Bioblog: Biology in the News

An article at the New York Times’ Well blog on the retraction of the 1998 Lancet paper that was instrumental in sprouting the anti-vaccine movement is a prime example of a new, internet-enhanced relationship among scientists, media, and the public.

As alluded to in the blog, it used to be that internal scientific squabbles and tossing-around-of-wacky-ideas were never in the public eye. Scientific papers were discussed within the scientific community, and only after consensus emerged about a new idea did that idea enter the public realm; this process generally took years.

But the internet coming into popular use changed all that, in several stages. First, years before the internet was widely used by average citizens, scientists were already online in the 1980s, collaborating and having discussions via email and news groups (now known as chat groups). This allowed ideas to flow more freely and widely to a larger scientific audience, generally to the benefit of science.

Then, beginning in the late 1990’s, journals finally began producing online editions instead of being in print only. At the same time, use of the internet skyrocketed among the public. So suddenly, anyone could do a search and look at paper abstracts online (full articles still require expensive subscriptions) whereas before this, a person had to make the effort to go to a scientific library to locate a specific journal article in the stacks, which had to first be identified through obscure search engines generally only available to academics.

Naturally journals and institutions producing research have always tried to garner publicity, so they have always produced press releases that got some science in the news. But only recently has it become much easier for interested non-scientists such as journalists or bloggers to regularly follow discussions that used to stay in the scientific community.

Unfortunately, many scientists still believe they are living in a world in which science is controlled by the scientists until they make it available for public consumption, even while numerous recent “controversies” have belied that belief. While there have always been wacky scientists who promote ideas that are unsupported by the overwhelming scientific evidence, they used to be collectively relegated to the scientific fringe and generally ignored, their occasionally published rants unknown to the general public.

Now, the availability of the internet has caused the problem that these fringe scientists collect a devoted following among the scientifically illiterate, and their discredited ideas go viral on the internet, sucking in people who want easy answers that science cannot always provide. Why does a particular anti-science idea gain traction? In the case of climate-change denialism, there are obvious short-term economic motivations by powerful interests. In the case of vaccines, there seems to be an intersection of many regular people wanting answers for a condition that does not yet have any clear answers, and an anti-medical establishment/corporate anger and paranoia that is easy to fuel given the grain or two of truth in the idea that pharmaceutical companies do not always have the general public’s best interest as their number one priority.

(Ironically, the anti-vaccine furor has also been so easy to stoke because vaccines have all but eliminated many deadly and debilitating diseases from our society, and thus people do not truly grasp anymore the magnitude of the benefits they provide; they simply take those benefits for granted, believing that the vaccines must not be necessary (see many “homeopathic” web sites for examples). Simply reminding someone of the lives that used to be destroyed by infectious diseases is not enough for denialists, because they have no personal connection to that particular tragedy; their personal connection is to a condition for which they would probably gladly embrace a vaccine, if we had one.)

One more example of a large denialist community is among the HIV/AIDS connection deniers. They have been in the scientific news as well because of an unfortunate sequence of events in which anti-HIV papers were published in the journal Medical Hypotheses, and then retracted. This has sparked a heated discussion (see comment thread in the above article) about the role of peer review and scientific consensus in the application of scientific ideas. What is only being touched on in these discussions is how interactions among scientists are now, for better or for worse, in the public view, and what the consequences should or should not be for the scientific progress.

It is good that the Well blog has begun a discussion on the implications of fringe (non)scientific ideas going viral in the public, but that still leaves the question of whether or how scientists should address these in how they conduct themselves. It is this scientist’s opinion that scientific business-as-usual must change if we want to keep control of a narrative that we are actually the ones trained to deliver. It is simply not working in the world of the internet to tell the public, “The scientific mainstream knows best, so listen to us,” because in the growing trend of anti-elitist populism, this will not be accepted; in any case the statement is undermined by the growing awareness that a scientist is a human being just like everyone else, with his own ambition and agenda that can color scientific conclusions. Science simply must change to accommodate this new reality, and this will be the subject of a future essay.

Estrogen is a hormone that in females has many functions. We still do not have a complete understanding of the relationship between estrogen, estrogen-like compounds (which can bind to an estrogen receptor), and cancer.

Several factors complicate these relationships. First, there are estrogen receptors all over the body, and there are at least two types of estrogen receptors, alpha and beta. These different receptor types are distributed differently in the body, and activate different genes, sometimes in opposition to each other (Palmieri et al., 2002).

When a compound binds with an estrogen receptor, it has different effects depending on the part of the body that the receptor is in. Non-estrogen compounds such as tamoxifen may mimic estrogen in their actions in some body parts, while acting as an estrogen blocker in others. In fact, when tamoxifen was first introduced, it was believed it would be an estrogen blocker across all receptors, when in fact it blocked estrogenic effects in cancer cells, and mimicked them in bone cells (thus helping to prevent bone loss in women taking the drug for its anti-cancer properties).

The association of estrogen with breast and endometrial cancer (McGuire, 1973) makes sense because the action of estrogen in several contexts is to cause the proliferation of cells, in the breast or uterus. Every menstrual cycle, cells in the breasts and uterus proliferate, and then die off if a pregnancy does not occur, because estrogen levels drop. Over time, our cells acquire mutations, for many reasons. The problem for women is that the more menstrual cycles there are, the more chances that a cancer-causing mutation exists in a few of the cells, and that estrogen will stimulate them to proliferate out of control (Henderson et al, 1988).

One of the reasons that using birth control pills increases cancer risk is that the pills were designed to mimic “natural” cycles in women, even though there is no known physiological requirement for women to bleed as often as every month. This causes a high cumulative number of cycles for women who take the pill for years (plus they have more cycles because they have not had any pregnancies). Having a late first pregnancy (over age 30) is also a slight risk factor for breast cancer even above having no children at all, because not only has there been a lot of time and menstrual cycles for mutations to accumulate, but following mutation with long term exposure to estrogen during pregnancy can then cause those mutated cells to proliferate. (All breast lumps should be investigated, but if a lump appears in the breast of an older mother soon after giving birth, it should be considered doubly suspicious.)

But, as it turns out, estrogen mediates lung cancer in too: lung cancer is twice as prevalent in female smokers as it is in male smokers (Dougherty et al., 2006), twice as prevalent in female nonsmokers as in male nonsmokers (Wakelee et al., 2007) and estrogen stimulates tumor progression in females with lung cancer (Hammoud et al., 2008).

Because as yet not enough is understood about how the different types of estrogen receptors mediate gene activation both normally and in cancer cells, we also know little about the mechanisms of phytoestrogens, despite ubiquitous claims of both benefit and harm (Rice and Whitehead, 2006).

Phytoestrogens are compounds in plants that can bind with estrogen receptors. They occur throughout the plant kingdom, but are especially highly concentrated in flax and soy. There have been debates for years about whether phytoestrogens are protective against breast cancer or promote it, or whether they could spark a breast cancer recurrence through estrogenic activity. Because non-estrogen compounds that bind with estrogen receptors may have either estrogenic or estrogen-blocking activity, and the mechanisms of phytoestrogen effects are still not well understood, these questions have not been answered definitively.

Coming soon: a discussion of recent research on phytoestrogens and soy diets which provides another piece to the puzzle of the role of estrogen-like compounds in cancer risk and prognosis.

More information about cancer and estrogen receptors is available from the National Cancer Institute.

References

Dougherty SM, Mazhawidza W, Bohn AR, Robinson KA, Mattingly KA, Blankenship KA, Huff MO, McGregor WG, Klinge CM. Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer. 2006 Mar;13(1):113-34.

Hammoud Z, Tan B, Badve S, Bigsby RM. Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocr Relat Cancer. 2008 Jun;15(2):475-83.

Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 1988 Jan 15;48(2):246-53.

McGuire WL.Estrogen receptors in human breast cancer. J Clin Invest. 1973 Jan;52(1):73-7.

Palmieri C, Cheng GJ, Saji S, Zelada-Hedman M, Wärri A, Weihua Z, Van Noorden S, Wahlstrom T, Coombes RC, Warner M, Gustafsson JA. Estrogen receptor beta in breast cancer. Endocr Relat Cancer. 2002 Mar;9(1):1-13.

Rice S, Whitehead SA. Phytoestrogens and breast cancer–promoters or protectors?Endocr Relat Cancer. 2006 Dec;13(4):995-1015.

Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, Holmberg L, Yong LC, Kolonel LN, Gould MK, West DW. Lung cancer incidence in never smokers. J Clin Oncol. 2007 Feb 10;25(5):472-8.

The recent medical opinion that anthracyclines (such as Adriamycin) are not effective in breast cancer patients that are HER2 negative is now joined by a potential test to further refine who will benefit from these chemotherapy drugs, which generally make patients very sick and are dangerous enough to cause permanent heart damage in some people.

Two genes were studied, and the mechanism of the action of one of the genes is fascinating: cancer cells with this gene sequester the toxin outside the nucleus, where it needs to be to kill the cell. The result is high resistance to Adriamycin (doxorubicin), which up to this point has been offered commonly and indiscriminately to many women with stage II cancer and above. So women with the gene who suffer through a common chemotherapy such as TAC (Taxol-Adriamycin-Cytoxan) are much more likely to have a recurrence than women without the gene.

About 20% of sampled patients in the study had the gene, and they had worse outcomes than the majority of women. The good news is that the authors find that cancer cells resistant to this class of chemo drugs are still susceptible to others. And, genetic tests these days are pretty simple and cheap to conduct (despite what companies like Myriad Genetics might tell you).

Big Pharma shouldn’t be too worried. Surely they will fight tooth and nail to patent as many genetic tests related to cancer as possible. But they’d better get cracking, because they missed this one. And it’s easy to imagine that perhaps an executive or two at a few companies would secretly rather this information weren’t available at all, because that will cut in on their profits. But perhaps this is overly cynical - surely it’s just those who don’t know someone with breast cancer who would have a tendency to feel that way. Of course, at the rate things are going, eventually most of them will.

The ecological conditions that cause a given introduced species to become invasive are complex and rarely well understood. One of the problems in attempting to promote legislative barriers to the introduction of alien species, which continues at a high rate in the U.S., is that invasions seem to follow roughly what is known as the “Ten Percent Rule.” That is, about ten percent of introduced species become naturalized, and about ten percent of naturalized species become expensive and destructive pests.

When only one in a hundred species will be an economic problem, it is not easy to take political steps to prevent the importation of aliens in general, which most ecologists would prefer. If we knew which species were most likely to cause damage, we might have better success with a regulatory pathway, but unfortunately the problem remains that ecologists are not yet capable of predicting which particular species will get out of control (with a few exceptions - Burmese python in Florida was pretty much a no-brainer).

Our current policies are clearly not working to prevent new invasives, because the species importers (pet stores, commercial nurseries) currently get all the financial benefit of importing new species, without any of the societal cost for those that become invasive. Some argue sometimes that even if a species becomes a pest, the local ecosystem will just eventually adapt to its presence. It’s not really a great argument given that multiple native species affected by the invasive could go extinct over a much shorter time scale than evolution would normally act to curb it, but a recent paper could (unfortunately) give this idea some legs.

Some species become invasive because they have been released from their natural predators, making them much more prolific in the new habitat. Nils et al. (2009) found that cropping up are a few cases of native predators adapting to invasives, so there will be potential for control. There are several reasons why this might happen, but in most cases it is because predators are forced to use a less-preferred prey because the preferred one is decreasing in abundance (often due to negative interactions with the invasive).

Of course there is likely to be a lag in this process, but the authors find several hopeful examples, including turtles and Great Lakes whitefish eating zebra mussels; native snakes eating cane toads in Australia; and red rock crabs eating European green crab in North America.

The authors avoid the issue of “evolution taking care of aliens,” but instead comment on the intriguing notion that because some of the adaptive predators are harvested by humans, we have a new factor that we need to consider when defining a sustainable catch of those species. In fact, populations of alien species that have so far been kept in check by natives, without us even realizing it, could start to spread out of control if catch limits are set too high for that ecosystem function to be preserved. Up to this point, such food web considerations have not been made in setting harvest limits.

The trouble is, harvest limits usually have little basis in any ecological information. From the perspective of a resource economist that I know, this is probably partly because ecologists have not done a great job historically of quantifying ecological impacts (although partly due to invasive species impacts, economic measures of ecological issues have more commonly entered into ecological discussions). But when I asked if it would ever be realistic to take information on novel ecological interactions - such as presented in this paper - into account, he didn’t see any reason why not, if ecologists obtain reasonably quantified data that they could deliver to resource economists for use in their model.

It seems at this point (when it is almost too late anyway) that it will be a stretch for such a politicized issue as harvest limits to take into account the more subtle effects of food-web interactions, but community ecologists should certainly take note of Carlsson et al.’s findings, and start to attempt to quantify the ecosystem value of key predators (and the resulting economic value, when costs of damage and control of invasives are quantified) , starting with those that are preyed upon by humans. If they don’t, not only might native communities continue to collapse, but a slew of invasive species may become a whole lot more damaging than they already are. We shouldn’t be spending $10 on a crab that truly costs us thousands of dollars in the end.

Reference

Nils OL Carlsson, Orlando Sarnelle, David L Strayer, 2009. Native predators and exotic prey - an acquired taste? Frontiers in Ecology and the Environment 7(10):525-532

Apparently the “several top cancer doctors” interviewed by the New York Times (about a couple of recently presented studies suggesting that oral bisphosphonate drugs, such as Fosamax, prevent breast cancer in some women) haven’t been keeping up with the literature in their field.

To be sure, in a scientific vacuum, their skepticism would be warranted. They rightly point out that one should be cautious interpreting data associations in the absence of randomized studies, which these are not. Women choosing to take bisphosphonates are those with weaker bones, which may have been caused by lower estrogen in the first place. Lower estrogen also reduces risk for hormone-positive breast cancer, so lower breast cancer and use of oral bisphosphonates may simply have low estrogen in common; thus there could be no direct causal effect of taking oral bisphosphonates.

But the data did not emerge in a vacuum. For example, it has been known for some time now from randomized trial data (Gnant et al, 2008) that breast cancer patients taking the closely related drug zoledronic acid (Zometa) (which is taken intravenously rather than orally) have somewhat fewer cancer recurrences than comparable patients who do not. In fact, zoledronic acid was originally used to treat cancer patients with bone metastases, and has only secondarily been prescribed for osteoporosis.

So, it is quite possible that there is indeed a preventative effect being seen in the observational studies with oral bisphosphonates, despite the problems of interpretation associated with non-randomization.

But even if it can be shown that bisphosphonates help prevent cancer, that doesn’t necessarily mean everyone should take them. As with all drugs, there are risks that anyone considering medication should discuss with her doctor. Unfortunately our cultural yearning for cure-all drugs, stoked to a high-stakes quest by pharmaceutical companies trying to make a profit, will likely lead to a distorted interpretation of the data that results in these drugs being pushed hard on all older women. Already, far more women take bisphosphonates than really need them for bone health, partly due to clever manipulation of the definition of “disease” by drug companies. No doubt because of this announcement we will see shortly another big push to get as many more women as possible on these drugs.

I have already heard at least one doctor assert that every single American should be on statins, because they prevent heart disease in a subset of adults.  But if there were a pill to prevent each disease you could possibly get in your lifetime, would you take them all? A hundred pills would certainly not be practical, but would you draw the line? Where should doctors and insurance companies draw the line?  People who claim loudly to believe in unlimited health “care” (i.e., are anti-”rationing”), would perhaps believe there should be no line.  Just remember, though, that drug companies absolutely support that view, but not so much for philosophical reasons. Drugs such as bisphosphonates and statins may or may not benefit a particular individual, but every individual taking them absolutely benefits the drug company. It’s a fine, blurry line between health and profit.

Reference:

Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Poestlberger S, Menzel C, Jakesz R, Kubista E, Marth C, and Greil R. 2008. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12.  Journal of Clinical Oncology 26 (May 20 suppl; abstr LBA4)

A new paper enters the cancer screening fray: Shappley, W.V. III, Kenfield, S.A.,Kasperzyk, J.L., Qiu, W., Stampfer, M.J., Sanda, M.G., and Chan, J.M. 2009. Prospective study of determinants and outcomes of deferred treatment or watchful waiting among men with prostate cancer in a nationwide cohort. Journal of Clinical Oncology 27:4980-4985.

The study, which showed no statistical difference in outcome between cancer patients who deferred treatment and those that did not, was weak in many ways. The most obvious problem was that it was not controlled, but instead compared men who made their own decisions either to monitor their cancer for awhile, or to treat immediately. This led to not only a skew in sample size (the waiting group was 10% of the total) but in significantly different initial pathologies in the groups.

But, in a way, the unequal comparisons show why this study is important. The patients who chose to wait had were unsurprisingly older, and had cancers at an earlier stage, with lower Gleason scores. So from one perspective, it is easy to say that the waiters did as well as the treated because their cancers were less likely to progress anyway. If the treatment group had more aggressive cancers, those men were still likely to die, despite treatment.

From another perspective, though, this study demonstrates exactly the pathologies for which deferred treatment, or “watchful waiting,” makes sense. As an accompanying editorial (Zietman, A., 2009. Evidence-based medicine, conscience-based medicine, and the management of low-risk prostate cancer. J Clin Oncol 27:4935) points out:

Contemporary data do show that local failure is now infrequent after radical treatment but it is also true that symptomatic local progression is unlikely even without treatment and thus little, in reality, is gained.

It is easy to fall into the trap that if I was treated, and I got better, it must have been because of the treatment. This study is important because it clearly demonstrates the fallacy of that reasoning.

Another important point of perspective is that the percentages of both death or metastasis after an 8-year follow-up were comfortingly low: death rates ranged from 0.72% to 4.5%, and metastasis rates ranged from 2.6%-10.5%. Thus, even with sample sizes of 2989 in the treated group and 342 in the waiting group, there were too few events to show any statistical difference in outcomes:

We found the relative risk to be similar between the patient groups, but the numbers of metastases and deaths as a result of PCa were low, potentially underpowering this analysis.

But what does “underpowering” mean in this context? It means you have to collect a whole lot of data to find any significance in the effect you are looking for. Some people think this means that researchers have a responsibility to collect enough data to find a statistical effect. But someone actually trying to place what is being studied in a biological context might notice that if an event you are trying to measure (in this case metastasis or death from prostate cancer) is so rare that you need a giant sample to detect a difference in the event between groups (in this case treated or untreated men), then how important is that event really, in the large scheme of things?

Very important, would say many people injecting themselves in the current health care debate. If one life can be saved by treating dozens more men, we shouldn’t even question it. We all have a bias if ours is the life being saved, and so at an individual level, some consider any amount of time and expenditure to save it is worth it - even necessary. This, precisely, is what the outraged charges of “rationing” are all about. The logic goes: if even one life is lost because a bureaucrat says that a group of people with a particular diagnosis cannot have a particular treatment, it is a moral travesty.

But of course this argument can be shown to be fallacious at its logical conclustion. Putting aside the curious lack of outrage by the “anti-rationers” at the fact that nearly 50,000,000 people in this country are rationed completely out of any but emergency care (and many of them die due to this current rationing), anyone with any intellectual honesty at all understands that unless you want to give everyone a complete body scan every week, an absurd proposition for many obvious reasons, a lot of people are going to continue to unfortunately die from cancers that weren’t “caught early” - because many cancers grow too fast to catch them early, under current yearly screening guidelines. Limiting screening to yearly visits for just a few cancers is rationing. We have rationing now, and under any possible system, we always will. The only rational point of contention is where to draw the line. Anyone who claims that line is obvious and absolute, for any type of screening, is disingenuous and talking through his hat, because anyone’s location of the line is based on their own preferred cost/benefit ratio, a matter purely of opinion.

Except, there really is only so much money out there. So even the most vocal of the “anti-rationers” will recognize that a barrier to constantly increasing care, based on cost, is eventually reached.

The accompanying editorial contained some surprisingly forthright statements that need to be discussed in the mainstream health media. For example:

The training of resident doctors has to date been so focused on cure, and the culture of early detection/early treatment so deeply ingrained, that it is little wonder that this shift in thinking is yet to reflect itself in everyday practice. What is respectfully acknowledged at major meetings and in editorials is not, in the daily reality of the clinic, being applied to patients…

The PCPT (Prostate Cancer Prevention Trial) trial reported in 2004 demonstrated that systematic needle biopsy could find prostate cancer in 27% of all men with a normal prostate-specific antigen (PSA).

It may sound surprising, given the shrillness of the current debate, but the idea that cancer exists at at least a low and nondangerous level in many of us is not a new one. A 1985 autopsy study in Finland (Harach, H.R. Franssila, K.O., and Wasenius, V.-M., 1985. Occult papillary carcinoma of the thyroid. A normal finding in Finland. A systematic autopsy study. Cancer, 56(3):531-538) found carcinomas in the thyroids of 36 out of 101 people who died of other causes. The prevalence of tumors, or their size, was not correlated with age, suggesting that thyroid cancers arise at a young age, and most do not progress:

To conclude, the smallest forms of OPC [occult papillary carcinoma] of the thyroid are, according to our series, so common in Finland, possibly also in other countries, that they can be regarded as a normal finding.

The authors conclude by suggesting that doctors avoid using the word “cancer” in regard to any small tumors found in the thyroid, because it is so loaded down with baggage that results in overtreatment. So none of this is new. It is just becoming highly relevant as we discuss what to do about medical costs that are spiraling out of control, and leaving more and more ruined lives in their wake.

Bottom line: if you look for potential problems through scans of perfectly healthy people, you are going to find a lot of them. The logical extension for those who are demanding more and more screenings (to be paid for by somebody else) is constant full body scans. And setting aside the impossibility of this, imagine the disaster of overtreatment that would ensue as we treat more and more asymptomatic conditions.

And as a final note, putting more and more money into screening does nothing to solve the problem that we are focusing too much on looking for and treating disease, rather than health itself. The same amount of money spent on prevention rather than treatment can help a whole lot more people. But, as another commentary (Esserman, L., Shieh, Y. and Thompson, I. 2009, Rethinking screening for breast cancer and prostate cancer, Journal of the American Medical Association 302(15):1685-1692) points out, the entire medical culture of the U.S. causes this:

Three barriers hinder the acceptance of prevention: failure of physicians to make clear to patients (and patients to understand) their individual risk of cancer, the belief that early detection and “cure” are ensured with screening, and organized medicine’s focus on treatment rather than prevention.

If Tea-Partiers really want to have control over their own health care, demanding more screening is not the way to do it. Instead, they should educate themselves about what the actual value of screening is, and know before they screen how they would approach treatment. They just might find themselves rationing their own care.

The U.S. Preventative Services Task Force agrees with Bioblog that it is finally time to admit that there are risks to cancer screening, in addition to benefits. It turns out that the benefits are marginal at best for women under 50 being screened for breast cancer.

Not too surprisingly (in fact, rather laughably, given their blatant conflict of interest), the American College of Radiology has gone, shall we say, hysterical on the issue, declaring that if the USPSTF’s recommendations are followed, “countless American women may die needlessly from breast cancer each year.” This hyperbolic statement is completely belied by the data that show clearly that screening affects mortality minimally at best.

In fact, the “classic” breast cancer screening study, known as the “HIP” (Shapiro, 1997) found a modest drop in mortality associated with mammography; in absolute terms, the difference in death rate was 5 deaths over 10 years over 1000 people, versus 7 deaths - hardly an example of “countless” women dying needlessly.

In addition, this and several other studies were reviewed (Olsen and Gøtzsche, 2001) with the conclusion that it had major methodological flaws (explained in more detail in Welch, 2004). The first was that deaths whose cause was unclear were more likely to be called breast cancer deaths in the non-screening group than in the screened group. This effect could account for half the observed difference in death rate.

Second, more women were excluded from the mammography group for prior history of breast cancer (once the trial started) than from the non-screened group, because women in the screened group were examined more closely than those in the control group, who did not actively participate in the trial, but rather went about their business. Because women in the screening group were far more likely to be identified as previous breast cancer patients, there were probably hundreds more previous cancer patients in the control group.

Both of these methodological problems clearly skew the results towards a conclusion that screening prevents deaths.

And here’s another serious problem with screening resulting in overtreatment that you have not read about in any of the articles describing this controversy - surgery itself can cause the spread of cancer (Retsky et al., 2003):

As a result of screening, cancers are found at an earlier stage than would be found without screening, which is favorable, but then surgical intervention to remove the primary tumor accelerates metastatic growth, offsetting the early detection advantage.

The fact remains that the panel changed its recommendations with regard to screening (since recommending it much more favorably in 2002) because the data simply aren’t there to show an obviously positive effect, and more and more negative effects of overtreatment are coming to light. It would be most beneficial to be able to separate screening from treatment in our minds; but the fact is that our lawsuit-happy society combined with the “cancer=death” attitude promoted by the very people who push screening on us in the first place makes it nearly impossible for any doctor/patient combination to adopt a “watchful waiting” approach when cancer is found.

Another fact is that radiologists rake in a pile of money for cancer screening. Obviously they are scared to death that their cash cow might be slaughtered, so they are resorting to extremely un-Hippocratic scare tactics to make sure it is not. The USPSTF’s report lists the breast-cancer screening recommendations of various national and international groups, and their new suggestion is far from radical; it fits right in a large range. The assertion that “countless” cancer deaths will be caused by their analysis is outrageous and irresponsible and ignores reams of data that say otherwise.

All the health advice given by all kinds of official-sounding groups can be dizzying. But a good rule of thumb is to ignore recommendations from groups that have a financial stake in what they are recommending. That’s pretty obvious when it comes to pharmaceutical companies, but organizations representing doctors are influenced by money too. It’s another example of the irrational distortions created by the “fee for service” system, which needs to be eliminated in favor of salaries for doctors, in order for health care reform to succeed.

References

Olsen, O., and Gøtzsche, P.C. 2001. Cochrane review on screening for breast cancer with mammography. The Lancet 358(9290):1340-1342.

Retsky M, Demicheli, R., and Hrushesky, W. 2003. Breast cancer screening: controversies and future directions. Current Opinion in Obstetrics and Gynecology 15(1):1-8.

Shapiro S., 1997. Periodic screening for breast cancer: the HIP Randomized Controlled Trial Health Insurance Plan. J Natl Cancer Inst Monogr 22:27-30.

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

A federal judge has recently denied the defense’s motion to dismiss the the class action suit against biotech company Myriad Genetics and the University of Utah. Thus, one small hurdle on the hopeful road to repealing disastrous patent rules, allowing gene sequences to be locked away from scientific research for decades, has been overcome.

Others have pointed out that you are not allowed to study 20 percent of your own genome (even if you have the skills to do so). At this rate, eventually no one will even be able to do a cheek swab on themselves without having to pay royalties to a corporation.

Is this really what patent law was supposed to achieve?

The case most often cited as the landmark in biological patent law is Diamond v. Chakrabarty (1980). While it might be a reasonable argument that a human-designed organism was created, and thus constitutes a patentable invention, it is unclear why this precedent led to patents for genes, which are existing natural products. The isolation and sequencing of a gene is a completely different act from the creation of a new biological organism, and these should never have been lumped simply because they are both biological.

Most people do not realize that there are hundreds of mutations to the BRCA genes patented by Myriad that make people more susceptible not only to breast cancer, but any cancer involving hormone targets, including ovarian and prostate cancer. But no one is allowed to study any of these sequences without paying Myriad Genetics royalties or getting their express permission (which comes with a lot of restrictions about reporting research results). Thus, most of the data languishes in a cybervault, unstudied by Myriad Genetics or anyone else, even though these mutations could potentially tell us a lot about the genetics of cancer susceptibility.

Most of the outrage against Myriad is because their patent allows them to charge thousands of dollars and take a week or more to do an analysis that could be done in any molecular lab in the country (including the one at my small regional liberal arts campus) in less than a day for around a hundred dollars, if the genetic code were freely available to work with. Myriad’s argument that no one would do this test if they could not charge thousands of dollars to do it is absurd. This is just the sort of thing that public health labs do all the time.

Or think of it this way: in the normal world of patents, people use their knowledge of nature to build a machine. Someone else has access to the same knowledge, to build a better machine, if possible. If genetic data were freely available, anyone could develop a patentable test for it. In fact, different people or companies could compete to produce the best test possible. This is the kind of world that all the Rand disciples, so common in the business world, should be supporting. When the natural phenomenon itself has been patented, we are left with one company doing a test, and we have to just take their word for it that it is the best test to do. Any competition to produce a better product has been eliminated. Not very free-market.

From an academic perspective, the most important issue is of patents that tie up genes so that research cannot be done by other scientists, and thus scientific progress is retarded. Genetic data from most organisms goes into GenBank, a public sequence database that is invaluable to researchers who want to build on the work of others.

Building slightly on previous work is all that Myriad did. Their discovery of the exact sequence of nucleotides making up the BRCA gene was made possible by taxpayer-funded groundwork laid by other scientists, particularly Mary-Claire King, who identified the region on chromosome 17 where BRCA turned out to be located. One of the founders of Myriad himself, Mark Skolnick, was the recipient of more than $5,000,000 in National Institutes of Health grants given specifically to look for BRCA1 (one of two genes he later patented through his company) (Williams-Jones, 2002). Myriad simply won a race to sequence the genes, because they spent more money to run more sequencing machines than anyone else.

Of course it is not necessarily wrong for taxpayer money be spent in a way that will create jobs and growth in certain sectors of business. This is the point of many government programs, not least the current stimulus package. And certainly anyone who creates something of value, even when the work that led to the creation was publicly funded, should be able to profit from it. Many patents developed in this way benefit society and the economy.

But patents are supposed to be there to protect people who actually did the work to create something. Leaving aside the argument that Myriad (and for that matter, any scientist who worked on any step of the process) created nothing in the first place, all the dozens of other people who worked hard to lay the scientific foundation for Myriad’s patent claim had no say in the decision to allow Myraid to have complete rights over that genetic data that they had a significant role in revealing. Most biological researchers and scientific organziations (including the American College of Medical Geneticists) believe that genetic data should be open source, because they themselves never would have been able to do their own research without “standing on the shoulders of giants.”

Imagine if each small step of the long process that has now led to the fairly trivial final step of gene sequencing and patenting was itself patented along the way. The result would be a completely prohibitive cost and complication of doing basic research, because of the royalties needed to pay out along the way. It is this belief of thousands of government and academic scientists, that the pursuit of knowledge for the benefit of society is more important than profit, that has led to companies like Myraid even having the opportunity in the first place to make their big bucks.

For a University to be one of the codefendents in the lawsuit is a sad state of affairs indeed for the pursuit of scientific progress. The argument that without the patenting of genes all scientific progress will grind to a halt is mythological. If scientists cared only about making a lot of money for what they do, why would any of them work for a university? In acutality, as put by Williams-Jones (2002):

If the BRCA patents stand, hundreds of other gene patents are likely to follow, exacerbating the current rush to patent genes – what former [Canadian] Premier Harris described as the ‘Wild West’ situation. This will have a direct impact on the manner in which scientific knowledge and discoveries are commercialized and transformed into clinical practice. Unrestrained DNA patenting could lead to a situation where all genes are patented and new research becomes prohibitively expensive, what Heller and Eisenberg have described as a ‘tragedy of the anticommons.’ Unrestrained gene patenting would also have a significant impact on the provision of genetic services through the public health care system, potentially making genetic tests and therapeutics unaffordable, and thereby raising serious issues of justice in access to medical services.

Of course, we don’t have a public health care system, at least not yet. But really, what difference does it make? Most of us pay large health premiums, so we are indeed paying these outrageous royalties to companies who performed the now-trivial act of running a sequencer - or a whole bunch of them. (If companies chose not to pay for the tests, it just would not do, because that would be rationing!) So, if you could benefit from a genetic test, you will be happy to realize now that you have paid for the test twice - first as a taxpayer, for the research that led to the test, and now as an insurance holder.

Isn’t capitalism great?

Reference

B. Williams-Jones, 2002. History of a gene patent: Tracing the development and application of commercial BRCA testing. Health Law Journal 10: 124-146.

We are hopefully witnessing an important turning point in the way people think about cancer.

Thirty or so years ago, the public was promised that a “cure for cancer” was imminent. That was before all the powerful biological techniques of today made it clear that “cancer” is not a simple, single disease, but instead a catch-all term for uncontrolled cell growth that has many different forms and occurs in many different contexts. Indeed, trying to find a genuine cure for cancer may be similar to trying to find one for the common cold, which exists in too many forms to make such a search practical.

Just as with colds, prevention is the best strategy, because effective treatment, though there have been a few resounding successes, remains so elusive. And yet the money in cancer research may always be more in the testing of new treatments, which is supported a lot by private industry, rather than in learning more basic biology about different types of cancer themselves, which will only be funded by the government. Not only do we need to learn more about what prevention strategies might be effective, but (perhaps in the shorter term) how to better target treatment, and especially whether to treat at all.

The fact that we don’t really know yet which early cancers detected by screening will develop into full-blown disease is the elephant in the room whenever screening is questioned as a cancer-treatment strategy. An individual facing a positive breast or prostate small cancer screen cannot yet be consoled with the absolute knowledge that the particular cancer they have is unlikely to progress, despite the fact that it is now clear that the majority of such cancers do not. But we do have information that should provide ample justification for any healthy person to make the informed decision that he or she does not wish to be screened.

First, current research (Esserman et al., 2009) finds that breast and prostate cancer rates are indeed rising, but that this rise is attributable to more small, asymptomatic cancers being found via mammography and the PSA test. The rate of metastatic cancers, i.e. those that cause death, has not declined. This suggests strongly that the only thing that screening of healthy people has accomplished is to reveal cancer rates that were already high, causing a lot of angst and unpleasant - and sometimes quite damaging - treatment.

Second, very few deadly cancers are found by screening, because the deadliest progress very quickly, and probability dictates that screening once a year is very unlikely to “catch” them. This means that unless you increase screening rates to something like once a month, screening will never be a useful tool for finding the cancers most likely to kill. And given that the probability for a specific individual getting one of those aggressive cancers is relatively low, the burden of screening would simply be prohibitive for both the individual and the system, in both time and money. Furthermore, finding an aggressive cancer early is no guarantee that it will be “cured,” because the most aggressive are also the most difficult to check through current treatments.

So, despite our inability to sort out the “benign” cancers from the aggressive ones, there are multiple reasons for us to try to alter the culture of breast and prostate cancer screening, because the prevailing belief that all cancer must be destroyed immediately is frankly costing us a lot in blood and treasure. The truth that the medical culture must be reformed to understand is that everybody has cancer cells in their body, but these only progress to be invasive in a small subset of the population.

The tendency is to think of screening as a “prevention” strategy in the first place, rather than as “treatment,” which it becomes for a lot of people, is a major reason we have the problem today in which lots and lots of small cancers are found through screening, most of which will never cause harm to the person. Dr. H.G. Welch brilliantly illuminated this problem (and those outlined above) in his 2004 book, “Should I Be Tested for Cancer?” in which he pointed out five years ago that a general fear of cancer and the promotion of screening as a “prevention” strategy create a vicious cycle of more and more screenings finding more and more cancers. More (asymptomatic) people are diagnosed through screening, increasing our awareness of an “epidemic” of cancer, which causes more promotion of screening for the general population, many of whom get screened, and thus diagnosed.

This is only one of the problems in the current cancer culture. Everybody who does not have cancer should read Dr. Welch’s book now, because cancer screening is a complex problem that does not lend itself to sound-byte reporting do’s and don’ts. (Just read the comments on this health blog entry on cancer screening from the New York Times, and it is clear that news outlets simply aren’t up to the task.) Thus, although it is a huge breakthrough that the American Cancer Society is finally admitting the problems associated with excessive screening, changing the cancer culture will be a long and difficult hill to climb - especially with other organizations still sending the conflicting message that everybody needs to get screened, now.

A somewhat discouraging take-home message from Welch’s book is that most doctors are not well informed about the downsides of cancer screening (although it is certainly true that muddying the waters further is overly defensive medicine through fear of lawsuits). This is because although you might assume that doctors are trained scientifically and understand numbers and statistics well, shockingly few of them do. Dr. Welch is one of them, thankfully, and through his expertly and clearly written book, you can be too.

Hopefully, we really are undergoing a sea change about how we think about cancer, and that this will lead us in more productive research directions, such as who should actually receive particular treatments, and who should not. But in the meantime, resisting the urge to package the benefits - but not risks - of cancer screening to a pink political campaign, and instead thinking logically about what the cancer screening numbers really mean, would result in a lot better health care.

References

Esserman L., Shieh, Y. and Thompson, I., 2009. Rethinking screening for breast cancer and prostate cancer. Journal of the American Medical Association 302:1685.

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

David Goldhill’s otherwise astute piece in the Atlantic on multiple reasons for our unsustainable, haphazard way of providing health care in the U.S. has one major failing: his anecdotes and analogies assume that health insurance and insurance for material goods should be analogous. But if someone does not have home or car insurance and loses her house or car through an accident or personal negligence, the rest of us do not have to pay for its replacement. And no one will cry foul when a car or home insurance company kicks someone out who makes too many claims, but most of us believe in (and the law supports) the moral obligation to provide emergency care to anyone, regardless of their ability to pay. Fundamentally, the solution to this problem is so hard because it can never be a purely economic one.

There is nothing wrong with the conclusion he reaches that knowing someone else is paying for our health care makes us push for more potentially unnecessary tests and treatment. The inherent problem with his solution to make people responsible for “routine care,” however, seems to ignore the fact that many - if not most - people who are required to pay for physicals, check-ups, and screenings simply will not attend to their health until it becomes a “massive, unpredictable” problem that has to be paid for by insurance. This brings us right back to the problem of hospitals/insurers having to overcharge responsible users to make up for the irresponsible (or currently, uninsured) users, which is exactly where we are right now.

This issue exists right now for people with high-deductible health plans. Just read the comments on this post at the New York Times’ Well blog to see how many people will simply put off any sort of preventative medicine when they have to pay for it themselves. Goldhill suggests vouchers for occasional checkups, but there is a lot more to preventative medicine than a biannual physical - just think of all the disease-preventing maintenance Americans could do on our bodies for practically free, but do not, such as adjusting our diets or getting a minimum amount of exercise. How many people out there are maintaining their cars better than themselves? Our relationship with our health unfortunately is not based on rational economic decisions. No matter how we decide to pay for it, health care decisions will always be clouded by the issue of moral entitlement, because a productive society supports all its members.

Some commenters on the Well blog are also understandably a bit angry at the idea that they will make better health care decisions simply because they have to pay for their care. Would the elimination of insurance for “routine care” include an instant medical degree? If my doctor recommends a $2000 colonoscopy and I decline it due to cost (which almost anyone with no specific risk factors - and many people with the risk factors - will do), how has putting money in the equation made for better health care than when money was not part of it? Goldhill suggests that “professional health-care agents” would fill this gap. But is an average American really going to pay even more money for a paraprofessional to help make their health-care decisions? Think of the divide between the haves and have-nots we would see then. Poor people will still be a lot sicker than rich people, maybe more so than now. (And yes, I am making the assumption that it often, if not usually, isn’t someone’s own fault they are poor; if you assume otherwise you are blind to reality.) The biggest problem with Goldhill’s economic solutions is that he assumes that a patient can be as much of an informed consumer as someone buying a stereo. Sure, I can come close after a huge time investment because I have a doctorate in biology. Most people, however, must rely on their doctors’ expertise, which you simply cannot buy, now matter how many vouchers the government gives you.

He certainly has a point about elective procedures, but how are we to define them? Lasik surgery, which is already not covered by most insurance, is elective, and absolutely should be paid for by the beneficiary - whether or not you do it will not affect anyone else, and if you can’t afford it, glasses will do. Childbirth could be considered elective as well, and Goldhill indeed lumps this as a predictable event that people should pay for themselves. Except, you then run into the problem that a lack of prenatal care can affect you and me, if it results in a child that has health issues big enough that insurance has to kick in. Is your lifetime of little decisions leading to obesity, diabetes, and heat disease going to result in higher cost for your “unexpected” catastrophic care, the way that points on my driver’s license drive up my car insurance premiums? Figure out how to do that, and get back to me.

Many of Goldhill’s ideas make a lot of sense. But beginning his discussion with the presumption that the health care problem can be solved by economic logic undermines his argument. At least, though, it’s a good place to start, because (like every intelligent commentator who doesn’t actually have to try to shepherd reform through congress) he recognizes the need for a fundamental, ground-up change, rather than the useless, minor tweaks that politicians always seem to come up with to appease idealogues.

My prediction? No substantive health care reform until people in the top 30% or so income bracket can no longer get decent insurance. The tragedy of this is that the dead end road we are on will be harder and harder to get off the longer we stay on it, as our President has tried to make understood over the partisan clamor. Because of the current economics of health care, primary care physicians are an endangered species, and research money goes more to developing new devices and treatments that will make someone money, instead of refining our knowledge of who will actually benefit from the ones we have (which will lose people money). Those issues hardly have even come up in discussions of reform, let alone the proposed bills, but in reality they are the most urgent because it will take a decade or more to change our trajectory on them, once we decide we need to. It’s the politicians’ jobs to understand this, and to realize that as our elected representatives they are supposed to be better informed than their constituents, and therefore can make decisions that might be good for us even if we disagree with them. But because politics is also about money, they are continuing to fail us in every way.