed not as top-down regulations with no input by those affected, but by regional councils which take local interests into account.  But although that should help reduce opposition to the rules, there’s no way to eliminate it.  Charges of lack of scientific rigor in developing the rules are generally self-serving, because fish population estimates can be inaccurate, because they are dependent on assumptions that are difficult to verify.  All environmental regulations are automatically political these days, so attempts are already underway by congress to make the regulations toothless.  (Arguments that underestimating a sustainable catch level has far more benign long-term consequences than overestimating it are not the type that resonate well with politicians.)

Of course, such regulations will work much better if other countries follow suit (especially if there were to be an international agreement to suspend the absurd subsidies supporting fishing fleets), and there is more of a concerted effort to quell poaching.  It should also be obvious for there to be an accompanying trade agreement so that the U.S. isn’t hypocritically importing more and cheaper fish of the same species that we are tightly regulating for our own fishermen (and thus putting them at a competitive disadvantage), but because trade agreements are subject to congressional whim and as political as environmental regulations, don’t expect progress on that front anytime soon.

Still, it’s a welcome first step.  Because even the most pandering politician cannot spin depleted fish stocks away, it is one of the few laws that everyone should be able to find reasons to support.  Let’s hope it doesn’t become a victim of election-year congressional craziness.

Politics has unfortunately colored the term evidence-based medicine (EBM).   For some it became synonymous with top-down control of health-care decisions.  For example, there seemed to be widespread outrage over the USPSTF changing mammography guidelines a couple of years ago, because some people seemed to think this meant that they no longer would be able to get mammograms if they want them.  But lost in all the kerfuffle was an explicit recognition in the report that a given individual might have specific, valid reasons for getting mammograms more often than the panel recommended, because the recommendations specifically addressed routine screening of women with no known added risk for breast cancer (such as having a close relative with the disease).  The “death-panels” hysteria hardly needs mention, but it warped purely for political gain the incentives for doctors to find out what their patients’ wishes are for end-of-life care.  So, to appease a small political faction the provision was taken out, and we are still mired in a system that often continues unwanted treatment in patients who can no longer speak for themselves, lowering quality of life and raising the nation’s health care costs.

Image courtesy Wikimedia Commons.

But the medical community does understand that individuals always need the option to tailor national public health directives to their own situation, and that’s where they need to encourage more doctors to get to know them well enough to understand what they want. And contrary to what many people think, EBM is not incompatible with patient-centered care, and in fact both are crucial for the best outcome possible (Sackett et al., 1996; Barratt, 2008):

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research…Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients’ predicaments, rights, and preferences in making clinical decisions about their care…
Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. (Sackett et al., 1996)

It seems clear that much of the opposition in reforming health care in the U.S. is rooted in the misconception that EBM ignores what the patient wants, and this is where the “government takeover of healthcare” hyperbole comes from. In fact, in the early days of EBM discussion, in the 90s, there were even many doctors who had this misconception as well as another that their own clinical expertise was no longer valid, and opposed the whole concept of EBM in practice. Dr. David Sackett, one of the pioneers of the practice, attempted to dispel the idea that EBM was necessarily top-down control of doctor-patient relationships, and that it actually integrates science, experience, and patient preferences.

However, the fear of some doctors and patients that EBM will be used as a tool to mandate reductions in cost is not entirely unfounded. In some single-payer systems, such as Australia, incentives are used to raise the level of cancer and other health screenings (Barratt, 2008), which may, for example, put pressure on patients to undergo screenings that they would prefer to avoid for valid reasons. Part of the Affordable Care Act (ACA) involves numerous pilot studies to reduce costs in Medicare, and as many have written, there are certainly a lot of opportunities to do so. But it is important for whoever holds the purse strings — whether it be the government or an insurance company — to realize that using scientific studies to create screening or treatment guidelines at the population level is completely different from deciding what the best course is for an individual patient, both vis a vis the patient’s health, and his or her cost burden.

It is this recognition of the necessary difference in thinking between populations and individuals where many doctors (and the purse-string-holders) are still deficient. Part of this deficiency comes from relying too much on flawed medical studies (a common topic of this biology blog), and part of it comes from the misconception that EBM has nothing to do with the personal preferences of the patient.

Groopman hits the nail on the head in his review that the patient-preferences piece of the EBM puzzle is often missing in how doctors are currently trained, especially that even the best EBM is not usually appropriate for direct application to an individual patient:

Like all doctors educated over the past decade‚ residents [have] been immersed in what is called evidence-based medicine. This is a movement to put medical care on a sound scientific footing using data from clinical trials of treatment rather than on anecdotal results. To be sure, this shift to science is welcome, but the evidence from clinical trials is often limited in its application to a particular patient’s case. Subjects in clinical trials are typically cherry-picked, meaning that they are included only if they have a single disease and excluded if they have multiple conditions, or are receiving other medications or treatments that might mar the purity of the population under study…Yet these excluded patients are the very people who heavily populate doctors’ clinics and seek their care.

It’s important that as a patient you expect the doctor to listen to you, and to incorporate your values and preferences into science-based discussions, as well as to acknowledge when the science isn’t very good. My own experience with cancer doctors has shown me the whole range. Some doctors will only present an opinion based on statistics even as they are smart enough to understand that the statistics are essentially useless in application to a single individual. I have had trouble with one particular oncologist like this who simply did not listen to me, and instead recommended a course of treatment that I believed in my case made very little sense (although he has been a very helpful and valuable doctor in other contexts).

Of course I have the advantage of an advanced degree in biology helping me understand better the current state of research in breast cancer.  That may come across as arrogant since I do not have an M.D., but I have another doctor who does listen to me, who will discuss the issues as we believe they apply to me specifically and to whom I listen. With him I have felt much more confident in my treatment decisions, which we made together and which thus far have worked out successfully (and were not what the first doctor recommended).  By the way, this doctor also dispels the notion that our system doesn’t allow the time to get to know patients.  Although it is clear that the pressure for doctors to see as many patients as possible is not a good thing, this doctor learned enough about me in a fifteen-minute conversation to make me completely trust that he was taking my preferences into account when he made his recommendations.  His skill was knowing exactly what questions to ask me.  This is a skill that obviously many doctors don’t have, but it seems it could be learned, if medical schools thought it was important enough.

There is also another type of doctor who seems to want to incorporate the patient’s wishes more but has a little trouble figuring out how to do so in a constructive way. Several medical oncologists gave me a chemotherapy recommendation among several options, but then just said, “but any of these choices would probably appropriate, so you decide,” without really giving me any tools to make an informed decision. In this case my professional experience doing primary literature research proved indispensable, so that I could make the best decision possible myself. (I am often grateful for this added expertise which of course most people do not have as a resource when navigating difficult decisions.) These doctors could probably use some help learning what questions to ask a patient to figure out her outlook and preferences about treatment, so crucial especially in oncology in which there frankly are usually many options, each of which is not particularly likely to work because no one knows yet what works for a given individual.

A final piece of the problem of putting true EBM into practice is the trend that American medical schools have been increasing their emphasis on doctors trusting machines to make diagnoses for them, instead of developing their own observation and listening skills. Thus their knowledge base becomes less supported by their own clinical experience, which is also an essential part of EBM as defined by Sackett. Abraham Verghese, author of the fantastic Cutting for Stone, which has as a major theme the skill of diagnosis via physical exam, is trying to reverse this trend by helping medical students revisit this forgotten skill. There are not enough doctors like him left to reverse this trend, however. So it is up to you, the patient, to be sure to find a doctor who listens to you and responds to your concerns in a way that makes sense.

And don’t let her tell you that she doesn’t have the time.  The difference in quality of life between someone who has had a doctor who has truly been a listening partner in helping make uncertain treatment decisions, and someone who has been told what to do based on statistics (or even worse, based on no convincing scientific evidence), should not be underestimated, because quality of life in turn affects a patient’s sense of well being and outlook, which do have an effect on treatment success.

References

Barratt A. 2008. Evidence Based Medicine and Shared Decision Making: the challenge of getting both evidence and preferences into health care. Patient Educ Couns. Dec;73(3):407-12. Epub 2008 Oct 8.

Davidoff F, Haynes B, Sackett D, Smith R., 1995. Evidence based medicine. BMJ. Apr 29;310(6987):1085-6.

Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS., 1996. Evidence based medicine: what it is and what it isn’t. Clin Orthop Relat Res. 2007 Feb;455:3-5.

In a paper published online in Science, Anastasiou et al. (2011) took an important line of cancer research a step forward. Their research also furthers what is known about reactive oxygen species (ROS, also known as oxidants or “free radicals”), which are of interest to those studying general health and nutrition. Although anti-oxidants are a big part of the annual twenty-billion-dollar supplement industry, because they bind to ROS which are believed to play a role in aging, their complete range of physiological roles is still clearly not understood.*

But we know that it is true that ROS are damaging to cells, because it is based on this very principle that chemotherapy drugs were and continue to be developed:  they attack dividing cells using free radicals. Conversely, protection against ROS helps cells to grow and proliferate. The ability of cancer cells to proliferate is exactly the problem with them, as it is uncontrolled growth of cancerous tumors that can ultimately impair organ function and lead to death. Ironically, conditions leading to the growth of cancerous tumors actually produce extra ROS, so cancer cells have to be especially good at thwarting their effects to continue to survive and grow uninhibited.

Glucose is the energy form used by cells to grow and proliferate.  All food we eat is eventually converted to glucose for this purpose.

A pyruvate kinase molecule

Pyruvate kinase (PK) is an enzyme that helps to enable glucose utilization by proliferating cells. There are two major variants of this enzyme: PKM1, found in many normal body tissues, and PKM2, which is associated with cancer cells. When Anastasiou et al. treated both PKM1 and PKM2 with oxidants, they observed very different effects. The activity of PKM1 did not change, but PKM2 was inhibited by the presence of oxidants, and this diverted glucose into a different metabolic pathway which resulted in detoxification of the ROS, which reduced damage to the cells. That is, the changing activity of PKM2 under different oxidation conditions makes cancer cells especially resistant to ROS; when oxidants are present, they tend to shut down, rendering those oxidants ineffective.  This shows why cancer cells are pre-adapted to resist many of the chemicals we use to treat them. Anyone who has suffered through months of chemotherapy and all its attendant complications only to learn that their cancer was unaffected or even proliferated further understands the grave implications of this.  (Most cancer patients also learn that the reason for the worst side-effects of chemotherapy drugs – hair loss, mouth sores, nausea – is that chemotherapy drugs attack dividing cells, and the cells associated with these parts of the body are dividing a lot more than other cells.  This is why fasting before chemotherapy is now being explored as a method to mitigate side effects:  it tends to shut down normal cell activity, making them divide less, thus making them more resistant to the oxidizing action of the drugs.)

The researchers were able to use a method to keep PKM2 activated in mice in the presence of oxidants to show that taking away the ability of this enzyme to shut down results in much reduced tumor activity, because the cells are no longer protected from ROS.  Scientists are very far, of course, from developing a therapeutic version of their procedure but it could be a fruitful avenue to pursue. They envision that it may be possible in the future to use PKM2 activators in conjunction with chemotherapy. One would expect that this would result in much lower doses of chemotherapy being effective against cancer, which would alleviate a lot of needless suffering.  Then again, several therapies which have shown promise in vitro have not panned out in the real world, showing that we have a long way to go in knowing enough about cancer – in all its many variants – to be able to control it.

* Multiple studies on anti-oxidants and other supplements over the last several years have shown increasing evidence that they are bad for your health. A meta analysis by Bjelakovic et al. (2007) showed increased mortality associated with supplement use, and most recently a study on older women (Mursu et al., 2011) grabbed media attention for its similar conclusions. A further paper on anti-oxidants and exercise (Ristow et al. 2009), previously discussed on Bioblog, demonstrated that ROS may have important positive functions being overlooked in the anti-aging, supplement craze.

References

Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC. 2011. Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Antioxidant Responses. Science. Nov 3. [Epub ahead of print]

Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C., 2007. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. Feb 28;297(8):842-57.

Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr., 2011. Dietary Supplements and Mortality Rate in Older Women: The Iowa Women’s Health Study. Arch Intern Med. Oct 10;171(18):1625-33.

Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M. 2009. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. May 26;106(21):8665-70.

Image courtesy Richard Wheeler (Zephyris) 2006 (Wikimedia Commons).

Asian longhorned beetle (courtesy Kyle Ramirez and Wikimedia Commons)

An Associate Press report confirms what everyone working for APHIS knew by 2003.

In the political realignments that occurred after 9/11 and the subsequent internal anthrax attacks, APHIS (the USDA’s Animal and Plant Health Inspection Service) was gutted to send people and resources to the Department of Homeland Security with the charge of protecting the nation from bioterrorism. APHIS’s job is to protect us from another kind of biological security threat: pests that can damage crops and other invasive species that can cost billions of dollars to control after the fact in order to protect both our agricultural system and natural ecosystems (including vital watersheds).

At the Entomological Society of America’s annual meeting in 2004 many attending APHIS workers were lamenting the change, and how it was going to blow a big hole in APHIS’s ability to protect the country from pests.

Since then, associated with the rising trade with China we have seen the emergence of many new pest species, nearly all inadvertent introductions in shipments from Asia that have not been adequately inspected. Asian longhorned beetle, a generalist destructor of hardwood trees, emerald ash borer, another beetle now spreading from Michigan, and spotted-wing Drosophila are all major threats to our ecosystems and economy.  The first two entered the country before this realignment, demonstrating that we already were not prioritizing this threat enough at that time.

Now, we have left the door virtually wide open and added a “Welcome” sign.  How much crop and forest damage will it take to change the public views on this?  Sadly, it is one more clear example of government money being allocated based on special interests rather than any sort of cost-benefit analysis.  Anti-terrorism policies are politically popular, despite their enormous cost-to-benefit ratio.  The numbers of people killed by cars and guns in one year exceeds by well over an order of magnitude the number of people who have ever been killed in terrorist attacks on U.S. soil, so clearly government policy is not really about saving lives.  At the same time, there are lots of lobbyists for business interests that resist any sort of actions, including time-consuming pest inspections, that might affect their bottom line slightly.  And outrageously, although we have a bond system (although inadequate) in place for most mines to pay for their clean-up when the mining companies cut and run, we have no such system for importers to provide a fund to clean up the mess their imported species make (this should be a no-brainer at least for those intentionally importing alien species that could eventually become pests).

No one is questioning the need to protect the nation from bioterrorism threats. Obviously, one agent getting through could wreak havoc and cost many lives.  So it’s understandable that resources have been allocated to this threat, even while alien invasive pests are eating their way through our agricultural and natural resources.  Disturbingly, it’s unclear how effective the money redirected toward anti-bioterrorism policy has been though.  If any attacks have been thwarted in the last ten years, the government has been keeping it secret.  In fact, apparently all that redirected money may not be truly protecting us anyway:   it seems that a big portion of the equation, the ability to coordinate a rapid response to a biological agent that does get through our defenses, has been virtually ignored, even though a lot of lives could be saved by having a plan.

The point is that once again, the long-term policies we need to support our society without hardship in the future are trumped by policies that are arguably less crucial, but that benefit someone financially in the short term.  There was no real reason why any of the money shifted to DHS had to come from the USDA, but certainly there was some political opportunism by decision-makers that probably was influenced by business interests.  Slowly but surely, our sense of place is being chipped away as a result, and in the end that could arguably take more away from us as a society than a single terrorist attack.

The details of their argument are not that important, because what they miss is the big picture. Simply, their argument is completely anthropocentric in a couple of ways, and this is where they and the invasive species biologists who responded are talking past each other.

Chew and Carroll take the central position that it is nothing but anti-alien bias that makes most ecologists demonize invasive species. Their essay has almost embarrassing overtones (accusing other ecologists of “personifying and demonizing the unfamiliar”) of the type used by those who argue that those trying to prevent destruction of local habitats by nonnative species are anti-immigration nativists when it comes to humans too. This is a tired diatribe, one also used by species importers who are simply defending their own financial self interest, and often containing inflammatory terminology such as “xenophobes” to describe the scientists trying to preserve species diversity in fragile habitats. The very fact that Chew and Carroll interpret attempts to protect native ecosystems as “personifying” alien species trivializes their argument by showing that it is they who are anthropomorphizing.

Another huge weakness of their anthropocentric essay is the arrogant assumption that we are equipped to understand all the ecological ramifications of introduced species, including those not showing invasive tendencies. My own food web research indicates that ecosystem-level effects below the radar of human observers (because they involve small invertebrates, soils, etc. or happen over a longer timescale than that of a human generation) can occur with established species not currently considered invasive (generally due to lack of an economic impact).

Despite this, the great majority of ecologists who advocate control of nonnative species are focused on the invasive species that destroy native habitats and cause irreversible ecological damage. To answer the charge that Chew and Carroll (and their Nature co-authors) have unfairly declared invasion ecologists as anti-nonnatives, including noninvasive species, they simply respond that their characterization is correct, and all the letter-writers are wrong. This is patently absurd, of course, because one of the basic tenets of invasive species research is the “tens rule”, which means that only about a tenth of introduced species establish, and only about a tenth of those that establish become invasive. It is because those promoting the importation of species are so lousy at predicting which will become invasive (if they even care) that invasive species ecologists promote prevention as the better ecological and economic strategy than control.

Finally, their argument is essentially circular in that they state that once invasives are fully established and integrated into the community, they are an essential part of that community and thus should not be controlled because of unintended effects. Because they maintain we should not worry about those species that do not appear to be invasive to us (yet), it of course follows logically that no invader should ever be controlled because either they don’t matter, or they are absolutely essential to the ecosystem. Apparently there is nothing in between these two extremes, despite what we know about the huge complexity of ecosystems, which we are only beginning to understand ourselves. Again, this argument makes sense only from an anthropocentric perspective.

Even then, there are others who argue completely differently from the same perspective. Jeffrey Lockwood, entomologist-turned-philospher at the University of Wyoming, argues that a “sense of place” should inform our views on whether alien species (invasive or not) should be tolerated on the terms presented matter-of-factly by Chew and Carroll. He means that homogenizing the world through the distribution of certain species throughout the world diminishes not only local diversity, but global diversity as well. In other words, even if not a single species were driven extinct by alien species, their mere presence in a new habitat diminishes the wonder of worldwide habitat diversity, much as the presence of “strips” containing the same national chains in towns all over the U.S. diminishes our local cultural diversity.

Thus, even if one agrees with an anthropocentric position regarding alien species, there are quite divergent conclusions that one can come to. Chew, Carroll, and their Nature coauthors ignore these alternative ways of looking at the world, and Chew cynically comments on The Scientist rebuttal:

In that worldview maximizing beta diversity (in short, keeping different places different) is treated as a self-evident primary planetary objective; suppressing change detectable at any but geological timescales is another. But that worldview is unenforceable on the world. It turns out that most people want access to what most other people have.

Therefore, apparently, it is some sort of elitism to have Lockwood’s point of view. There is a somewhat disturbing element of — for want of a better term — class warfare here. In his commentary, Chew seems to be framing himself as an egalitarian defender of the little people who just want to share in the bounty of the more fortunate, while Lockwood and his ilk are snobbish in their desire to prevent the constant expansion of global commerce from overrunning nature. It’s as if we should abdicate on this issue because we cannot afford to strive for higher values than the lowest common denominator of what the masses want. It is a similar argument made by those who consider the arts, or space exploration, or ecological research in general to be a frivolous way to spend money. Ironically (because it is made by ecologists), it boils down to the pessimistic argument that humans should not bother striving to use our brains and culture to be something more than tribal exploiters of our environment.

The term has started popping up in ever more absurd contexts. In this case, the notorious oversight committee chairman Darrell Issa held a hearing in an attempt to prevent minimal (but common-sense) U.S. Fish and Wildlife regulations limiting trade in alien invasive snakes, prompted by the disastrous effects of Burmese pythons’ establishment in the Florida Everglades as a direct result of the exotic pet trade.

He invited laughable testimony from a reptile importer, who absurdly claims there is not adequate science to prove that pythons are doing harm, to make his case.

Anyone who knows anything about invasive species knows that almost by definition, non-native vertebrate species are destructive to new ecosystems. From Asian carp to nutria to wild horses, billions of dollars have been spent to try and reverse the damage caused:

Already, federal and state local officials have put forward a $7 million plan intended to halt the expansion of Asian carp into the Great Lakes. Regional officials fear intrusion of the fish could starve out native species and decimate the region’s sport fishery industry, estimated to be worth $7 billion to the local economy. A previous report from Ecological Economics conservatively estimated that the combined cost of managing environmental damages to invasive plant and animal species adds up to almost $120 billion per year. The report noted that invasive species threaten 42 percent of species protected under the Endangered Species Act.

Of course, in revisionist land, the ESA was an evil job-killing liberal plot, so more the better.

It really has reached the point at which taking any action perceived as hurting Obama is acceptable. The damage done by pythons in the Everglades has been documented for years, and threatens to undermine the billions of dollars already allocated and spent on restoration efforts, which include invasive species removal.

Fortunately there were some rational people at the hearing who, yes, happen to be Democrats:

In his opening statement, Committee Ranking Member Elijah Cummings (D-MD) noted, “with all due respect to our witnesses from the Association of Reptile Keepers, repealing a so-called ‘job-killing’ regulation to allow more pythons, boa constrictors and anacondas into the United States is not the kind of bold, bipartisan solution Americans are looking for to help the economy.” Committee Democrats also put forward several letters that countered many of the arguments of Barker and Chairman Issa regarding invasive pythons.

One thing is painfully, ironically certain: business interests nearly always get what they want in the U.S. — contrast our close-the-barn-door policies with those of New Zealand, a perfectly prosperous country, which has prevention-based (and therefore long-term money-saving) importation regulations*, rather than a belated regulatory reaction to obviously dangerous species that are introduced by the hundreds every year (both intentionally and not) in the name of “free trade.” So the “job-killing” mantra is so tired already in a system where the deck is already stacked in favor of short economic gain for a limited number of people.

But it is likely in this political climate (one pretty much defined by having an African-American Democratic president) that the mantra will hold sound-bite sway until we have irrefutable (and likely irreversible) evidence of its short-sightedness.  And even then, there will be plenty of Americans for whom individual “freedom” is defined by a delusional independence from all other persons and creatures which entitles them to exploit our common environment as they choose.

*

photo courtesy Wikimedia Commons.