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More Countries Are Seeing a Last-Ditch Antibiotic Failing

An E. coli bacterium.
An E. coli bacterium.
Photograph by the Public Health Image Library, CDC.gov.

(This post has been updated; read to the end.)

More news is emerging about the dire new antibiotic resistance factor announced last month: MCR-1, a gene that disables the action of colistin, a very last-resort drug in human medicine. (If you’re just coming to this, my past posts are here and here.)

Quick recap: A gene conferring resistance to colistin was found in pigs, retail meat, and human patients in China; then it was spotted in Malaysia; then in Portugal. Then, in the next major development, researchers in Denmark announced they had identified the gene in one human patient and five samples of imported meat.

Here’s the newest news: The Danish researchers tell me that they have identified another patient who was infected with a bacterium bearing that same resistance factor. And Public Health England has announced that it has found the gene in 15 stored bacterial samples in its databases: 10 Salmonella bacteria and three E. coli that came from hospitalized patients, and two Salmonella on a single sample of imported poultry meat.

The news is both alarming—more instances of this gene that creates resistance to last-ditch drugs, and that can transfer easily between bacteria—and also puzzling. The British samples were taken between this year and 2012. The Danish samples announced 10 days ago date back to 2012, and the newly discovered one comes from 2011. So the gene has been circulating for several years, without causing any outbreaks.

Is that a bullet dodged? Perhaps. But researchers studying the new gene say it may be a slow-burning fuse.

In human medicine, colistin is a rarely used drug, a survivor from the earliest decades of antibiotic development that was left on the shelf for decades because it was toxic. But in veterinary medicine, colistin has had wide use, which is probably what caused this resistance factor to emerge. Now, with the loss of other antibiotics to resistance, colistin use in humans is climbing, and that could set the stage for this effectively untreatable resistance to bloom.

“This seems to have been around for five to six years,” Robert Skov, MD of the Statens Serum Institut in Copenhagen, and the senior author in the Danish team’s rapidly produced article on their discoveries, told me by phone. “One thing is for sure: We are using more and more colistin in humans due to the increase in [bacteria resistant to carbapenems, the next-to-last-resort drug], and thus we are probably selecting for this colistin resistance to emerge.”

How the gene—which resides on a plasmid, a mobile piece of DNA that can move between bacteria— is traveling the world is a puzzle. Skov said the Danish government has done an emergency survey of the country’s animal herds and found no trace of the gene. (Which, before now, no one would have been looking for.) The chicken meat in which the gene was found in Denmark was imported from Germany. The two people in whom the MCR gene has been found had not traveled to Asia. In Britain, three out of 10 patients had been to Asia, and the meat on which two MCR-bearing Salmonella strains were found was imported from elsewhere in Europe.

When NDM, the last last-resort resistance threat, began to spread across the world, it did so in the guts of patients who visited India, where it first emerged, and then traveled home to Europe and Britain. It’s possible a similar thing is happening with MCR. “We have five chicken isolates [bacterial samples] and one human isolate, and when we compare the plasmids in the chicken and human isolates and what has been published from China, the greatest resemblance to the Danish human isolate is the isolates from China and not from the German chicken,” Skov said. “This suggests it was brought, not by chicken, but by people coming from Asia to Denmark.”

In the past few days, I asked antibiotic resistance experts in various parts of the world whether they had seen MCR yet, and whether they were looking for it. All of them were looking; outside of Britain, none had discovered it yet in any national collections of bacterial isolates. (Or, given that disclosing a finding might keep them from publishing in major medical journals, were willing to admit to discovering it.)

Lance Price, PhD of the Antibiotic Resistance Action Center at George Washington University, told me that additional analysis of the isolates found in Denmark shows two troubling things. All of the bacteria in which the gene was found were unique—six different strains of E. coli—and the gene has found a home in two different plasmids. Together those suggests that it has no difficulty moving among bacteria and finding a comfortable home in them. “It’s real world, empiric evidence that this thing can spread very widely,” he said. “Its’s almost like it possesses a universal key.”

Price told me that one concern at this point will be which bacterial strains the gene jumps into: indolent ones that cause little disease, or fast-moving virulent ones that cause infections in many body systems and are already resistant to many other drugs. One of the Danish isolates that carries MCR, he said, is an E. coli of a type known as ST131—which in the United States is already multi-drug resistant and causes thousands of serious bladder and bloodstream infections every year. “At this point we don’t know what the denominator is going to be,” he said. “We don’t know how many different strains this is going to get into, and this underscores the possibility it will jump into something really bad.”

Update: On Dec. 17, Dutch authorities announced they too had identified MCR-1 in a bacterial collection in the Netherlands. The Central Veterinary Institute, housed at Wageningen University, said it found three bacterial isolates containing the MCR-1 gene in a collection of 3,274 Salmonella strains from 2014 and 2015. Two similar strains came from chicken meat that originated in the Netherlands, and a different strain from imported turkey. (It does not give the source of the turkey.) They are now undertaking a broader search through other bacterial collections.

There will no doubt be more such discoveries as other health authorities complete searches through whatever national collections they have. But as Lance Price says above, this is further evidence that this gene has great facility for jumping among different bacteria and bacterial species.

Meanwhile, if you’re interested in more on this, Price, Skov and I were on the NPR show On Point on Dec. 16, discussing MCR. Replay and podcast instructions at the link.

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Will panda blood solve the antibiotic crisis? Unlikely.

There’s a story going round about Chinese scientists who have discovered a “powerful antibiotic” in the blood of the giant panda. It seems to have originated in the Daily Telegraph, where Richard Gray wrote:

“Researchers discovered the compound, known as cathelicidin-AM, after analysing the panda’s DNA… Dr Xiuwen Yan, who led the research at the Life Sciences College of Nanjing Agricultural University in China, said: “It showed potential antimicrobial activities against wide spectrum of microorganisms including bacteria and fungi, both standard and drug-resistant strains. Under the pressure of increasing microorganisms with drug resistance against conventional antibiotics, there is urgent need to develop new type of antimicrobial agents.“

Let me put this plainly: If this discovery actually leads to a new antibiotic—one that is actually used in the clinic to treat real people—I will eat a panda.

(Actually, that sounds bad. A man in a panda suit. Wait, still not good. A stick of bamboo. You get the point.)

Stories like these are a dime a dozen. Scientists have discovered a new antibiotic, hundreds of new antibiotics, thousands of new antibiotics, in panda blood, in alligator blood, in cockroach brains, in ocean mould, in frog skin, in frog skin, and in yet more frog skin. All are billed as potential sources of bold new treatments that will solve our antibiotic crisis, and provide new weapons against drug-resistant superbugs like MRSA.

And yet, despite decades of such claims, none of these sources has yielded a single marketable drug. We’re still sitting in the drug discovery doldrums, with just one class of new antibiotics in the last 50 years. We are running out of ideas, bacteria are becoming increasingly resistant to our frontline drugs, and nothing is coming in to fill the gap.

In a new piece for The Scientist, I discuss why panda blood and frog skin are of academic interest only, and unlikely to solve this problem. Head over there to get the details.

For now, I’ll clarify that, obviously, there’s an outside chance that one of these sources will lead to a new drug. But there’s a huge gulf between finding a substance that kills bacteria in a dish and actually creating a new drug that works in real people. These stories are being hyped too early by press offices, covered too uncritically by journalists, and maybe even published too readily by journals.

As one of the scientists I spoke to said: “A reasonable starting point for any story worthy of publishing is to have an effective compound in a systemic mouse model of infection. Once you cross that barrier, then it makes sense to talk about it.”

So, if Substance X can actually treat bacterial infections in a sick mouse, let’s hear about it. Otherwise, you’re just promoting red herrings in the shape of pandas.

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Abnormal brain structures hint at poor self-control and vulnerability to drug addiction

Our lives are full of instances where have to hold ourselves back. We stop ourselves from eating that tempting slice of cake to avoid putting on weight. We bite our tongues to avoid insulting our friends. We slam on the brakes to avoid killing a pedestrian.  To quote Yoda: “Control! Control! You must learn control.”

People with drug problems clearly have a problem with this. Their ability to resist their own impulses falters at the promise of the next hit. Now, scientists are starting to understand the changes in the brain that underlie these problems.

Karen Ersche from the University of Cambridge found that drug users have abnormalities in parts of the brain that are important for inhibiting unwanted actions. These same anomalies even exist in the brains of their siblings, who don’t have any drug problems themselves. They could act as a marker for people who are vulnerable to addiction. “Our findings provide further evidence for drug addiction being a brain-based disorder,” says Ersche.

This is far from the first study to examine the brains of drug users. But it’s never been clear whether changes in such brains were caused by drugs, or made people vulnerable to addiction in the first place. Both are possible. Stimulant drugs typically act on parts of the brain involved in motivation, and interfere with those that inhibit our impulses. But these effects could be worse if these neural circuits are already weak.

To separate these possibilities, Ersche studied 50 volunteers who had a long history of drug abuse. She compared them to their siblings, who had no drug problems, and to 50 unrelated volunteers who were also drugs-free. All of the recruits sat through a stop-signal test – a commonly used way of measuring self-control. Volunteers have to respond as quickly as possible to a stream of on-screen symbols – say, by pressing a key. If they hear a tone, which pops up unpredictably, they have to restrain themselves. (Try it yourself here).

The drug users struggled with the test compared to the unrelated volunteers, and needed more time to withhold their responses. Critically, their siblings fared just as badly, even though they weren’t using drugs. This strongly suggests that poor self-control isn’t the result of the drugs themselves, but of a shared (and probably inherited) vulnerability. “If you have brain with existing problems, the drugs have an easier play. It’s easier for them to take over,” says Ersche.

Ersche found the same pattern when she looked at her volunteers’ brains. First, she focused on their white matter tracts – the fibres that transmit signals from one area to another. These are the brain’s communications network, and their density indicates how good different areas are at shuttling information between them.

These connections were weaker among both the drug users and their relatives, compared to the healthy unrelated volunteers. The fibres were particularly sparse around the right inferior frontal cortex (IFC), an area involved in controlling our inhibitions. These abnormalities were linked to the volunteers’s scores on the stop-signal test – the weaker the connections, the slower their reaction times. With its communication lines weakened, the IFC was less able to exert its suppressive influence.

The siblings also shared anomalies in the size of some brain areas. Their putamens and medial temporal lobes were bigger, and their posterior insulas were smaller. All of these areas have been implicated in learning and memory. “This may be an indicator of an enhanced propensity to form habits,” says Ersche.

From these results, a cohesive picture emerges. Some parts of the brain are larger, increasing the attractiveness of potential rewards, and the odds of habitual, addictive behaviour. The IFC, which would normally suppress such desires, has less of a say because the fibres connecting it to other parts of the brain are weaker. It’s like having a mob of reckless friends who are egging each other on over fast broadband connections, while their sensible parents send them words of caution on a dial-up modem.

This is uncannily similar to what happens in  the teenage brain, where areas associated with reward mature before the prefrontal areas that exercise restraint. Other scientists have suggested that this gap in timing explains why teens are so prone to risky and impulsive behaviours. They’re not making thoughtless decisions – they simply weigh risks and rewards in a different way to adults. Perhaps people who are vulnerable to addiction never grow out of this asymmetry between desire and inhibition. “It does look like a developmental problem,” says Ersche, “but we really need to compare these brains to those of adolescents to know for sure.”

“This is a very important and well-designed study,” says Susan Tapert from the University of California, San Diego. She adds, “It will be important to understand how the non-drug dependent volunteers were able to avoid drug problems given same brain features as their siblings.”

This is a key point. Drug dependence runs in families, and it is clearly influenced by a person’s genes. But genes do not determine behaviour; they merely influence it. The non-addicted siblings in Ersche’s study illustrate the point beautifully. “They share so much,” says Ersche. “They have the same vulnerabilities as their drug-dependent brothers and sisters. They had a lot of domestic violence and troubled childhoods but they didn’t get into drugs. Their average age was 33. They may have had many opportunities to develop dependence, but they didn’t.”

Perhaps the other one had environmental influences that set them down a different path. Perhaps they also had inherited some “resilience factors” that their siblings did not.  In an earlier study with some of the same siblings, Ersche found that all of them are more impulsive, but only the drug users were “sensation-seekers”. These are subtly different traits. “Impulsive people act on the spur of the moment,” Ersche explains, “but sensation-seekers crave excitement and adventure. In contrast to the drug-dependent individuals, their siblings do not seem to crave for excitement and sensations, which might have protected them from taking drugs in the first place.

In the meantime, Ersche’s study suggests that the white fibre tracts around the IFC could be used as a marker for vulnerability to addiction. That’s useful for two reasons. We could use it to identify people who are most at risk of abusing drugs, before they actually encounter any problems. We could also see if people can strengthen the connections in this critical area. Many scientists have developed programmes for improving self-control at an early age. Monitoring the IFC’s white matter could provide an objective way of measuring whether those programmes are working. As Tapert says, “We might be able to modify these risky brain characteristics, to see if the misuse of drugs can be reduced.”

Reference: Ersche, Jones, Williams, Turton, Robbins & Bullmore. 2011. Abnormal Brain Structure Implicated in Stimulant Drug Addiction. Science http://dx.doi.org/10.1126/science.1214463

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Alcohol tastes and smells better to those who get their first sips in the womb

Blogging on Peer-Reviewed ResearchPregnant women are generally advised to avoid drinking alcohol and for good reason – exposing an unborn baby to alcohol can lead to a range of physical and mental problems from hyperactivity and learning problems to stunted growth, abnormal development of the head, and mental retardation.

But alcohol also has much subtler effects on a foetus. Some scientists have suggested that people who get their first taste of alcohol through their mother’s placenta are more likely to develop a taste for it in later life. This sleeper effect is a long-lasting one – exposure to alcohol in the womb has been linked to a higher risk of alcohol abuse at the much later age of 21. In this way, mums could be inadvertently passing down a liking for booze to their children as a pre-birthday present.

Now, Steven Youngentob from SUNY Upstate Medical University and Jon Glendinning from Columbia University have found out why this happens. By looking at boozing rats, they have found that those first foetal sips of alcohol make the demon drink both taste and smell better.

The duo raised several pregnant rats on diets of either chow, liquids or liquids that had been spiked with alcohol. The third group eventually had a blood alcohol concentration of about 0.15%, a level that would cause a typical human to slur, stagger or become moody.

When the females eventually gave birth, month-old pups born to boozy mothers were more likely to lick an alcohol-coated feeding tube than those whose mothers were tee-total. These rats had been born with more of a taste for booze.


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Beta-blocker drug erases the emotion of fearful memories

Blogging on Peer-Reviewed ResearchThe wiping of unwanted memories is a common staple of science-fiction and if you believe this weekend’s headlines, you might think that the prospect has just become a reality. The Press Association said that a “drug helps erase fearful memories“, while the ever-hyperbolic Daily Mail talked about a “pill to erase bad memories“. The comparisons to The Eternal Sunshine of the Spotless Mind were inevitable, but the actual study, while fascinating and important, isn’t quite the mind-wiper these headlines might have you believe.

The drug in question is propranolol, commonly used to treat high blood pressure and prevent migraines in children. But Merel Kindt and colleagues from the University of Amsterdam have found that it can do much more. By giving it to people before they recalled a scary memory about a spider, they could erase the fearful response it triggered.

The critical thing about the study is that the entire memory hadn’t been erased in a typical sci-fi way. Kindt had trained the volunteers to be fearful of spidery images by pairing them with electric shocks. Even after they’d been given propranolol, they still expected to receive a shock when they saw a picture of a spider – they just weren’t afraid of the prospect. The drug hadn’t so much erased their memories, as dulled their emotional sting. It’s more like removing all the formatting from a Word document than deleting the entire file. Congatulations to Forbes and Science News who actually got it right.

Kindt’s work hinges on the fact that memories of past fears aren’t as fixed as previously thought. When they are brought back to mind, proteins at the synapses – the junctions between two nerve cells – are broken down and have to be created from scratch. This process is called “reconsolidation” and scientists believe that it helps to incorporate new information into existing memories. The upshot is that when we recall old memories, they have to be rebuilt on some level, which creates an opportunity for changing them.

A few years ago, two American scientists managed to use propranolol to banish fearful responses in rats. They injected the animals in their amygdalae, a part of their brains involved in processing emotional memories. The drug didn’t stop a fearful memory from forming in the first place, but it did impair the memory when the rats tried to retrieve it. Now, Kindt has shown that the chemical has the same effect in humans.


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Impulsive minds are primed for drug addiction


Blogging on Peer-Reviewed ResearchWe’ve all acted impulsively before, and we have the horrendous clothes, echoing bank accounts and hilarious memories to show for it. But science is beginning to show that impulsive people may be particularly vulnerable to drug addiction, and there is little funny or harmless about that.

img_0046_o.jpgAccording to Government statistics, half a million people in the UK are addicted to class A drugs like cocaine, heroin and amphetamines. All too often, drug addiction and other compulsive disorders like obesity are dismissed as issues of ‘willpower’ and those who succumb to temptation are labelled as ‘weak’. But this attitude is, at best, wrong and, at worst, stigmatising and self-righteous. And it provides no clues for ways of helping people with these problems.

In fact, the evidence suggests that drug addiction is linked to certain personality traits. Being impulsive is one of them, and a tendency to seek out new sensations (often described as “living life to the full”) is another. But do these traits drive people towards drug addiction, or are they a result of the drugs themselves?


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The brain’s addiction centre


Blogging on Peer-Reviewed ResearchIt’s mid-October. For most of us, our New Year’s resolutions have long been forgotten and our bad habits remain frustratingly habitual. The things that are bad for us often feel strongly compelling, be they high-fat foods, gambling or alcohol. And nowhere is the problem of addiction more widespread, serious and dangerous than the case of cigarette smoking.

800px-papierosa_1_ubt_0069.jpgSmoking is the leading preventable cause of death in the developed world, and in the UK, it kills five times more people than all non-medical causes combined. The dangers of smokers are both well-established and well-known, and surveys repeatedly show that the majority of smokers want to quit. But weaning oneself off a substance as addictive as nicotine is not easy.

People often view quitting smoking as a question of willpower – a problem of the mental world. But like all mental processes, addiction eventually boils down to physical matter, to our brains and the chemicals that reside within. Neurological studies have found that smoking causes long-term changes to various parts of the brain including the dopamine system involved in feelings of pleasure, and the amygdala, involved in emotional responses. Even cues associated with smoking such as the smell of smoke or the sight of a cigarette, can trigger distinctive patterns of activity in these areas, and are likely to contribute to the urges that smokers feel.

Now, Nasir Naqvi and colleagues from the University of Iowa have tracked down the neurons that control the addictive urges of smokers to a part of the brain called the insula. Located deep inside the brain, the insula is involved in emotion. It collects and processes sensory information from the rest of the body, and translates them into conscious emotional experiences, such as cravings, hunger or pain. And in doing this, the insula could control cravings for cigarettes in response to smoking-related cues.


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Brain-enhancing drugs work by focusing brain activity… for better or worse

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It’s late at night and although I want to finish this post, I’m pretty shattered. At the moment, I sorely need to boost my concentration and attentiveness and stave off the effects of fatigue. In lieu of actually getting some sleep, the ability to pop a little pill that will have the same effect sounds pretty enticing. Unfortunately (or perhaps luckily), the closest thing I have available is some coffee in the kitchen.

ritalin.jpgBut for many people, taking a pill to sharpen your mental faculties – a so-called “cognitive enhancer” – is a much easier deal. A large number of prescription drugs can indeed give you a little mental boost, including amphetamine and methylphenidate (more familiarly known by its brand name Ritalin). Both the use and the range of such drugs are on the rise and they seem capable of stimulating debate just as readily as they do the brain.

They have their medical uses; as Ritalin, methylphenidate is used to treat attention deficit hyperactivity disorder (ADHD) and, less commonly, narcolepsy. Even this is not without controversy, but the fact that they seem to have the same enhancing effects in healthy people opens up the potential for recreational use, and that is far more divisive.

Last year, Nature published a commentary which looked into the ethics of such drugs and sparked off a heated debate in a Nature Network forum and among fellow bloggers. More recently, the magazine released the results of an informal survey of over 1,400 readers, which showed that about 20% admitted to using cognitive enhancers for non-medical reasons and a far higher proportion approved of such use.

The ethical issues at stake are incredibly broad, but one specific problem is that cognitive enhancers represent a case of technology outpacing science. Common though these drugs are, we still don’t fully understand how some of them work. Take methylphenidate, for example. At a basic level, we know that it interferes with protein pumps that import two signalling molecules – dopamine and norepinephrine – into neurons and as a result, these molecules build up in the spaces between neurons, the synapses. But why should such a build-up improve a person’s performance?

Nora Volkow, Director of the National Institute on Drug Abuse, thinks she has the answer. By studying the metabolic activity of brains dosed up with methylphenidate, she has found evidence that the drug works by focusing the brain’s activity and making it more efficient. And crucially, the benefits (and costs) you reap from that may depend on how focused your brain already is.