Playing the Big Fiddle while Rome burns?

We've seemed to have forgotten the trust-busting era that was necessary to control monopolistic acquisition of resources.  That was over a century ago, and now we're again allowing already huge companies to merge and coalesce.  It's rationalized in various ways, naturally, by those on the gain.  It's the spirit and the power structure of our times, for whatever reason.  Maybe that explains why the same thing is happening in science as universities coo over their adoption of 'the business model'.

We're inundated in jargonized ways of advertising to co-opt research resources, with our  'omics' and 'Big Data' labeling.  Like it or not, this is how the system is working in our media and self-promotional age.  One is tempted to say that, as with old Nero, it may take a catastrophic fire to force us to change.  Unfortunately, that imagery is apparently quite wrong.  There were no fiddles in Nero's time, and if he did anything about the fire it was to help sponsor various relief efforts for those harmed by it.  But whatever imagery you want, our current obsession with scaling up to find more and more that explains less and less is obvious. Every generation has its resource competition games, always labeled as for some greater good, and this is how our particular game is played.  But there is a fire starting, and at least some have begun smelling the smoke.

Nero plucks away.  Sourcc: Wikipedia images, public domain

The smolder threatens to become an urgent fire, truly, and not just as a branding exercise.  It is a problem recognized not just by nay-saying cranks like us who object to how money is being burnt to support fiddling with more-of-the-same-not-much-new research.  It is an area where a major application of funds could have enormously positive impact on millions of people, and where causation seems to be quite tractable and understandable enough that you could even find it with a slide rule.

We refer to the serious, perhaps acute, problem with antibiotic resistance.  Different bugs are being discovered to be major threats, or to have evolved to become so, both for us and for the plants and animals who sacrifice their lives to feed us. Normal evolutionary dynamics, complemented with our agricultural practices, our population density and movement, and perhaps other aspects of our changing of local ecologies, is opening space for the spread of new or newly resistant pathogens.

This is a legitimate and perhaps imminent threat of a potentially catastrophic scale.  Such language is not an exercise in self-promotional rhetoric by those warning us of the problem. There is plenty of evidence that epidemic or even potentially pandemic shadows loom.  Ebola, zika, MRSA, persistent evolving malaria, and more should make the point and we have history to show that epidemic catastrophes can be very real indeed.

Addressing this problem rather than a lot of the wheel-spinning, money-burning activities now afoot in the medical sciences would be where properly constrained research warrants public investment.  The problem involves the ecology of the pathogens, our vulnerabilities as hosts, weaknesses in the current science, and problems in the economics of such things as antibacterial drugs or vaccinations.  These problems are tractable, with potentially huge benefit.

For a quick discussion, here is a link to a program by the statistical watchdog BBC Radio program MoreOrLess on antibiotic resistance  Of course there are many other papers and discussions as well.  We're caught between urgently increasing need, and the logistics, ecology, and economics that threaten to make the problem resistant to any easy fixes.

There's plenty of productive science that can be done that is targeted to individual causes that merit our attention, and for which technical solutions of the kind humans are so good at might be possible. We shouldn't wait to take antibiotic resistance seriously, but clearing away the logjam of resource commitments in genetic and epidemiological research to large weakly statistical efforts well into diminishing returns, or research based on rosy promises where we know there are few flowers, will not be easy...but we are in danger of fiddling around detecting risk factors with ever-decreasing effect sizes until the fire spreads to our doorsteps.

Antibiotic resistance

Ken and I just saw Michael Grazione's excellent, sobering film, Resistance, about the looming loss of antibiotics in the medicinal arsenal.  Bacteria that can make us very ill, and even kill us, are quickly, and unavoidably developing resistance to the chemicals that control them.  As Meryn McKenna writes in her excellent, also sobering piece, "Imaging the Post-Antibiotic Era", a world without antibiotics is going to look a lot like 1935; simple infections will become fatal once again, routine surgery, and cancer treatments that require repressing the immune system, and so on will no longer be possible. (McKenna is a journalist specializing in public health issues; her work is always worth reading, and she has a major role in the film.)

There are several very serious problems here, as we stare into the maw of the post-antibiotic era: despite the fact that the problem is widespread and growing, antibiotics are still being widely, and wantonly misused.  And, economic and political interests are standing in the way of changing this.

Penicillin, of course, was the first antibiotic discovered, in the 1930's.  Even before it was being widely used, bacteria were developing resistance.  Indeed, all antibiotics quickly lose their effectiveness, as the discoverer of penicillin, Alexander Fleming, warned in the 1940's, because they are a potent artificial selective force for resistance.  That's why they should be used only when necessary.

Year of first use and then clinical resistance for each antibiotic; Nature Chemical Biology, 2007; Clatworthy et al.

Antibiotics are like any other environmental agent when it comes to the evolutionary dynamics of any species, including bacteria.  If gene variants are present in the bacterial population that allow a subset of bugs to survive the chemical onslaught, this leads to resistance.  Antibiotics and chemotherapy against tumor cells are similar in this regard -- generally not strong enough to wipe out the entire population of cells.  When protective mutations are present, the overall population diminishes initially, as the majority of susceptible individuals are killed off, which leaves the field to the resistant few, which then proliferates, rendering therapy that was previously beneficial to the patient useless.

The situation is usually not quick or simple, but this is the simple nature of evolutionary adaptation.  Molecular attacks on cells can in principle act as selective factors that lead to resistance to the attack. There is no perfect or permanent solution, unless there is a mode of attack so fundamental to the target cells that they simply cannot evade it by modifying their own molecular makeup.  Such modes would be very desirable, but are not generally part of the arsenal we have against microbes or cancer cells and the like.

Instead, intervention approaches need to be used cleverly and sparingly so that resistance mutations don't have any advantage in the organism's population.  Indeed, since these organisms like bacteria (or your normal body cells) are the produce of eons of adaptation, most changes will be at least slightly harmful if they do anything, and will be outcompeted into oblivion by the 'normal' competitors in the population.  The problem is that this basic evolutionary truth is too often neglected. The reasons are only human, about short-sightedness, unawareness, personal vested interests, and so on.

There are several ways in which antibiotics are over-used that apparently lead to the present state of the problem.  Doctors and patients both are part of the problem; patients demanding treatment, even for viral infections, and doctors prescribing antibiotics just in case the infection is actually bacterial.    Of course, a big villain in the piece, discussed at length in Resistance, is routine use of antibiotics in animal agriculture, to promote growth in their densely raised livestock.  These are well-documented ways in which too much use leads to natural selection of resistant strains.

As the film also notes, there are widely known financial reasons for under-development of antibiotics by pharmaceutical firms.  There are also many technical limits, such as that many pathogens have not been growable and hence testable in the lab.  Clever ways around these problems probably exist--but we must make the research fundable.

There is no current known way to avoid the development of antibiotic resistance.  But, eliminating its use as a growth promoter in livestock would slow down the speed at which new drugs become useless, culturing infected tissues in real time in the doctor's office so that only bacterial infections are treated with antibiotics would help, patients using them for the proper length of time would help, and so on.

More research into drugs that are less likely to spawn resistance would help enormously as well.  And, subsidies for drug companies who do choose to invest in what is not a highly profitable class of drugs.  We need somehow to decouple research from profits so that this research will be done.  But this requires recognition of the enormity of the problem and its potentially catastrophic consequences.  If we take that seriously, we would divert huge amounts of funds in this research direction.

Infectious diseases and their potential future pandemic effects are far more important to study than many of the things we are currently pouring money into.  Of course, we think that much of research on enumerating individually trivial genetic variants related to late-onset, mainly environmentally caused diseases (the goal of the proposed 'precision' medicine) is hugely wasteful.

Indeed, many who do genomic research that leads hardly anywhere have the gear and technical skills to take the antibiotic issues on with much more potential for real health gains.  There's no sense in knowing a person's minor genetic risks factors for, say, adult-onset diabetes, if they're going to be eaten alive by bacteria first.  That's research emperors fiddling while Rome burns.

Genetics -- fiddling while Rome burns

Stories about the growing threat of antibiotic resistance generally include alarming predictions about the coming post-antibiotic era, about how even simple medical procedures that are now safe will become dangerous once we lose the ability to fight infections, and indeed simple infections will once again become life-threatening, as they might have been for most of human history.  We in the rich world can still imagine that this future might be avoidable, as we've still got useful drugs for many of our microbial illnesses -- plus, we're pretty good at being delusional (see climate change).

But that ominous future is already here for much of the world.  A reader sent us a link to a heart-wrenching story in the Dec 3 New York Times; "'Superbugs'" Kill India's Babies and Pose an Overseas Threat", Gardiner Harris.  Lack of widespread public health measures including sanitation are largely responsible for high infant mortality rates in poor nations.  Infectious diseases that would be avoidable or easily treated in rich countries are lethal in countries where the health care infrastructure is weak.  Antibiotic resistance is more widespread in these same countries, exacerbating the health care challenge.

The infant mortality rate (IMR) in India was 41/1000 live births in 2013, or 4%! -- by contrast, the lowest rates in the world in 2013, in Israel and Ireland and several other nations, were 3/1000, or 0.3%.  The IMR hasn't been as high in the United States as it is now in India since the beginning of the antibiotic age.  But India may never see the kind of decrease in infant mortality that the US experienced beginning in the 1940's, and it looks as though growing antibiotic resistance will be a major reason.

Infant, post-neonatal and neonatal morality rates, United States, 1940-2006; deaths per 1000 live births; CDC

In India, Harris reports, many infants are already dying of infections that are resistant to multiple antibiotics.  And, "a significant share of the bacteria present in India— in its water, sewage, animals, soil and even its mothers — are immune to nearly all antibiotics."  And those bacteria are quickly traveling around the world.

For many reasons, bacterial infections spread quickly in India; people defecate outdoors, sewage is untreated, drinking water can be contaminated, hospitals can be a source, even as they are in the West, and so on.  The most frequent bacterial infections in infants are from bacteria found in human waste.  And to compound the problem, antibiotics are available over-the-counter, in recent years women have been encouraged to give birth in hospitals, often in unsanitary conditions, and, Harris reports, infants have often been given antibiotic injections preventatively, all of which adds to growing resistance.

“Reducing newborn deaths in India is one of the most important public health priorities in the world, and this will require treating an increasing number of neonates who have sepsis and pneumonia,” said Dr. Vinod Paul, chief of pediatrics at the All India Institute of Medical Sciences and the leader of the study. “But if resistant infections keep growing, that progress could slow, stop or even reverse itself. And that would be a disaster for not only India but the entire world.”

In addition, antibiotic resistance is linked to widespread use in animal husbandry; the increased industrialization of meat production in India, with accompanying antibiotic use, may be adding to the problem there.

None of this is a surprise.  Just as the increase in 'super weeds' as a result of the widespread use of plants genetically modified to resist herbicides, which are then liberally sprayed on fields, was completely predictable.  Like the herbicide Round-Up, antibiotics are a strong selective force that encourage resistance.

But this is much more than a science problem.  It's a social, and an economic and a moral problem. Antibiotic resistance is developing much more quickly in poor countries, because of lack of public health infrastructure, and more infectious disease in general.  Preventing it takes resources, and it hasn't been a very glamorous claim on resources for high-flying research investigators who are driven by our society's worship of high technology.  But as we've written before, spending billions of dollars on things like genetics -- or, say, flights to Mars -- may well turn out to be fiddling while Rome burns.

Faith in science? Industrialized agriculture and antibiotic resistance

Someone asked me the other day on Twitter whether I thought that the words "science" and "belief" were compatible.  I said yes, though I know that a lot of scientists think (...believe...) that faith has nothing to do with science.  Science is facts, faith is religion, based on sacred texts and the like, which are basically hearsay without empirically acceptable evidence.  But, the history of science indicates that this distinction is far from being so simple -- there was a time when people believed that the moon was made of cheese, diseases were caused by bad air, Newton was right about physics, the continents didn't move.  And these beliefs were based on empirical evidence, observation -- dare I say 'facts'? -- not mere guesswork.

In that light, two recent pieces about the role of agriculture in the rise of antibiotic resistance are interesting.  The New York Times described a new study in the Journal of Occupational and Environmental Medicine ("Persistence of livestock-associated antibiotic-resistant Staphylococcus aureus among industrial hog operation workers in North Carolina over 14 days," Nadimpalli et al.)
that reports that workers at industrial hog farms can carry antibiotic-resistant bacteria, Staphylococcus aureus, in their nostrils for up to four days.

Twenty-two workers provided 327 samples. S. aureus carriage end points did not change with time away from work (mean 49 h; range greater than 0-96 h). Ten workers were persistent and six were intermittent carriers of livestock-associated S. aureus. Six workers were persistent and three intermittent carriers of livestock-associated multidrug-resistant S. aureus. One worker persistently carried livestock-associated methicillin-resistant S. aureus. Six workers were non-carriers of livestock-associated S. aureus. Eighty-two per cent of livestock-associated S. aureus demonstrated resistance to tetracycline. A majority of livestock-associated S. aureus isolates (n=169) were CC398 (68%) while 31% were CC9. No CC398 and one CC9 isolate was detected among scn-positive isolates.

As the NYT piece notes, eight-six percent of this sample of hog farm workers carried bacteria for at least 24 hours, compared with about one-third of the non-farm worker population.

This is a problem because the resistant variety of S. aureus, MRSA, has made its way into hospitals and is responsible for thousands of deaths.  Further, many people believe that industrial farming is the cause of much of the antibiotic resistance that is now becoming such a problem, because animals are fed antibiotics to speed their growth, and many of those antibiotics are used to treat human diseases.  Indeed, the majority of the antibiotics used in the industrialized world are given to animals.  When bacteria on the farm become resistant to antibiotics, as this study shows, they don't necessarily stay on the farm.  How they spread has been difficult to document, but might include consumption of contaminated meat, and Nadimpalli et al. report another pathway.

Hog farm; Wikipedia

Responding to the increase in antibiotic resistance that many believe industrial farming to be responsible for, the US Food and Drug Administration this year put a voluntary ban on the use of antibiotics for growth promotion. Critics saw this as a weak response to a very large problem, but pharmaceutical companies and some farmers say it will do what it is meant to do; reduce the use of antibiotics for non-medical purposes, and thus reduce the possible evolution of resistant bacteria that are harmful to humans. Of course one always has to ask the political question of who wields the power and influence over any sort of decision that may affect a particular industry.

But much of this is controversial. Is agricultural use of antibiotics in fact to blame for the problem, or is it overuse of antibiotics by the medical system?  Indeed, there's less of a problem in, say, Scandinavian countries where for decades physicians have prescribed antibiotics at a much lower rate than they have done in the US. Do resistant bacteria really spread in considerable numbers from farm to city?  This may be less controversial with the publication of the Nadimpalli et al. paper, but critics will say that the sample size was small and anyway, documenting a mechanism doesn't mean this is what has happened.

We all tend to pick and choose facts to support our convictions.  Indeed, if you look at how scientists, in any field, cling to their explanations, 'convictions' is perhaps a muted term for what is being clung to.  How we think about these questions may well reflect what we believe more generally about the food system, how or even whether animals should be farmed for meat, whether we patronize farmers'  markets rather than industrially produced food, and so forth rather than what we, or anyone, actually know about the causes of antibiotic resistance.  That is, our personal sociopolitical positions seem clearly be correlated with, if not strongly influencing, our scientific position.

Yesterday, an opinion piece by Iowa veterinarian and pig farmer Howard Hill appeared in our local paper, and in papers around the country.  Hill believes that farmers are being unfairly blamed for antibiotic resistance in humans.

...the claim that "70 to 80 percent of all antibiotics sold in the United States each year are used in livestock" is a straw man. More than a third of those drugs aren't used in human medicine, another third are not considered highly important to human medicine, and most of them aren't used for growth promotion. Critics also ignore the fact that there are a lot more cows, pigs and chickens than people. In 2011, for example, 30 million pounds of antibiotics were sold for use in more than 3 billion livestock and poultry, compared with 7 million pounds for 311 million people, meaning each person used nearly five times more antibiotics than were used in each food animal.

Is he making selective use of the data?  Yes, but isn't everyone who talks about this issue?  And does that make our assertions wrong?  Doesn't prior belief influence our understanding of what the data show?

While Rome burns
President Obama yesterday issued an executive order aimed at combating antibiotic resistance.  The order accepts that industrial agriculture may have a role in increasing resistance, but it adds little to the FDA order of several months ago:

The Food and Drug Administration (FDA) in HHS, in coordination with the Department of Agriculture (USDA), shall continue taking steps to eliminate the use of medically important classes of antibiotics for growth promotion purposes in food-producing animals.

Not many teeth here.  Years ago Europe took much the same approach, requiring that the use of antibiotics for growth promotion be reduced, but a lot of reclassification of antibiotic use for medical purposes followed, as many expected in the US following the FDA announcement last December, which we blogged about here,  and again with this Executive Order.

Again in Scandinavia, the use of antibiotics for growth promotion has been banned, beginning in Sweden in 1986, but farmers have not suffered.  According to a piece in the BCMJ in 2011:

In 1986, Sweden became the first country to regulate the withdrawal of antibiotics used in food animal production. By 2009, Swedish sales of antibiotics for use in agriculture were reduced from an average of 45 tons of active substance to 15 tons. Sweden was followed by Denmark, the United Kingdom, and the Netherlands. 

Danish swine and poultry production continued to flourish with gradual reductions of antibiotic use beginning in 1992 and continuing to 2008 (latest data). During this time, Danish farmers increased swine production by 47% while reducing antimicrobial use by 51%. As well, poultry production increased slightly while reducing antimicrobial use by 90%. Denmark remains one of the largest pork ex­porters in the world.

So, whether or not growth promoting antibiotic use in animals is a major cause of resistance is not really an issue, and we needn't even continue to have the discussion.  If there is any chance it is, why not ban it entirely?  Experience in Scandinavia suggests there won't be dire economic consequences -- unless you're a pharmaceutical company making antibiotics for animals.

Faith in science
We have often written here about the economic interests that drive the course of Big Science.  Can we have faith in science if there is considerable faith in science?  People are, after all, only human, and people of all faiths, including science, defend their faiths.  Further, it's often impossible to disentangle belief from vested interest.   If you've got a hammer, or a hammer to sell, everything looks like a nail.

Antibiotic resistance: Move the money (and control it)!

The BBC Radio4 program Discovery had a two-part series (August 18 and 25th) on the real health danger that we face and the research challenge it presents.  No, not Big Data mapping of diabetes or cancer, or athletic ability or intelligence.  Instead, they were about an impending biomedical disaster, one that essentially trivializes much of which we are throwing away resources on: antibiotic resistance.

Growing antibiotic resistance seems to be imminent or at least inevitable, both in terms of issues like treatment of disease in hospital patients, and in the control of spreadable diseases.  This doesn't seem to be too speculative.  Some strains of infectious bacteria are already resistant to multiple antibiotics, and these are often contracted by hospital patients who were there for some non-infectious reason, and some infectious diseases are not responding to antibiotics at all.

If we no longer have antibiotics, of course, the simplest infection can again become life threatening again, surgery, chemotherapy, kidney dialysis, even an ear infection will become risky again, and infectious diseases will again be the killers in the rich world that they once were.

The antibiotic Novamoxin; Wikimedia Commons

Pharmaceutical firms simply aren't investing in antibiotic development as needed.  Not surprisingly, the reasons are commercial: an antibiotic that becomes widely used may be profitable, but not nearly as much as anticancer agents, or recreational drugs like Viagra, or anti-balding cream.  And, if it's widely used the cost may be lower but resistance is sure to evolve.  If saved for the most dire cases, then sales will be low, cost too high to bear, and not enough profit for the company.

The cost of development and testing and the limited duration of patent exclusiveness present additional issues.  So, nobody is investing heavily in antibiotic development, not even governments that don't have quite the greedy commercial motive for what they do.

The Ebola epidemic is another biomedical disaster that has caught international medical care unprepared.  This is a virus, but there is basically no known antiviral agent; one with some effectiveness seems to be in the works and there are some other stop-gap strategies, but nothing systematic.  But the problem, dangers, and challenges are analogous to the fight against pathogenic bacteria.  Indeed, lately there's been discussion of the possibility--or inevitability?--that Ebola will evolve an ability to be transmitted via the air rather than just physical contact with infected persons.  But of course this is a repeat of the story of SARS, MERS, and other emerging infectious diseases, and surely not the last.

So the question for potential investigators or those worried about the looming disasters becomes: where is the money to solve these problems going to come from?  The answer isn't wholly simple, but it isn't wholly top secret either.

Move the money!
Developed countries are spending countless coinage on the many chronic, often late-onset diseases that have fed the research establishment for the past generation or so.  These are the playgrounds of genomics and other 'omics approaches, and more and more resources are being claimed by advocates of huge, long-term, exhaustive, enumerative 'Big Data' projects--projects that will be costly, hard to stop, and almost certainly will have low cost-benefit or diminishing returns.

We already know this basic truth from experience.  Worse, in our view, many or even most of these disorders have experienced major secular trends in recent decades, showing that they are due to environmental and behavioral patterns and exposures, not inherent genetic or related 'omic ones. They do not demand costly technical research.  Changing behavior or exposures is a real challenge but has been solved in various important instances, including iodized salt, fluoridated water, the campaign against smoking, urban pollution, seat belts/air bags, cycle helmets and much else.  It doesn't require fancy laboratories.

Unfortunately, if we continue to let the monied interests drive the health care system, we may not get antibiotic development.  The profit motive, evil enough in itself, isn't enough apparently, and some of the reasons are even reasonable.  So we have to do it as a society, for societal good rather than profit. If funds are tight and we can't have everything, then we should put the funds we have where the major risks are, and that is not in late-onset, avoidable or deferrable diseases.

Let's not forget that the reason we have those diseases is that we have enjoyed a century or so of hygiene, antibiotics, and vaccines.  The 'old man's friend', pneumonia and things like it, were put at bay (here, at least; the developing world didn't get the kind of attention we pay to ourselves).  But if we dawdle because we're so enamored of high-tech glamour and the sales pitches of the university community (and the for-profit pharmas), and because of our perfectly natural fear of the complex degenerative diseases, we could be making a devil's bargain.

Instead, what we need to do is move the funds from those diseases to the major, globally connected problem of infectious diseases (and similar problems combating evolving pests and infections that affect our food crops and animals as well).  We need a major shift in our investment.  Indeed, quite unlike the current Big Data approach, combatting infectious diseases actually has a potentially quick, identifiable, major payoff.  Some actual bang for the buck. We'll need somehow to circumvent the profit and short-term greed side of things as well.  Of course, shutting down some labs will cost jobs and have other economic repercussions; but the shift will open others, so the argument of job-protection is a vacuous one.

"What?!" some might say, "Move funds from my nice shiny omics Big Data lab to work on problems in poverty-stricken places where only missionaries want to go?" Well, no, not even that.  If plagues return, it won't matter who you are or where you live, or if you have or might get cancer or diabetes or dementia when you get old, or if you've got engineered designer genes for being a scientist or athlete.

The battle to control infectious diseases is one for the ages--all ages of people.  It perhaps is urgent.  It requires resources to win, if 'winning' is even possible.  But we have the resources and we know where they are.

Bacteria, bacteriophages and resistance - an evolutionary arms race

When I was a student at the University of Texas School of Public Health in the late 1970's, infectious diseases were a quaint, passé concern.  Smallpox had just been eliminated, we'd gotten tuberculosis under control, antibiotics could treat all the important infectious diseases of recent decades, as well as many unimportant ones, and we were moving on to addressing the diseases that had taken over as the leading causes of death, chronic diseases of middle and old age -- cancers, heart disease, stroke, and so forth. The Department of Epidemiology only had one rather ancient and bedraggled TB specialist still holding on, while Biostatistics was thrumming with hot new faculty.

And then HIV/AIDS happened, TB came back with a vengeance, drug and multi-drug resistant to boot, and drug resistant malaria started to spread.  Bacterial infections that we'd thought were easily controlled began to resist treatment, and public health workers began to worry that perhaps the future wasn't going to be all about controlling chronic diseases after all.  Now we've got MRSA, C dificile, gonorrhea, several classes of streptococcus, gram-negative bacilli, malaria, TB, and many other drug resistant bugs that used to be treatable and now are not.

We've passed peak antimicrobial and are on a fast slide to the bad old days when a simple infection was often lethal.  Much ink has been spilled, many keys have been tapped documenting the coming return to the pre-antibiotic era because our drugs no longer kill microbes.  The overuse of antibiotics in medicine and the widespread use of antibiotics in the food chain, in both agriculture and aquaculture, are the essential causes, but even used sparingly, resistance is inevitable because, well, because evolution.

It's been known since the advent of antibiotics in the 1940's that resistance was a potential problem, but we've not done nearly enough to prepare.  And, pharmaceuticals are no longer investing in research into new antibiotics in large part because their effectiveness is so short-lived, and thus the likelihood of recouping the cost of product development and going on to make a profit, in the time of wonder drugs like Viagra, which are goldmines worth investing in, is low.  Is there hope, or are we destined to go back to the days when simple infections and easy surgery were life threatening?

In a feature article in American Scientist last month, "How to Fight Back Against Antibiotic Resistance", Gautam Dantas and Morten O. A. Sommer write that the only hope is for scientists to figure out the molecular pathways that make resistance inevitable.  Probably they would say that, given that's what they do, but is that right?

Attention is being paid to a suite of genes called the 'resistome' (yep, yet another omics term), those genes responsible for, as the authors put it, turning a susceptible pathogen into a superbug.  Even so, understanding how bacteria resist death by the chemicals we throw at them is like generals fighting the last war.  As Dantas and Sommer put it, "the pool of resistance genes, and the mechanisms of resisting antibiotics, available to bacteria are effectively limitless."  Any new strategy we come up with, they'll come up with a way to resist.

How Phages Work

All known bacteria are thwarted by phages, which are extremely specific and only attack the strain of bacteria they evolved to inhabit and kill (mammalian and plant cells lack the receptors required for phage infection, so phages are harmless against them). Phages first attach to and puncture the bacterial membrane. Phage DNA is injected into the host cell. The host cell’s DNA transcription is suppressed, and phage-specific proteins are synthesized instead. New phages are assembled, the host cell membrane is disrupted, and large numbers of new phages are released from the host bacterium, which dies.22

Phages first attach to and puncture the bacterial membrane. Phage DNA is injected into the host cell.
© Medi-Mation Ltd/Science Source

The host cell’s DNA transcription is suppressed, and phage-specific proteins are synthesized instead.
© Medi-Mation Ltd/Science Source

New phages are assembled, the host cell membrane is disrupted, and large numbers of new phages are released from the host bacterium, which dies.
© Medi-Mation Ltd/Science Source

An estimated 1030–1032 phages exist in the biosphere,22 and an estimated 1023phage infections occur per second.24 Every 48 hours, phages destroy about half the bacteria in the world,25,26 a dynamic process that occurs in all ecosystems.14,24

Phages have infected bacteria for billions of years, and just as bacteria mutate to resist drugs, they also mutate to render phages ineffective. However, new phages continually evolve against the mutated bacteria.27 “It’s an evolutionary arms race,” says Daniel Nelson of the University of Maryland’s Institute for Bioscience and Biotechnology Research. Because phages cannot reproduce on their own, they must infect bacteria, which, in turn, spend massive amounts of energy trying to avoid death by phage.

However, phages are not totally bad and even offer bacteria a fitness advantage by transferring genes for antibiotic resistance and toxins to bacteria. To acquire desirable traits while avoiding death, bacteria use restriction modification systems to cut out deleterious phage DNA and keep beneficial phage DNA.27 “Nonetheless, phages adapt and evolve more rapidly than bacteria, so the cat-and-mouse game continues as both sides try to out-evolve each other,” says Nelson.

From Dantas and Sommer

A short essay in the New York Times last week by Matti Jalasvuori, in a Room for Debate discussion of antibiotic resistance, describes what some are seeing as a new old strategy, corralling bacteriophages, viruses, to target specific bacteria, which they do naturally, and kill them for us.  Phages were successfully used to treat infection in Russia in the pre-antibiotic era, but pretty much dropped with the development of penicillin.  They've caught people's interest again.

Jalasvuori writes,

Phages are natural antibacterial entities that continuously struggle for existence among diverse bacterial systems. They are as old as life itself, indicating that they have been successfully exploiting bacteria for billions of years already. Unlike chemical antibiotics, viruses evolve and therefore bacteria are unable to become resistant to all of their viruses. 

Some viruses have evolved to specialize on infecting bacteria that host hopping genetic elements. These viral agents can be directed to attack resistant bacteria for which alternative means of control have failed. Moreover, prolonged exposure to these viruses can cause bacteria to become treatable again with conventional antibiotics. This is because bacteria benefit by dropping the genetic element and thus becoming resistant to viral infection: evolution is acting in our favor.

Yes, bacteria can quickly develop defenses against phages by the usual evolutionary processes of mutation and natural selection, but the idea is that therapeutic use would involve cocktails of phages and a bacterium would be unlikely to become resistant to all of them.  This is the same evolution-based idea that motivates multiple drug attacks on cancer cells, TB, and so on.  The strategy will work for a while but everyone knows that even then, resistant they will be become, which is one reason that some people are interested in harnessing the mechanism by which phage kill bacteria.

Lysins, the enzyme that phages produce that make bacteria explode, are being isolated and explored as an alternative.  Like phages themselves, lysins would be bacteria specific.  It is thought to be very unlikely that bacteria can develop resistance to lysin because they've co-evolved, and, according to Fenton et al. in 2010, "...lysins evolved to target specific molecules in the host peptidoglycan that are essential for bacterial viability."

Maybe, and indeed we have what is known as the 'innate' immune system (contrasted with our other, 'adaptive' antibody-based immune system that changes all the time to attack whatever we may be infected with).  In a nutshell, the innate system attacks general properties of bacteria and other pathogens, rather than species-specific ones, working on fundamental aspects of the outer covering of the pathogens' cells that is more generic and less subject to mutational variation.   So we'll see how approaches such as targeting with lysins fare.

Another question is whether phages will mutate to become harmful to eukaryotic cells -- us -- or whether they could spread resistance genes via horizontal transfer, or whether there will be unintended, unforeseen consequences are also important concerns.  And, they do trigger the immune response so each one could be used in any individual only once.

Is there a permanent solution to the antimicrobial resistance crisis?  No, because evolution.  But phages may be a possible short-term strategy, and they should be tried.

The FDA's new 'ban' on antibiotic use in animals needs more teeth

The CDC estimates that 2 million people in the US every year contract antibiotic resistant infections, and 23,000 die as a result.  Antibiotic resistant bacteria -- another on the list of looming crises we're smart enough to do something about but are doing far too little far too slowly.  So it would be good if, as reported by New York Times, the US Food and Drug Administration had announced what will be a major policy to slow down the routine overuse of antibiotics in the food supply.  But it seems unlikely.

For decades, healthy cows, pigs and chickens have been given antibiotics to maintain their health and to boost their growth, and more recently, so have farmed fish, but this is a major cause of the waning effectiveness of antibiotics. There seem to be multiple pathways leading from antibiotic use in animals to antibiotic resistance in humans.*  

Chicken house; Wikimedia Commons

 Low dose, prolonged use of antibiotics in animals creates ideal conditions for the selection and growth of antibiotic resistance.  How they spread from animals to humans is difficult to document and probably there are numerous pathways, but it does seem sometimes be possible by consumption of food carrying resistant bacteria, and indeed farm workers often harbor antibiotic resistant strains of gut bacteria that indicate they originated in animals on the farm, but so can people who eat meat or fish contaminated with resistant bacteria.  There is evidence of horizontal transfer of resistance genes, too, from bacteria most often found in animals to those that prefer human hosts.

The 'ban'
Now the FDA says it is effectively banning the use in food animals of those antibiotics that are medically important in human health, and that are used solely to enhance animal growth. A second piece of the new regulations is that a licensed veterinarian will be required to oversee antibiotic use if the grower wants to deliver these drugs to prevent illness.  The changes will become effective over the next three years.

How will it work?  The FDA is requesting that drug makers change antibiotic labels to exclude their use in animal growth promotion.  Whether they do this or not is entirely voluntary.  Given the huge vested interest drug manufacturers have in selling antibiotics to food producers -- 70-80% of antibiotics in the US are used in the food supply** -- and that farmers have in promoting fast growth in their animals, whether this will actually work is an open question, and there are many doubters. Though, the two pharmaceuticals that make the majority of antibiotics have said they will comply.

Comply or not, there are loopholes.  A food producer can claim that the same daily use of low doses of antibiotics now meant to enhance growth is required to prevent illness, which would mean it's allowed.  Thus, it's possible that nothing will change.  Many critics would much prefer that antibiotics be allowed only to treat infection, and would like to see the FDA ban the preventive use of antibiotics. 

Why we need a policy that works
It is important that we have a policy that works.  Maryn McKenna describes the dire consequences of losing antibiotics in her sobering, excellent recent piece for Wired, ("When We Lose Antibiotics, Here's Everything Else We'll Lose Too").  Not only will we lose the obvious, the ability to treat infection, but also, as she writes, we'll lose the ability to treat cancer when it requires suppressing the immune response, to do organ transplants, kidney dialysis because it relies on an implanted portal into the blood stream, many kinds of surgery, Caesarian sections will be risky, and much more.  As she points out, in the pre-antibiotic era, "one out of every nine skin infections killed" -- life will be a lot more dangerous again. 

And, clearly, the way animals are raised for food on industrial farms will also have to change.  But there are many arguments in favor of this already, even apart from the antibiotic resistance issue.  Animals raised in the kinds of crowded conditions pig or cattle or chickens are too often raised in increases their risk of illness.  And, these animals are often raised on feed that that also makes them more susceptible; smaller farms, and more humane conditions would greatly reduce the need for antibiotics.  And, as McKenna also points out, many crops depend on antibiotics as well.  When fruit or vegetable diseases now controlled with antibiotics can no longer be, that will be another major problem.

So, the FDA may be taking a desirable first step, but the stakes in public health terms are very high.  If the critics turn out to be right about the loopholes, there's a lot to lose. 

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*Smith, DL et al., Animal antibiotic use has an early but important impact on the emergence of antibiotic resistance in human commensal bacteria, PNAS, 2001. 

Marshall, BM; Levy, SB., Food Animals and Antimicrobials: Impacts on Human Health, Clinical Microbiology Reviews, 2011. 

**Mellon M, Benbrook C, Benbrook K L. Hogging It: Estimates of Antimicrobial Abuse in Livestock. Cambridge, MA: Union of Concerned Scientists; 2001. 

National Research Council, Committee on Drug Use in Food Animals. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: Natl. Acad. Press; 1999.

What is an organism? Lessons from bacteria on cooperation in life

The battle against antibiotic resistance is in the news a lot lately, because if our over-use of antibiotics causes resistance to evolve, we and our livestock will be in deep trouble.  Resistant strains of pathogenic bacteria are already proving to be a serious problem.  Major pandemics could be in the offing.  Even the simplest of surgical procedures could become dangerous again. 

From what we read, pharmaceutical research is rather stalled in this respect.  New drugs coming onto the market are mainly minor tinkering with older approaches, and are both costly to develop and test but also have diminishing effectiveness.  Yet entirely novel approaches seem hard to come by as well as prohibitively costly to develop. 

Part of the apparent reason for the problem of increasing resistance is that to be economically viable, antibiotics tend to be broad-spectrum. That is, they work against whole classes of bacteria, which means that eventually they don't work against whole classes of bacteria.  Developing an antibiotic directly against a specific bacterial type gets too costly for the potential payoff.  At least that's the argument that's often made.

But might there be a wholly different approach?  The BBC Radio 4 program Discovery on July 8 (here for download) took a refreshing and clever approach to this challenging subject.  And it's based on a rather little-known characteristic of bacteria that has been part of their lives for about 3.5 billion years.

Bacteria societies.
Bacteria are single-celled organisms that live and reproduce on their own (though sometimes a version of sexual reproduction is undertaken).  Because of the way we've studied them in science, cell by cell, we have tended to think of them as lone wolves, but they are not.  At least under some conditions, they live in large social groups (sometimes including members of more than one species).  They form layered structures of large numbers of bacteria, called biofilms (or, in the fossil record, their mineralized remains are called stromatolites).

Stromatolites in Shark Bay, Australia; Wikimedia

A phenomenon associated with this environmental monitoring is called quorum sensing.  Like all cells--and indeed all organisms including you and me--bacteria are constantly monitoring their environment.  They secrete substances that they can also detect, and they can assess the concentration of these substances in their environment.  This means they can sense how many of each other there are in the vicinity.  This among other triggers is used to stimulate the formulation of a biofilm when there are enough bacteria in the vicinity to make that work.

Five stages of biofilm development: (1) Initial attachment, (2) Irreversible attachment, (3) Maturation I, (4) Maturation II, and (5) Dispersion. Each stage of development in the diagram is paired with a photomicrograph of a developing P. aeruginosa biofilm. All photomicrographs are shown to same scale. Wikipedia

Under some conditions, they respond to these signals by aggregating, huddling together and even forming physical connections among each other.  Their gene expression pattern changes as well.  Sometimes this is a protective means of herding in hostile environments.  But other times, they aggregate because together they can mine a food source that an individual cell can't effectively access.

Unfortunately, sometimes that food source is you!

As the story was told on the BBC program, individual bacteria often are rather quiescent because too much activity could trigger an immune response and that means curtains to the bug.  For example, if they were to attack your cells--and that, after all, is their menu!--the materials leaking from the cells would be detected by your immune system.  But when there are enough bacteria, they decide to go ahead with their attack, and they activate mechanisms that lead to the lancing of your cells, releasing its cornucopia of nutrients.  By then, there may be enough of them to overwhelm your immune reactions, and survive to live another day.

A stealth attack
The idea for a new approach is to design chemotherapeutic agents that interfere with the quorum sensing mechanism, not even trying to kill the bacteria but just preventing them from ganging up on you and eating away.  If this works, and experimental trials are under way, then bacteria will face a very subtle attack: they won't 'know' that they're being targeted because all their cells and those of their fellow travelers' will be normal and unaffected.  They just will never know that there are enough of them around to make a frontal assault possible.

The idea here is that resistance won't evolve because you're not putting the bacteria under any sort of stress.  By contrast, antibiotics kill all vulnerable cells but that means that they open a clear path for any cells in which mutation has led to resistance to the agents.  This makes evolution work against our epidemiological hopes, and (sorry, creationists) evolution works!

A limitation will be that different species of bacteria use different quorum sensing compounds or receptors and the like, so drugs may have to be more species-specific and less broad spectrum--and hence much more costly to develop.  We'll see if this clever strategy works.

However, in the interview at least, the investigators seemed to be very naive about evolution, and as a result perhaps highly over-optimistic.

How evolution works and why it will again
Resistance to lethal attack is easy to understand.  When a bacterial gene undergoes a mutation that, say, makes the cell no longer able to be bound by some chemical (an antibiotic), then the chemical will be harmless.  Since mutations are always happening, and antibiotics work by molecule-to-molecule interactions, mutations leading to bacterial proteins that no longer bind to the antibiotic, and hence to resistance, are all too common.

This is one, rather classical, view of evolution.  But there are others, and perhaps they are more subtle.  After all there are differences among bacterial species in how they do their quorum sensing or what conditions trigger the formation of their biofilms.  Since these vary among species, this must occur by mutational chance.  Whether or not selection is involved, variants have become established.

Thus, even if you devise a way to confuse the current quorum sensing mechanism, without killing the bacteria, they won't be eating you (that's the idea), but will just continue to flit about singly and in rather a dormant state.  But the food source (i.e., your cells) are still there as a waiting harvest.  So it is inevitable that mutations in quorum sensing will lead some bacteria to be able to detect each other or to modify their predatory behavior.  They will feast while their confused fellows die out.

This may take longer and be more complex an adaptive scenario, but it is hard to imagine that it would not occur.  The BBC interviewees seemed unaware of this aspect of evolution, thinking that if you don't try to kill the bacteria you don't put adaptive selective pressure on them, but that is only one way that adaptation works.  If there are other reasons to argue that bacteria can't adapt to interfering with their quorum sensing mechanisms, that wasn't stated.

Cooperation: a rigorous, vigorous, ubiquitous part of life
Our book, after which this blog was named, was written to take obsessive attention away from a competition-is-everything worldview that is so common in biology and biomedicine.  Cooperation takes many forms and is far, far more widespread and ever-present than is competition (which, of course, does occur).  The way bacteria join together to find a meal, and cause big problems, is an interesting example of cooperation even at the simplest level of life.