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.      

    

Microbiome: passenger or vehicle?

Remember how you learned in BIO 101 that many fluids in the human body are normally sterile? And you know how you laugh with condescension when someone dares to question this dogma? After all, we know that the gut and the skin are full of microorganisms, but the lung? The bladder? This is inconceivable, heretical!

Well, actually, this, like many other dogmas that seemed like God's word at the time, has been broken open by some very interesting research emerging from multiple laboratories around the world. I was first stopped in my tracks about a year ago, while listening to an NPR story in my car and learning that the number of bugs we carried on and in us was about 10-times greater than the number of our own cells. Then, in a farm house in Cornwall a couple of weeks ago, while on vacation, I read an article in an October 2009 issue of Eureka, The Times monthly science magazine, which once again made me ponder our sojourns in life, the bacteria that cohabitate with us. And finally, today I saw this story in yesterday's NYT, which galvanized me into writing action. This grabbed me in particular:

Scientists are even discovering ecosystems in our bodies where they weren’t supposed to exist. Lungs have traditionally been considered to be sterile because microbiologists have never been able to rear microbes from them. A team of scientists at Imperial College London recently went hunting for DNA instead. Analyzing lung samples from healthy volunteers, they discovered 128 species of bacteria. Every square centimeter of our lungs is home to 2,000 microbes.

It grabbed me for two reasons:
1). I am a lung doctor, and a lot of the research that I do centers around lung infections. One type of this infection, ventilator-associated pneumonia or VAP, is the subject of much scrutiny by policy makers and payers, and is emerging as a quality indicator. There are many challenging issue in VAP, not the least of which is its treatment: because it is likely to be caused by an antibiotic resistant organism, and because at least one-half of all cases of suspected VAP never grows out a specific microbe, the recommended empiric treatment is with broad-spectrum drugs. The clinician treads a fine line between undertreating the patient at the expense of increased mortality or overtreating and promoting antibiotic resistance.
2). I have already written here about my thoughts on evidence and how we tend to approach our knowledge with the arrogance that blinds us to the possibility of being either under-informed or plain wrong. Well, here is the case where we were so convinced of what we knew, yet it was plain wrong! With the scientific skepticism and appropriate tools we are learning something completely opposite to what we thought we knew.

Taking this line of thinking one step further, can we now conceive of the possibility that what we expose our bodies to actually plays a role in our long-term health? To be specific, I mean something as simple as food and the way our food is produced. Monoculture and food engineering have become staples of our food production. Animals are raised in CAFOs in conditions requiring them to be on antibiotics to ward off infections and to help with growth. Additionally, to leverage the subsidized and abundant corn supply, food animals are forced into diets completely unnatural to them. Cows, for example, evolved over millennia to be ruminants meant to eat grass and hay, are fed a corn-based grain diet, which, by altering their gut environment, makes them much more likely to carry toxigenic E. coli. Although there is much nay-saying about whether antibiotics (and hormones, by the way), are passed on to humans through meat or milk, I have never seen any convincing scientific evidence to the contrary. So, if we eat meat that is microbiologically altered, and may also be exposed to antimicrobial residues that may in turn change our own native microbiome, is it possible that at least some of the emerging health issues are due to the travesty of monoculture production?

I am not saying that I have all the answers -- clearly, this research has a long way to go to establish causal pathways and potential points of intervention. But let's exercise our common sense and at least ask the questions. Do it early and often. And let's please agree that there is a certain burden of proof here that resides with the food production oligopoly. Oh, yeah, and let's not forget to continue limiting the use of antibiotics in human health too. And have a little bit of dirt... for lunch... every day...  

The lost art of evidence-based debate

When people first find out that I was not born in the US (that's right, there go my presidential aspirations!), their question is about culture shock. They want to know what I perceived to be the biggest differences in cultures in the old vs. the new country. Over the nearly 35 years that I have spent in the US my thinking on this has evolved. Initially I was flabbergasted that teachers in high school tolerated students' putting their feet up on the desks. In my old country such behavior would have been punished corporally.

Today I consider myself to be a more sophisticated judge of cultural differences. I have come to appreciate that the US is not a monoculture, but a conglomeration of many different philosophies. And I do not mean just based on race, ethnicity and other obvious cultural drivers. Take for example politics as a profession: its culture is quite distinct from many others. Social scientists tell us that successful politicians are necessarily narcissistic, which is a blessing and a curse. This makes them not only über confident and decisive, but also prone to philandering and other forms of deception. I am also struck by how well they have perfected the art of not responding to questions by taking every opportunity to drive their talking points. Particularly astonishing is their ability, derived from Karl Rove's playbook, to turn a complete fabrication into what is accepted as reality by some. Just look at the death panels rhetoric.

I have to say that over the years I have cynically come to expect this and other bad behaviors from politicians. What is concerning to me is the pervasiveness of the same Rovian tactics in other sectors. Remember the recent E. coli outbreaks linked variously to Mexican peppers, tomatoes and spinach? Well, keeping this in mind, let's consider the work by the Center for Science in the Public Interest on FDA-regulated foods that have been implicated in E. coli outbreaks. This work, citing such seemingly innocuous and even desirable foods as lettuce, tuna and potatoes, has apparently incensed some of the corporate food lobby. Indeed, the Chicago Tribune reports that

...the Produce Marketing Association disagrees with putting them on the list, saying it is committed to providing safe produce and is working with the FDA and CDC to create "food safety solutions to help safeguard public health" and that "fruits and vegetables are necessary for better health."

All points well taken. But how does this address the issue at hand? Take back your data because we are committed and working on doing better? Why this is like a doctor saying "take this malpractice suit off my record because I am committed and working on doing better". Absurd logic? I think so.

The article further cites objections from the tuna organizations thusly:

But the National Fisheries Institute was even more scathing the study (sic) in their statement, saying "Seafood is a safe and healthy product that is an essential part of the American diet. CSPI has a history of attempting to scare consumers by playing fast and loose with definitions that might lead the casual reader to think people are getting sick left and right from seafood...Consumers should take this report with a grain of salt and a heaping helping of perspective."

Scare? Fast and loose? Have they ever heard of scombroid? No, it is not fatal, just unpleasant, but it happens despite the FDA regulation to gut and stuff the fish with ice immediately upon catching. Instead of addressing the evidence, they are quick to deny the allegation by casting doubt on the source.

And this brings me to my central point. Do these tactics of killing the messenger originate in relentless pursuit of market share even at the expense of public's health? Or is this just ignorance of how to debate a legitimate point? Is it possible that these executives and lobbyists do not have the skills to structure a logical evidence-based argument? Perhaps our educational institutions have lost sight of this critical skill as well. My guess is that it is a little bit of the latter and a lot of the former. Seems like public debate continues to deteriorate into voyeuristic entertainment, aided by shallow reporting.

But it does not have to be this way. The public needs to be empowered to make their own decisions based on a critical look at the evidence presented by both sides. If we can vet this evidence ourselves, there will be no room for corporate deception. Their antics will take their rightful place in the comics section of the paper.