Some implications of biologic plausibility

Ever since my... ahem... skirmish... with the folks over at the SBM, I have been contemplating the issue of biologic plausibility. They contend that our tax dollars are wasted by being allocated to the NCCAM to pursue research into CAM. Their reasoning is that there is no biological plausibility to any of it having any therapeutic effect. Now, this is a big bite to swallow. As I have said before there is CAM and then there is CAM. CAM seems to be a convenient wastebasket of modalities that we feel justified in bashing as "woo" since there is limited scientific evidence behind them. But really, I am more willing to give acupuncture and massage the benefit of the doubt than, say, healing crystals (even though I confess I really like rocks!).

So, what of this biologic plausibility, and who came up with it anyway? And is it truly fiscally irresponsible, and possibly even unethical, to test interventions that do not fit our biological plausibility criteria? As a corollary, is there a level of our understanding of biology that makes testing equally wasteful or even unethical? And finally, should plausibility of benefit and harm be required to reach the same evidentiary bar?

For the definition of biological plausibility we apparently thank the milestone 1964 Surgeon General's report linking smoking to cancer. This report was the first official US government document to state that there was enough evidence to implicate cigarette smoking in the rise in lung cancer and cancer deaths. Since the limitations of observational research were used by the critics for decades to derail this definitive statement, the report itself does a nice job laying out the methodologic considerations and the need to rely on the Bradford-Hill criteria. It was in the "coherence" criterion that biologic plausibility entered the picture.

A quick check of my favorite crowd-sourced information site, the Wikipedia, uncovers this treasure from Sir Bradford Hill himself:

It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day. To quote again from my Alfred Watson Memorial Lecture [1962], there was

"…no biological knowledge to support (or to refute) Pott’s observation in the 18th century of the excess of cancer in chimney sweeps. It was lack of biological knowledge in the 19th that led to a prize essayist writing on the value and the fallacy of statistics to conclude, amongst other “absurd” associations, that 'it could be no more ridiculous for the strange who passed the night in the steerage of an emigrant ship to ascribe the typhus, which he there contracted, to the vermin with which bodies of the sick might be infected.' And coming to nearer times, in the 20th century there was no biological knowledge to support the evidence against rubella."

In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr. Watson, "when you have eliminated the impossible, whatever remains, however improbable, must be the truth."^[1]

Aha, so biologic plausibility is a function of the state of our current knowledge, today. By this litmus test, Marshall and Warren should have been laughed out of all funding agencies. Instead, they rewrote our understanding of what can live in the stomach, and how a microorganism can cause peptic ulcer disease and stomach cancer. And got themselves a cool Nobel to boot. So much for the ethics and finances of biologic plausibility informing meaningful research.

Now, on to the question of whether there exist relationships with such high biologic plausibility that they do not require irrefutable proof. Well, how about tobacco and its health effects? How about radiation exposure? Now, how about what we know today about the evolution of microbial resistance to antibiotics? Is it enough that the biologic plausibility for ill-effects of antibiotics in our food chain is strong? Can we now stop the madness? If my colleagues over at SBM are given to the same logic, they would say yes to this. However, extrapolating from this post about organic food production, I somehow think that they would not. So, I am guessing that, although they believe that lack of biologic plausibility should preclude attempts at study, they will nevertheless be reluctant to set a threshold for biologic plausibility that might obviate the need for further research. I am just guessing, and would love to hear what they really think.

And finally, what of the plausibility of benefit vs. that of harm? Should our bar for biologic plausibility for harm be lower than that for benefit? Well, the question really boils down to this: How many bodies do we need to see lying in the streets before we concede that there is a problem? My point is that we Americans have a hard time subscribing to the precautionary principle, applied generously in other parts of the world. If we were a tad less reckless with our need for irrefutable evidence, how many decades of equivocation about tobacco and cancer would we have avoided? How many lives might have been saved? Biologic plausibility for the connection was known even in the 1930s, yet it took another three decades for us to act. What are we obfuscating today that will come back to bite us (and our children) tomorrow? Could it be the cynical injection of doubt that our food production system is causing irreversible damage to us and life around us?

So, what I am saying is that biologic plausibility has several facets. We have to admit humbly that its assumption relies on our necessarily incomplete knowledge, and denying this may prevent us from awe-inspiring discoveries that will advance science in leaps. However, if we feel strongly about the need for it in order to justify our research allocation, some careful soul searching is in order for those thresholds of probability, especially of harm, where we may admit that science makes us sure enough, and, instead of awaiting perfect evidence, we must act promptly.      

    

Dear Dr. Val

Dear Dr. Val,

I enjoy reading your blog and the contributions from many of the leading medical bloggers that appear on it. Occasionally, the spirit moves me to post a comment, but for the second time in just a few months my comment has not made it to your blog. Why? I also tweeted you to ask if there are technical difficulties peculiar to my comments, but I did not get a reply. Why?

I know that some bloggers have a policy about what comments get rejected. I know that I will not accept abusive, profane or overtly marketing comments on my blog. I am sure you have the same standards. So, why not accept mine? I read Dr. Novella's post with great interest yesterday, and got passionate enough to write a pretty lengthy response. I am grateful to you and to Dr. Novella for allowing me to think through some of the issues that I commented on. But I was hoping for a dialogue... How will we ever arrive at mutual understanding or even better individual understanding without a cogent dialogue?

I do understand that the blog belongs to you, and you must have many reasons not to accept all comments, and that is your right. Perhaps you never even saw it, perhaps you no longer follow my tweets and thus did not get my queries. That is all fine. If I cannot get my comment on your blog next to the corresponding post, I will put it here and hope that you will come for a visit. If you do, I will welcome your comments. So, here it is:

What a great post! Dr. Novella makes the point that there is no evidence for the superiority of consuming organically produced foods over the conventionally produced ones in terms of health benefits. To arrive at this conclusion he relies heavily on a recent systematic review supported by the UK Food Standards Agency, which examined 12 studies, 8 of them in humans, 6 of which were RCTs and the remaining 2 observational studies. Because the article is available by subscription only, I could not access the whole paper. However, knowing what conducting clinical trials entails, I doubt that the 6 experimental studies followed the subjects for all that long. Perhaps not long enough to detect the benefit? Would love Dr. Novella to comment on this.

Additionally, divorcing the potential direct health effects due to consumption of organic products from the effects of the production on the environment is a false dichotomy. The pesticides do not just stay on the skin of the produce, but get into our water supply; the antibiotics given to the animals in CAFOs do not just get into their meat, but also get into the water and produce resistant pathogens -- there is plenty of work from the Netherlands to support the connection between agribusiness practices and human pathogen resistance emergence. Also, look at the staggering findings by the USGS about the contaminants found widely in our water supply and in what amounts.

The monoculture model of conventional agribusiness also requires enormous amounts of petroleum for fertilizers and pesticides as well, a resource that is dwindling. And, perhaps most importantly, the impact of monoculture farming on the land itself is devastating, decimating arable lands and creating essentially sterile deserts which need centuries to recover.

Having said all this, the mass-produced organic food business is not much more environmentally friendly than the conventional agribusiness, relying on monocultures and artificial fertilizing and pesticide management, as Dr. Novella aptly points out. Additionally, because it is concentrated in places remote from where it is consumed, its carbon footprint is still enormous. The really sustainable way to farm and eat, environmentally and human health-wise, is returning to small local farming, with a short distance from farm to table and a self-perpetuating cycle of earth's nutrient consumption and repletion by a diverse biome, just like nature intended.

My final sentiment is that, as people involved in healthcare of our nation, we must care about social and environmental justice. While these issues may fall more comfortably under the rubric of Public Health, doctors and nurses and other personnel at the bedside need to develop a greater appreciation for the context in which disease develops. This context includes healthy and sustainable food production and other social and environmental concerns.