Antibiotic usage regulations – too little, too late?

This post is cross-posted from a blog post I wrote for the Science and Policy Exchange. For more insightful writing on science and how it relates to government, the media, and society at large, visit their site http://www.sp-exchange.ca

In Dr. Seuss’ The Lorax, the narrator reflects sadly upon his past. He recounts arriving at a pristine forest of Truffula trees, which he cuts down to make thneeds, a product that “everybody needs”. Ignoring warnings and later pleadings from the titular Lorax, he cut down trees one-by-one, later 4-by-4, growing his business enormously in the process. He continues to cut down trees until all of the sudden, the last one is gone. Without any more Truffula trees, his business collapses and he falls into poverty, and tells his story so future generations won’t make the same mistake. He realizes how he was blinded by the promise that his business would only grow bigger, and overlooked the fact that he was rapidly removing the key resource he and others depended upon. By the time he realized his wrongs, it was already too late – the forest was gone, along with its animals – the Brown Bar-ba-loots, Swomee-Swans, Humming-Fish, and the Lorax himself.

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Sure, The Lorax is a children’s story, but it illustrates some profoundly adult concerns. Take too much from a public good, and it will collapse, leaving everyone worse off in the long term. This story obviously parallels real-world issues like deforestation, pollution, and overfishing, but also applies to abstract public resources like transportation networks, taxation, and stability of financial markets. To protect common resources for the good of the public as a whole, regulations are needed to prevent individuals from exploiting these resources for short-term personal gain.

A somewhat obscure public good, but one that medicine depends upon is the efficacy of antibiotics. Antibiotics are only effective when the microbes they are used to treat are susceptible to the drug. If resistance to antibiotics spreads, antibiotics lose their utility, and this public resource is lost. We need these drugs not just to treat infections, but also to facilitate surgery, cancer therapy, and to protect immunocompromised patients, so losing our effective antimicrobials would be an unmitigated disaster.

Unfortunately, to retain antimicrobial effectiveness, we fight against formidable evolutionary forces. Add a strong selective pressure (antibiotic), and evolution drives the selection of the most fit (resistant) microbes. These resistant microbes will thrive where their non-resistant counterparts die, and take over the competition-free environment left behind. For this reason, we instruct patients to take the full course of antibiotics to completely eradicate an infection. Otherwise it could come back, stronger and tougher, and spread to other patients as well.

This example is usually framed around medical patients, but when we look into the emergence of antibiotic resistance, the more important subjects of antimicrobial use aren’t humans, but chickens, pigs, and cattle. Almost 80% of antibiotics are used in agriculture. These antibiotics are used in three ways: to treat acute infections, in feed as an additive for “prevention and control”, and lastly for use as growth promoters. The last usage doesn’t make much sense – why would chemicals that kill microbes alter the growth of livestock? The short answer is that don’t really know, this question is at the forefront of the burgeoning field of microbiomics. What matters for farmers and feedlot managers, however, is that it works, and their animals grow faster, bigger, or both, which means better profitability. It makes perfect economic sense to routinely add antibiotics to feed as growth promoters.

The problem is that this constant background of growth-promoting antibiotics in agriculture generates a selective pressure that drives the emergence and spread of antibiotic resistance. This was long suspected based upon our understanding of natural selection. Careful research has now shown that indeed, these growth-promoting antibiotics lead to increased emergence and spread of antimicrobial-resistant bacteria, and further, that these resistant bacteria cross over to human patients. Knowing this to be true, the widespread use of antimicrobials for growth promotion in agriculture is now viewed as a considerable public health hazard.

Recognizing this hazard, in 1977 the US Food and Drug Administration (FDA) committed to putting restrictions on antibiotic use in agriculture, a crucial step to limit the spread of resistance. The agency took the first step last December, 36 years later. Their Final Guidance for Industry 213 recommends that antimicrobial manufacturers discontinue indication of antibiotics as growth promoting agents. Some are celebrating this as an important first step. Many are rolling their eyes at what appears like a mostly empty gesture.

The FDA recommendation took far too long to happen. It also lacks teeth. First, it is voluntary, and it doesn’t seem likely that many manufacturers will embrace the opportunity to cut their revenues in half. Farmers operate on such narrow margins that discontinuing antibiotic use could force them out of business, and so change won’t happen there either. The recommendation also has a gigantic loophole: by simply rebranding antibiotic use from “growth promotion” to “prevention and control”, farmers and feedlot managers can continue business, fully compliant with the recommendation, without changing their de facto usage at all.

The FDA recommendation is a first step, but it’s a feeble one, and one that took far too long to happen. A knot of competing interests seems to be preventing much from happening. The medical community and food purity movements want antibiotics removed from agriculture. While the FDA seems to concur, its hands are often tied – the agency is caught between protecting public health and strong economic incentives to keep the status quo in agriculture. The US congress has meddled considerably in the matter, and no doubt lobbyists are pulling strings along the way. Comparatively low food costs have also contributed to the problem, as they push producers to squeeze every drop of efficiency they can from the system, growth promoters forming an important part of their plan. Given these opposing forces, it becomes less surprising that it took the FDA 36 years to publish their recommendation, but at this pace, by the time any substantial change happens, it may be far too late.

The Lorax in this story is the scientific and medical community, who have been pleading with industry for decades to adopt more responsible agricultural antibiotic practices. Individuals within agriculture, like Dr. Seuss’s tragic narrator, are mostly concerned with day-to-day operation of their business, and not esoteric concerns about the future of medicine. But as a collective, the industry needs to realize the loss of antibiotics will have long-term consequences for their business as well and take steps towards more sustainable use. In the absence of this kind of industry action, firm regulations on responsible antibiotic use are essential to protect antibiotics as a public resource. Otherwise, our antibiotics will drop one-by-one from pharmacists’ shelves like Truffula trees, until none remain, and like the animals in the Lorax’s forest, other life-saving innovations of medicine could be lost as well.

Full disclosure: I study antimicrobial resistance in a biomedical research lab, so I do have a stake in this matter. I’m also sympathetic towards farmers – I grew up on a beef farm, where my family still raises hereford cattle.

Edit 2015.09.02: I’ve updated my account since I first wrote this post. If you’d like to follow me online, find me @superhelical

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Who Watches the Watchmen? Blind Trust Isn’t Enough in Today’s Research Environment

This post is cross-posted from a blog post I wrote for the Science and Policy Exchange. For more insightful writing on science and how it relates to government, the media, and society at large, visit their site http://www.sp-exchange.ca

In the spring of 2012, an article appeared in the niche crystallography journal Acta Crystallographica, Section F (“Acta F” to those in the know). This article, “Detection and analysis of unusual features in the structural model and structure-factor data of a birch pollen allergen” describes a protein structure published in a 2010 Journal of Immunology paper. Following a thorough analysis, author Bernhard Rupp (of textbook fame) concludes there is:

… no doubt that model and data of [structure] are incompatible and that the deposited [data] are not based on actual experiments, and their standard uncertainties are not based on experimental errors.

 Translated to everyday language, this reads

The data isn’t real.

 He is accusing the authors of data fabrication.

fake

 Technical language and a deferential tone mask the severity of this accusation. The author response, published in the same issue, cuts to the chase.

The University of Salzburg immediately informed and commissioned the Austrian Agency for Research Integrity (OeAWI) to carry out an investigation into possible data fraud on the part of author Robert Schwarzenbacher, the co-author solely responsible for the Bet v 1d structure and the crystallographic section of the J. Immunol. paper. The OeAWI is presently preparing a report of this investigation.

This is a great example of researchers and institutions taking the appropriate steps to address concerns of research misconduct. Then:

Author Schwarzenbacher admits to the allegations of data fabrication and deeply apologizes to the co-authors and the scientific community for all the problems this has caused.

 Oh. Well then. No need for an investigation after all, right? Well….

Note added in proof: subsequent to the acceptance of this article for publication, author Schwarzenbacher withdrew his admission of the allegations.

 Presumably he talked to a lawyer.

 So, what went wrong? We can infer that researchers working in one field (immunology) brought in a collaborator from an outside field (structural biology) to add complementary experiments and drum up the impact of the project. The steep learning curve and specialized techniques of structural biology meant that the other authors had to trust Schwarzenbacher’s work was conducted rigorously and honestly. Obviously, this trust was misplaced.

 Almost two years after the Acta F paper was published, Schwarzenbacher has lost his job, but has sued for wrongful termination. The structure in question has been mothballed in the Protein Data Bank, and his contribution to the Journal of Immunology paper has been removed. The paper still stands on its other experiments, as the authors argue that the paper’s conclusions did not depend on the fraudulent structure work. Regardless, it’s a black mark on the record of the coauthors, the journal, funding agencies, the university, and the Austrian structural biology community. The reputations of many parties have suffered from the actions of one misguided researcher.

 Most have been happy to hang the blame on Schwarzenbacher’s shoulders, and rightly so. But does he carry all of the responsibility? I’ll argue he doesn’t. 7 co-authors all approved the work for publication. The Journal of Immunology, its reviewers and editor all gave it the stamp of approval. The department and university provided the environment where this misconduct could go unnoticed. The allergy and immunology research community also missed the fraud. Everyone appears to have been content to accept the credit and conclusions from presumably legitimate work, but once fraud was brought to light immediately distanced themselves from the situation. This is not a sustainable practice.

 This isolated case could be one of many to come. We need not just consider fraud, either. Even the most scrupulous researchers are subject to the insidious influence of wishful thinking. Critical mistakes can slip through when a “ringer expert” operates on their own, without any scrutiny. As technology drives ever more complicated experiments, and granting agencies continue to reward multidisciplinary work, lone specialists will increasingly be required in collaborations, and the chances of fraud or major errors slipping through will increase.

 Schwarzenbacher’s is a particularly good example of this problem because there is no ambiguity about his fraud – a novice crystallographer would find obvious problems with the data. Passing the data past a single critical eye could have caught the fabrication before publication. This drives home how the current environment can allow ethical or methodological problems to slip through, leading to flawed or fraudulent conclusions. A mechanism is needed to improve oversight – the assumption of good faith is not sufficient. Peer review is supposed to provide this function, but here, as elsewhere, it failed.

 Besides fixing peer review, how can future incidents like the be prevented? Movements like open data will play a role. Deposition of data is already a condition for publication of structural work, and Schwarzenbacher’s fraud was discovered through curation of the database. Post-publication peer review can also help identify problematic data and correct the scientific record, but neither of these mechanisms can prevent the initial publication of bad or fraudulent data.

 What is really needed is a culture change. The institutions, journals, and researchers involved in multidisciplinary collaborations can’t escape responsibility for scientific oversight. This could mean some sort of institutional review, or a requirement to pass the data by a friendly but impartial third party. Most importantly, the community needs to accept that scientific integrity is the responsibility of everyone involved, not just the person who processed the data. Researchers need to take steps to ensure that they can stand by the integrity of all of the work to which they attach their names. Ignorance is a poor excuse.

 It’s worth considering what drove Schwarzenbacher to cross the line. Rather than some master manipulation to trick his collaborators and journal reviewers, his actions appear more like simple indifference and laziness. As highlighted by the partial (not full) retraction, the structural work wasn’t central to the study, and the faked data is obvious enough that he clearly didn’t expend much effort to cover his tracks. Perhaps he didn’t think anyone would notice or care, and if so, he was somewhat correct. His collaborators and research environment allowed him to cut a corner that he shouldn’t have cut. He chose expedience over honesty.

 The editors of Acta F make the observation that

It seems clear that the pressures on scientists early in their careers are so severe that a few are compelled to risk their careers in order to further them.

 I think it’s time everyone else assumes a little responsibility for letting it happen.

Find out more about the Schwarzenbacher debacle on RetractionWatch:
http://retractionwatch.com/2012/04/02/protein-structure-retracted-after-investigation-into-highly-improbable-features-journal-calls-it-fraud/
http://retractionwatch.com/2012/04/12/salzburg-university-fires-crystallographer-robert-schwarzenbacher-for-faking-data-in-journal-of-immunology-paper/
http://retractionwatch.com/2013/05/27/a-partial-retraction-appears-for-former-salzburg-crystallographer-who-admitted-misconduct/
And in Nature:
http://www.nature.com/news/trial-tests-austrian-integrity-body-1.10564
As well as a relevant Nature editorial from around the same time:
http://www.nature.com/nature/journal/v483/n7391/full/483509a.html

Edit 2015.09.02: I’ve updated my account since I first wrote this post. If you’d like to follow me online, find me @superhelical

 

Poor Public Understanding is Killing Basic Research in Canada

This post is cross-posted from a blog post I wrote for the Science and Policy Exchange on December 1. For more insightful writing on science and how it relates to government, the media, and society at large, visit their site http://www.sp-exchange.ca

Years ago, I worked for the summer on my neighbours’ cash crop farm. We mostly worked with cabbages. It smelled terrible. My coworkers, tough guys in their forties, learned I was studying in the sciences, and had no end of recommendations of useful things I could do with my degree.

“Hey science-boy! You should make some cabbages that bugs won’t eat!”
“Hey science-boy! You should make cabbages that keep better in storage!”
“Hey science-boy! You should make stackable square cabbages!”

picOf course these comments weren’t serious, and came from small everyday frustrations on the job, but the assumptions behind them are interesting. These men viewed science solely as a tool to produce innovations, and by extension, to make their lives easier. I don’t think their attitude is unique. For the most part, today’s lay public views science as something that makes new smartphones and performance fabrics, not much more.

This is a problem. Science doesn’t work well when it’s focused at specific applications. When you work in the realm of uncertainty, one of the only things you can have confidence in is a high rate of failure. Spreading initiatives broadly and pursuing the most interesting questions as they arise is a more efficient use of resources, and improves the chance of success. This is especially important when we remember that many (most?) great innovations come from serendipity, not planned investigation, so the wider we spread our inquiry, the more likely we will hit upon something that will drive technology forward.

While fundamental science is poor at developing specific solutions, it excels in discovering new principles. Sometimes these principles can translate directly into commercial products, but more often they form part of an accumulated wisdom that moves our understanding incrementally forward. The useful applications emerge naturally, albeit slowly, from that understanding. But that’s boring. And certainly isn’t a compelling story.

What is a compelling story?

Innovative new technology will convert industrial greenhouse gas emissions into commercial products

Canadian companies developing natural health products will be able to get science-proven, competitive new products on shelves faster

“Canadian firms will now be able to transform agricultural and forestry by-products to create new materials and reduce the use of petroleum-based polymers (plastics).”

The amount of certainty in those statements should make any scientist bristle. It betrays a misunderstanding of the scientific process and a fundamental arrogance that the result is predetermined, not subject to any uncertainty. These projects are part of the National Research Council’s new mission to shift “the primary focus of … work at NRC from the traditional emphasis of basic research and discovery science in favour of a more targeted approach to research and development”.

At the NRC and other government research institutes across Canada, the research climate is moving towards projects with the potential to produce marketable products, away from pursuit of understanding of the world around us. Government-funded research agencies across the country are being retooled to stop looking outward and pursuing novel ideas, instead turning inward, transforming into glorified factories. This is an extremely short-sighted strategy, crippling our capacity for innovation.

If I’m generous, the politicians enacting these changes are influential laypeople, at least as far as science is concerned. They don’t recognize that the long-term benefits of fundamental research are being lost as they focus myopically on risky but sexy-sounding megaprojects. If I’m a little more cynical, they realize that the public thinks science exists solely to produce new products. They exploit this by claiming they’re working to improve the lives of the average Canadian, and will include that in their re-election platform. The amount of times the term “strengthening our economy” gets dropped into government research press releases suggests the more cynical interpretation.

So what needs to change? To start, those in power need to recognize the importance of fundamental research to the long-term health of a society. We’re on a treadmill moving forward, and if we don’t keep pursuing challenging questions, we fall behind. More importantly, the public perception of science has to change. As long as Mike from Canmore is happy that his tax dollars are propping up companies instead of pursuing important fundamental discoveries, nothing will change. Scientists need to hold politicians accountable, but more importantly, they need to educate the public on the importance of pure research to long-term innovation. The layperson needs to know that pure research is a long-term investment that pays economic dividends many election cycles into the future.

The current direction of government-funded research in this country is troubling. Without public understanding of the importance of fundamental research, the trend will continue, and the foundations of our research apparatus will continue to erode. However, there may be one positive effect – my coworkers might finally get those square cabbages.

Edit 2015.09.02: I’ve updated my account since I first wrote this post. If you’d like to follow me online, find me @superhelical