Read the latest articles relevant to your clinical practice, including exclusive insights from Healthed surveys and polls.
By reading selected clinical articles, you earn CPD in the Educational Activities (EA) category whenever you click the “Claim CPD” button and follow the prompts.
§
Elizabeth Blackburn has always been fascinated by how life works. Born in 1948, she grew up by the sea in a remote town in Tasmania, Australia, collecting ants from her garden and jellyfish from the beach. When she began her scientific career, she moved on to dissecting living systems molecule by molecule. She was drawn to biochemistry, she says, because it offered a thorough and precise understanding “in the form of deep knowledge of the smallest possible subunit of a process”. Working with biologist Joe Gall at Yale in the 1970s, Blackburn sequenced the chromosome tips of a single-celled freshwater creature called Tetrahymena (“pond scum”, as she describes it) and discovered a repeating DNA motif that acts as a protective cap. The caps, dubbed telomeres, were subsequently found on human chromosomes too. They shield the ends of our chromosomes each time our cells divide and the DNA is copied, but they wear down with each division. In the 1980s, working with graduate student Carol Greider at the University of California, Berkeley, Blackburn discovered an enzyme called telomerase that can protect and rebuild telomeres. Even so, our telomeres dwindle over time. And when they get too short, our cells start to malfunction and lose their ability to divide – a phenomenon that is now recognised as a key process in ageing. This work ultimately won Blackburn the 2009 Nobel Prize in Physiology or Medicine. In 2000, she received a visit that changed the course of her research. The caller was Elissa Epel, a postdoc from UCSF’s psychiatry department. Psychiatrists and biochemists don’t usually have much to talk about, but Epel was interested in the damage done to the body by chronic stress, and she had a radical proposal. Epel, now director of the Aging, Metabolism and Emotion Center at UCSF, has a long-standing interest in how the mind and body relate. She cites as influences both the holistic health guru Deepak Chopra and the pioneering biologist Hans Selye, who first described in the 1930s how rats subjected to long-term stress become chronically ill. “Every stress leaves an indelible scar, and the organism pays for its survival after a stressful situation by becoming a little older,” Selye said. Back in 2000, Epel wanted to find that scar. “I was interested in the idea that if we look deep within cells we might be able to measure the wear and tear of stress and daily life,” she says. After reading about Blackburn’s work on ageing, she wondered if telomeres might fit the bill. With some trepidation at approaching such a senior scientist, the then postdoc asked Blackburn for help with a study of mothers going through one of the most stressful situations that she could think of – caring for a chronically ill child. Epel’s plan was to ask the women how stressed they felt, then look for a relationship between their state of mind and the state of their telomeres. Collaborators at the University of Utah would measure telomere length, while Blackburn’s team would measure levels of telomerase. Blackburn’s research until this point had involved elegant, precisely controlled experiments in the lab. Epel’s work, on the other hand, was on real, complicated people living real, complicated lives. “It was another world as far as I was concerned,” says Blackburn. At first, she was doubtful that it would be possible to see any meaningful connection between stress and telomeres. Genes were seen as by far the most important factor determining telomere length, and the idea that it would be possible to measure environmental influences, let alone psychological ones, was highly controversial. But as a mother herself, Blackburn was drawn to the idea of studying the plight of these stressed women. “I just thought, how interesting,” she says. “You can’t help but empathise.” It took four years before they were finally ready to collect blood samples from 58 women. This was to be a small pilot study. To give the highest chance of a meaningful result, the women in the two groups – stressed mothers and controls – had to match as closely as possible, with similar ages, lifestyles and backgrounds. Epel recruited her subjects with meticulous care. Still, Blackburn says, she saw the trial as nothing more than a feasibility exercise. Right up until Epel called her and said, “You won’t believe it.” The results were crystal clear. The more stressed the mothers said they were, the shorter their telomeres and the lower their levels of telomerase. The most frazzled women in the study had telomeres that translated into an extra decade or so of ageing compared to those who were least stressed, while their telomerase levels were halved. “I was thrilled,” says Blackburn. She and Epel had connected real lives and experiences to the molecular mechanics inside cells. It was the first indication that feeling stressed doesn’t just damage our health – it literally ages us.§
Unexpected discoveries naturally meet scepticism. Blackburn and Epel struggled initially to publish their boundary-crossing paper. “Science [one of the world’s leading scientific journals] couldn’t bounce it back fast enough!” chuckles Blackburn. When the paper finally was published, in the Proceedings of the National Academy of Sciences in December 2004, it sparked widespread press coverage as well as praise. Robert Sapolsky, a pioneering stress researcher at Stanford University and author of the bestselling Why Zebras Don’t Get Ulcers, described the collaboration as “a leap across a vast interdisciplinary canyon”. Mike Irwin, director of the Cousins Center for Psychoneuroimmunology at the University of California, Los Angeles, says it took a lot of courage for Epel to seek out Blackburn. “And a lot of courage for Liz [Blackburn] to say yes.” Many telomere researchers were wary at first. They pointed out that the study was small, and questioned the accuracy of the telomere length test used. “This was a risky idea back then, and in some people’s eyes unlikely,” explains Epel. “Everyone is born with very different telomere lengths and to think that we can measure something psychological or behavioural, not genetic, and have that predict the length of our telomeres? This is really not where this field was ten years ago.” The paper triggered an explosion of research. Researchers have since linked perceived stress to shorter telomeres in healthy women as well as in Alzheimer’s caregivers, victims of domestic abuse and early life trauma, and people with major depression and post-traumatic stress disorder. “Ten years on, there’s no question in my mind that the environment has some consequence on telomere length,” says Mary Armanios, a clinician and geneticist at Johns Hopkins School of Medicine who studies telomere disorders. There is also progress towards a mechanism. Lab studies show that the stress hormone cortisol reduces the activity of telomerase, while oxidative stress and inflammation – the physiological fallout of psychological stress – appear to erode telomeres directly. This seems to have devastating consequences for our health. Age-related conditions from osteoarthritis, diabetes and obesity to heart disease, Alzheimer’s and stroke have all been linked to short telomeres. The big question for researchers now is whether telomeres are simply a harmless marker of age-related damage (like grey hair, say) or themselves play a role in causing the health problems that plague us as we age. People with genetic mutations affecting the enzyme telomerase, who have much shorter telomeres than normal, suffer from accelerated-ageing syndromes and their organs progressively fail. But Armanios questions whether the smaller reductions in telomere length caused by stress are relevant for health, especially as telomere lengths are so variable in the first place. Blackburn, however, says she is increasingly convinced that the effects of stress do matter. Although the genetic mutations affecting the maintenance of telomeres have a smaller effect than the extreme syndromes Armanios studies, Blackburn points out that they do increase the risk of chronic disease later in life. And several studies have shown that our telomeres predict future health. One showed that elderly men whose telomeres shortened over two-and-a-half years were three times as likely to die from cardiovascular disease in the subsequent nine years as those whose telomeres stayed the same length or got longer. In another study, looking at over 2,000 healthy Native Americans, those with the shortest telomeres were more than twice as likely to develop diabetes over the next five-and-a-half years, even taking into account conventional risk factors such as body mass index and fasting glucose. Blackburn is now moving into even bigger studies, including a collaboration with healthcare giant Kaiser Permanente of Northern California that has involved measuring the telomeres of 100,000 people. The hope is that combining telomere length with data from the volunteers’ genomes and electronic medical records will reveal additional links between telomere length and disease, as well as more genetic mutations that affect telomere length. The results aren’t published yet, but Blackburn is excited about what the data already shows about longevity. She traces the curve with her finger: as the population ages, average telomere length goes down. This much we know; telomeres tend to shorten over time. But at age 75–80, the curve swings back up as people with shorter telomeres die off – proof that those with longer telomeres really do live longer. “It’s lovely,” she says. “No one has ever seen that.” In the decade since Blackburn and Epel’s original study, the idea that stress ages us by eroding our telomeres has also permeated popular culture. In addition to Blackburn’s many scientific accolades, she was named one of Time magazine’s “100 most influential people in the world” in 2007, and received a Good Housekeeping achievement award in 2011. A workaholic character played by Cameron Diaz even described the concept in the 2006 Hollywood film The Holiday. “It resonates,” says Blackburn. But as evidence of the damage caused by dwindling telomeres piles up, she is embarking on a new question: how to protect them.§
At first, the beach seems busy. Waves splash and splash and splash. Sanderlings wheel along the shoreline. Joggers and dog walkers amble across, while groups of pelicans hang out on the water before taking wing or floating out of sight. A surfer, silhouetted black against the sky, bobs about for 20 minutes or so, catching the odd ripple towards shore before he, too, is gone. The unchanging perspective gives a curious sense of detachment. You can imagine that the birds and joggers and surfers are like thoughts: they inhabit different forms and timescales but in the end, they all pass. There are hundreds of ways to meditate but this morning I’m trying a form of Buddhist mindfulness meditation called open monitoring, which involves paying attention to your experience in the present moment. Sit upright and still, and simply notice any thoughts that arise – without judging or reacting to them – before letting them go. For Buddhists this is a spiritual quest; by letting trivial thoughts and external influences fall away, they hope to get closer to the true nature of reality. Blackburn too is interested in the nature of reality, but after a career spent focusing on the measurable and quantifiable, such navel-gazing initially held little personal appeal and certainly no professional interest. “Ten years ago, if you’d told me that I would be seriously thinking about meditation, I would have said one of us is loco,” she told the New York Times in 2007. Yet that is where her work on telomeres has brought her. Since her initial study with Epel, the pair have become involved in collaborations with teams around the world – as many as 50 or 60, Blackburn estimates, spinning in “wonderful directions”. Many of these focus on ways to protect telomeres from the effects of stress; trials suggest that exercise, eating healthily and social support all help. But one of the most effective interventions, apparently capable of slowing the erosion of telomeres – and perhaps even lengthening them again – is meditation. So far the studies are small, but they all tentatively point in the same direction. In one ambitious project, Blackburn and her colleagues sent participants to meditate at the Shambhala mountain retreat in northern Colorado. Those who completed a three-month course had 30 per cent higher levels of telomerase than a similar group on a waiting list. A pilot study of dementia caregivers, carried out with UCLA’s Irwin and published in 2013, found that volunteers who did an ancient chanting meditation called Kirtan Kriya, 12 minutes a day for eight weeks, had significantly higher telomerase activity than a control group who listened to relaxing music. And a collaboration with UCSF physician and self-help guru Dean Ornish, also published in 2013, found that men with low-risk prostate cancer who undertook comprehensive lifestyle changes, including meditation, kept their telomerase activity higher than similar men in a control group and had slightly longer telomeres after five years. In their latest study, Epel and Blackburn are following 180 mothers, half of whom have a child with autism. The trial involves measuring the women’s stress levels and telomere length over two years, then testing the effects of a short course of mindfulness training, delivered with the help of a mobile app. Theories differ as to how meditation might boost telomeres and telomerase, but most likely it reduces stress. The practice involves slow, regular breathing, which may relax us physically by calming the fight-or-flight response. It probably has a psychological stress-busting effect too. Being able to step back from negative or stressful thoughts may allow us to realise that these are not necessarily accurate reflections of reality but passing, ephemeral events. It also helps us to appreciate the present instead of continually worrying about the past or planning for the future. “Being present in your activities and in your interactions is precious, and it’s rare these days with all of the multitasking we do,” says Epel. “I do think that in general we’ve got a society with scattered attention, particularly when people are highly stressed and don’t have the resources to just be present wherever they are.”§
Inevitably, when a Nobel Prize-winner starts talking about meditation, it ruffles a few feathers. In general, Blackburn’s methodical approach to the topic has earned a grudging admiration, even among those who have expressed concern about the health claims made for alternative medicine. “She goes about her business in a cautious and systematic fashion,” says Edzard Ernst of the University of Exeter, UK, who specialises in testing complementary therapies in rigorous controlled trials. Oncologist James Coyne of the University of Pennsylvania, Philadelphia, who is sceptical of this field in general and describes some of the research on positive psychology and health as “morally offensive” and “tooth fairy science”, concedes that some of Blackburn’s data is “promising”. Others aren’t so impressed. Surgeon-oncologist David Gorski is a well-known critic of alternative medicine and pseudoscience who blogs under the name of Orac – he’s previously described Dean Ornish as “one of the four horsemen of the Woo-pocalypse”. Gorski stops short of pronouncing meditation as off-limits for scientific inquiry, but expresses concern that the preliminary results of these studies are being oversold. How can the researchers be sure they’re investigating it rigorously? “It’s really hard to do with these things,” he says. “It is easy to be led astray. Nobel Prize-winners are not infallible.” Blackburn’s own biochemistry community also seems ambivalent about her interest in meditation. Three senior telomere researchers I contacted declined to discuss this aspect of her work, with one explaining that he didn’t want to comment “on such a controversial issue”. “People are very uncomfortable with the concept of meditation,” notes Blackburn. She attributes this to its unfamiliarity and its association with spiritual and religious practices. “We’re always trying to say it as carefully as we can… always saying ‘look, it’s preliminary, it’s a pilot’. But people won’t even read those words. They’ll see the newspaper headings and panic.” Any connotation of religious or paranormal beliefs makes many scientists uneasy, says Chris French, a psychologist at Goldsmiths, University of London, who studies anomalous experiences including altered states of consciousness. “There are a lot of raised eyebrows, even though I’ve got the word sceptic virtually tattooed across my forehead,” he says. “It smacks of new-age woolly ideas for some people. There’s a kneejerk dismissive response of ‘we all know it’s nonsense, why are you wasting your time?’” "When meditation first came to the West in the 1960s it was tied to the drug culture, the hippie culture,” adds Sara Lazar, a neuroscientist at Harvard who studies how meditation changes the structure of the brain. “People think it’s just a bunch of crystals or something, they roll their eyes.” She describes her own decision to study meditation, made 15 years ago, as “brave or crazy”, and says that she only plucked up the courage because at around the same time, the US National Institutes of Health (NIH) created the National Center for Complementary and Alternative Medicine. “That gave me the confidence that I could do this and I would get funding.” The tide is now turning. Helped in part by that NIH money, researchers have developed secularised – or non-religious – practices such as mindfulness-based stress reduction and mindfulness-based cognitive therapy, and reported a range of health effects from lowering blood pressure and boosting immune responses to warding off depression. And the past few years have seen a spurt of neuroscience studies, like Lazar’s, showing that even short courses of meditation can forge structural changes in the brain. “Now that the brain data and all this clinical data are coming out, that is starting to change. People are a lot more accepting [of meditation],” says Lazar. “But there are still some people who will never believe that it has any benefit whatsoever." Blackburn’s view is that meditation is a fair topic to study, as long as robust methods are used. So when her research first pointed in this direction, she was undaunted by concerns about what such studies might do to her reputation. Instead, she tried it out for herself, on an intensive six-day retreat in Santa Barbara. “I loved it,” she says. She still uses short bursts of meditation, which she says sharpen her mind and help her to avoid a busy, distracted mode. She even began one recent paper with a quote from the Buddha: “The secret of health for both mind and body is not to mourn for the past, worry about the future, or anticipate troubles but to live in the present moment wisely and earnestly.” That study, of 239 healthy women, found that those whose minds wandered less – the main aim of mindfulness meditation – had significantly longer telomeres than those whose thoughts ran amok. “Although we report merely an association here, it is possible that greater presence of mind promotes a healthy biochemical milieu and, in turn, cell longevity,” the researchers concluded. Contemplative traditions from Buddhism to Taoism believe that presence of mind promotes health and longevity; Blackburn and her colleagues now suggest that the ancient wisdom might be right.§
I meet with Blackburn in Paris. We’re at an Art Nouveau-themed bistro just down the road from the Curie Institute, where she is on a short sabbatical, arranging seminars between groups of scientists who don’t usually talk to one another. In a low, melodious voice that I strain to hear through the background clatter, the 65-year-old tells me of her first major brush with Buddhist thinking. In September 2006, she attended a conference held at the Menla Mountain Buddhist centre, a remote retreat in New York’s Catskill mountains, at which Western scientists met with Tibetan-trained scholars including the Dalai Lama to discuss longevity, regeneration and health. During the meeting, the spiritual leader honoured Blackburn’s scientific achievements by inducting her as a “Medicine Buddha”. If Epel’s psychiatry research had been another world, the scholars’ Eastern philosophy seemed to Blackburn more alien still. Over dinner one evening, while explaining to the other delegates how errors in the gene for telomerase can cause health problems, she described genetic mutation as a random, chance event. That’s dogma for Western scientists but not for those trained in the Tibetan worldview. “They said ‘oh no, we don’t regard this as chance’,” says Blackburn. For these holistic scholars, even the smallest events were infused with meaning. “I suddenly thought, whoa, this is a very different world from the one I’m on.” But instead of dismissing her Eastern counterparts, she was impressed, finding the Dalai Lama to have “a very good brain”, for example. “They’re scholarly in a very different way, but it is still good-quality thinking,” she explains. “It wasn’t ‘God told me this’, it was more ‘let’s see what actually happens in the brain’. So there are certain elements of the approach that I am quite comfortable with as a scientist.” Blackburn isn’t tempted to embrace the spiritual approach herself. “I’m rooted in the physical world,” she says. But she combines that grounding with an open mind towards new ideas and connections, and she seems to love breaking out of established paradigms. For example, she and Epel have shown that the effects of stress on telomeres can be passed on to the next generation. If women experience stress while pregnant, their children have shorter telomeres, as newborns and as adults – in direct contradiction of the standard view that traits can only be passed on via our genes. In the future, information from telomeres may help doctors decide when to prescribe particular drugs. For example, telomerase activity predicts who will respond to treatment for major depression, while telomere length influences the effects of statins. In general, however, Blackburn is more interested in how telomeres might help people directly, by encouraging them to live in a way that reduces their disease risk. “This is not a familiar model for the medical world,” she says. Conventional medical tests give us our risk of particular conditions – high cholesterol warns of impending heart disease, for example, while high blood sugar predicts diabetes. Telomere length, by contrast, gives an overall reading of how healthy we are: our biological age. And although we already know that we should exercise, eat well and reduce stress, many of us fall short of these goals. Blackburn believes that putting a concrete number on how we are doing could provide a powerful incentive to change our behaviour. In fact, she and Epel have just completed a study (as yet unpublished) showing that simply being told their telomere length caused volunteers to live more healthily over the next year than a similar group who weren’t told. Ultimately, however, the pair want entire countries and governments to start paying attention to telomeres. A growing body of work now shows that the stress from social adversity and inequality is a major force eroding these protective caps. People who didn’t finish high school or are in an abusive relationship have shorter telomeres, for example, while studies have also shown links with low socioeconomic status, shift work, lousy neighbourhoods and environmental pollution. Children are particularly at risk: being abused or experiencing adversity early in life leaves people with shorter telomeres for the rest of their lives. And through telomeres, the stress that women experience during pregnancy affects the health of the next generation too, causing hardship and economic costs for decades to come. In 2012, Blackburn and Epel wrote a commentary in the journal Nature, listing some of these results and calling on politicians to prioritise “societal stress reduction”. In particular, they argued, improving the education and health of women of child-bearing age could be “a highly effective way to prevent poor health filtering down through generations”. Meditation retreats or yoga classes might help those who can afford the time and expense, they pointed out. “But we are talking about broad socioeconomic policies to buffer the chronic stressors faced by so many.” Where many scientists refrain from discussing the political implications of their work, Blackburn says she wanted to speak out on behalf of women who lack support, and say “You’d better take their situations seriously.” While arguments for tackling social inequality are hardly new, Blackburn says that telomeres allow us to quantify for the first time the health impact of stress and inequality and therefore the resulting economic costs. We can also now pinpoint pregnancy and early childhood as “imprinting periods” when telomere length is particularly susceptible to stress. Together, she says, this evidence makes a stronger case than ever before for governments to act. But it seems that most scientists and politicians still aren’t ready to leap across the interdisciplinary canyon that Blackburn and Epel bridged a decade ago. The Nature article has engendered little response, according to a frustrated Epel. “It’s a strong statement so I would have thought that people would have criticised it or supported it,” she says. “Either way!” “It’s now a consistent story that the ageing machinery is shaped at the earliest stages of life,” she insists. “If we ignore that and we just keep trying to put band-aids on later, we’re never going to get at prevention and we’re only going to fail at cure.” Simply responding to the physical symptoms of disease might make sense for treating an acute infection or fixing a broken leg, but to beat chronic age-related conditions such as diabetes, heart disease and dementia, we will need to embrace the fuzzy, subjective domain of the mind. This article first appeared on Mosaic and is republished here under a Creative Commons licence.
§
Newsletter: On receiving the 1945 Nobel Prize in Physiology or Medicine for discovering penicillin, Alexander Fleming finished his lecture with a warning: “There is the danger,” he told the audience, “that the ignorant man may easily underdose himself and, by exposing his microbes to non-lethal quantities of the drug, make them resistant.” In other words, we have known about bacteria’s ability to evolve resistance to drugs since the dawn of the antibiotic era. Dr Manica Balasegaram is Director of the Global Antibiotic Research and Development Partnership (GARDP), based in Geneva. It’s a joint initiative between the Drugs for Neglected Diseases Initiative (DNDi) and the World Health Organization (WHO) and aims to develop new or improved treatments for bacterial infections. “All antibiotics will have a shelf life – that’s just evolution,” he says. “It’s just a question of how quickly it will happen.” Antibiotic resistance is one of the biggest threats to global health, food security and development. Common infections, such as pneumonia and tuberculosis, are becoming increasingly difficult to treat. But GARDP has chosen to focus its attention on gonorrhoea as one of its four main priorities. The sexually transmitted infection caught Balasegaram’s eyes for a host of reasons. For one, a lot of the antibiotics that are currently used against gonorrhoea are used widely for other infections, and N. gonorrhoeae has the ability to acquire resistance from other bacteria frighteningly quickly, meaning it can rapidly build up resistance. Secondly, untreated gonorrhoea infections bring with them a range of potentially serious health implications that can have devastating consequences. “Gonorrhoea is the most important sexually transmitted infection; it’s the one we’re most concerned about,” Balasegaram says. Every year an estimated 78 million people are infected with gonorrhoea, making it the second most frequently reported sexually transmitted bacterial infection after chlamydia, according to WHO. Gonorrhoea can infect the genitals, rectum and throat. Symptoms include discharge from the urethra or vagina and burning during urination called urethritis, caused by inflammation of the urethra. However, many who are infected don’t experience any symptoms, meaning they go undiagnosed and untreated. Complications of untreated gonorrhoea can be severe and disproportionately affect women, who are more likely to experience no symptoms. Untreated gonorrhoea not only increases the risk of contracting HIV but is also linked with an increased risk of pelvic inflammatory disease, which can cause ectopic pregnancy and infertility. A pregnant woman can also pass on the infection to her baby, which can cause blindness. Fixing the threat of resistant gonorrhoea won’t be easy – the challenges in developing a new antibiotic can’t be overestimated. Is the money for research and development (R&D) available? Who will the antibiotic be available to? And most importantly, how will you control its use so you can extend its shelf life? What makes the search for a new antibiotic for gonorrhoea particularly challenging is the frequency of asymptomatic infections along with gonorrhoea’s ability to adapt to its host’s immune system and develop resistance to antibiotics. A major concern is that because N. gonorrhoeae can live in the throat without someone even knowing, the bug can acquire resistance from other bacteria that also live there and which have been exposed to antibiotics in the past. And with evidence that oral sex is becoming increasingly common in some parts of the world, this is particularly challenging. “Oral sex is driving resistance. It’s a network of people having lots of oral sex. It’s the new norm,” says Dr Teodora Wi, a medical officer in WHO’s Department of Reproductive Health and Research in Geneva, talking specifically about Asia. These challenges and concerns have gripped Balasegaram, but nonetheless he’s more determined than ever to bring a new drug to market. “People are dying from drug-resistant infections. This is undoubtedly because this area has not been prioritised in the past because other areas of R&D are far more lucrative,” he says. “Antibiotics are a global public good. I don’t think it’s easy to put a financial value to it.”§
Recent data collected by WHO examined trends in drug-resistant gonorrhoea in 77 countries – countries that are part of the health agency’s Gonococcal Antimicrobial Surveillance Programme (GASP), a global network of regional and subregional laboratories that track the emergence and spread of resistance. And the results are grim. More than 80 per cent of the countries that reported on azithromycin, a commonly prescribed antibiotic used to treat numerous common infections, including sexually transmitted infections (STIs), found resistance. Of greatest concern is that 66 per cent of countries surveyed have reported cases that resist last-resort antibiotics called extended-spectrum cephalosporins (ESCs). And as Wi points out, the real-world picture is undoubtedly far bleaker, because global surveillance for drug-resistant gonorrhoea is patchy and more frequently done in higher-income countries, which have greater resources. For example, of the 77 countries that were surveyed, few were in sub-Saharan Africa, a region where rates of gonorrhoea are high. “We’re only seeing half of the real picture. We need to prepare for the future when there’s no cure,” Wi says. But in a sign that time is running out, in March this year health experts’ worst fears were confirmed: a case of super-gonorrhoea, dubbed the world’s “worst ever” case, was found in a man who had attended a local sexual health clinic. He had reportedly had sexual contact with a woman in South-east Asia. Health officials said it was the first time this strain could not be cured with any of the antibiotics normally used to treat the disease. Although the patient has since responded to another antibiotic, doctors described him as “very lucky”. It’s an indication of a wider crisis – and one that knows no boundaries.§
Thailand is one country on the front line of the fight against antibiotic-resistant gonorrhoea. It’s a key destination for the sex tourism industry, where STIs like gonorrhoea can spread easily and quickly across borders and beyond. And like many other countries in the region, it has an over-the-counter culture of antibiotic access, which means patients put themselves at risk of being prescribed the wrong drugs – or even worse. I’m in a district close to Thailand’s capital, Bangkok, to meet Boontham, a pharmacist. We meet in the jam-packed stockroom of the herbal medicine company he also runs – a business that’s far more lucrative than his pharmacy. The stockroom is filled head to toe with boxes of tablets containing an array of funky herbs I’ve never heard of. The cost of visiting a doctor and the stigma surrounding STIs mean that many Thais rely on pharmacists like Boontham to cure their gonorrhoea. But he might be doing more harm than good. While Boontham has a degree in pharmacology and has been a pharmacist for more than 30 years, he has no idea of Thailand’s treatment guidelines for gonorrhoea. In fact, he’s more than a decade out of date. And he can’t, of course, diagnose patients accurately, particularly because gonorrhoea has similar symptoms to chlamydia. “If you’ve been doing this for a long time, you just do what you have to, and that’s an educated guess.” “As of now I use ciprofloxacin [to treat gonorrhoea],” he says. “If that doesn’t work, then I guess it’s chlamydia.” I tell him, however, that gonorrhoea in Thailand, as in many other countries, has shown widespread resistance to ciprofloxacin – and that his country actually stopped recommending it more than a decade ago. “It’s not resistant, even doctors use it,” he says. “I prescribe it because it’s cheap. In hospitals they prescribe newer antibiotics that are more effective, but they’re more expensive.” In countries where antibiotics are sold over the counter, research shows people are far more likely to visit pharmacists than a doctor. But while experts acknowledge that restricting the sale of antibiotics – particularly in rural and remote areas where there are few, if any, proper doctors – isn’t the answer, this still presents a major challenge in the fight against drug-resistant infections. “The problem is that when you go to a pharmacist and take antibiotics, maybe… your symptoms have disappeared, but in fact you still have the infection. That means you can transmit the infection and cause more resistance,” Wi says. I ask Boontham whether he’s concerned about resistance – if he’s worried that the people he’s treated for gonorrhoea aren’t cured. “Resistance to medication is a doctor’s job, not a pharmacist’s,” he says. The casual handing out of antibiotics without a prescription is not only confined to Thailand. It’s a huge concern across the rest of the region and in other parts of the world, with no clear vision of how to tackle this growing problem. Handing out antibiotics that likely no longer work for people with gonorrhoea has also been happening in high-income countries – countries that might be expected to have stricter treatment guidelines. In fact, a study published in the BMJ in 2015 found that many GPs in England were prescribing ciprofloxacin, even though it hasn’t been recommended for treating gonorrhoea since 2005. In 2007, ciprofloxacin still made up almost half of prescriptions for gonorrhoea. As recently as 2011, GPs still prescribed it in 20 per cent of cases.§
On a balmy afternoon in bustling Bangkok, I visit Silom Community Clinic @ TropMed, an STI clinic north-east of the city centre dedicated to men who have sex with men (MSM) and transgender women who have sex with men. Located on the 12th floor of the Hospital for Tropical Diseases, the clinic is spotlessly clean, with bright purple walls, rainbow flags and a sign that immediately catches my eye, which reads “Suck, F*ck, Test, Repeat”. Off the main corridor is a microbiology lab that is doing critical and urgent work in the fight against antibiotic-resistant gonorrhoea. In fact, the lab may be the best way Thailand can protect itself from this growing threat. Dr Eileen Dunne is an American epidemiologist and the head of the behavioural and clinical research section of the HIV/STI programme here, which is run as part of a collaboration between Thailand’s Ministry of Public Health (MOPH) and the US Centers for Disease Control and Prevention (CDC). She, along with her Thai staff, are Thailand’s best line of defence in slowing gonorrhoea resistance. In 2015, recognising the worldwide danger of increasingly difficult to treat gonorrhoea infections – and the specific threat they posed to Thailand – the US CDC, WHO and Thai MOPH joined forces to launch a programme to track and ultimately limit the spread of antibiotic-resistant gonorrhoea. The programme is an enhanced local version of the WHO’s GASP and is the first of its kind in the world. It’s called EGASP. It works like this. If a male patient comes into one of its two clinics with the telltale symptoms of gonorrhoea, he will have a sample collected for analysis and will fill out a questionnaire, which contains questions such as: “Did you take antibiotics in the last two weeks?” To create an open environment, the clinics are anonymous and the questionnaire is done privately on a computer. Men are the target group in the programme, Dunne explains, because the yield for isolating N. gonorrhoeae is very high among men who have urethritis compared with women and those who are asymptomatic. MSM are an important population, she adds, because research shows they are likelier to develop resistance earlier than the general population, for reasons that aren’t precisely known. She and the laboratory staff take me to see if there are any samples being cultured from swabs taken from patients’ penises. Inside the incubator, where the samples are kept in Petri dishes at 36 degrees Celsius with 5 per cent carbon dioxide to promote bacteria growth, there are three. The stench of agar, a brown gelatinous medium that provides nutrients and a stable environment for bacteria to grow, is overwhelming. One Petri dish contains a cluster of bubbly white dots, signalling that the patient does indeed have gonorrhoea. The next step is antibiotic susceptibility testing (AST) at a lab downstairs. The isolate will be measured for resistance to five antibiotics, including ciprofloxacin and the last-resort drugs cefixime and ceftriaxone. It’s resistance to these latter two which is of greatest concern. From the beginning of EGASP until 20 October 2017, of the 845 confirmed diagnoses of gonorrhoea that underwent AST, almost all isolates had widespread resistance to ciprofloxacin, as in many other countries. But encouragingly, none have shown resistance to the last-line drugs. That’s a relief for Thailand, but in no way an indication that Dunne and her team’s alacrity should wane. “People are surprised and have asked, ‘Oh, why are you doing this if you don’t show resistance?’,” Dunne says. “It’s actually good to do surveillance and not be detecting resistance yet. It means that we’re early enough to be prepared… and [to] have a plan of response. “Having strong surveillance activity in a region in which this is likely to emerge is important so we can detect it early.” Thailand’s neighbours, specifically Myanmar, India, Indonesia and China, have recorded a significantly higher percentage of gonorrhoea isolates that are resistant to last-line treatments compared to Thailand. With the increasing movement of people around the world and Thailand’s popularity for sex tourism, I can see just how rapidly this threat could have far-reaching consequences. “I think it’s really important to detect early, even one case, [because] it can be a harbinger for future developments of resistance. These bacteria are transmitted very rapidly between people. Being able to really find that one case early means that special steps can be in place to control transmission,” Dunne says. I ask if the focus on MSM means other groups might be being missed. What about women, who are more likely than men to not experience any gonorrhoea symptoms? Or itinerant sex workers from across the border in Myanmar and Cambodia? I wonder if, among this high-risk group, EGASP is missing some of Thailand’s most vulnerable. I ask if there’s potential for the programme to extend its work to include these people and their partners. Dunne agrees it’s a good idea. “This targeted approach in men with symptoms is purposeful but may not be generalisable to the whole population. It’s the tip of the iceberg.” But it’s early on in the programme, and she and the team have to start somewhere. “We need more time,” she says. But no one is really sure how much time Thailand – and the rest of the world – has.§
The number of people infected with gonorrhoea has risen rapidly in recent years. Australia has seen a 63 per cent increase in the number of reported gonorrhoea cases since 2012, with the fastest rate of increase being in young heterosexual urbanites. In England, gonorrhoea cases rose by 53 per cent between 2012 and 2015, led by young people, gay men and other MSM. Meanwhile, in the USA cases rose by nearly 50 per cent between 2009 and 2016. And according to some experts, one of science’s greatest achievements in the fight against HIV could be a factor. Like many, Mark King’s nonchalant attitude towards sex had come to a halt when the HIV epidemic hit the gay community in the USA. No longer was gonorrhoea simply seen as a small, insignificant price to pay for a night of fun. “Half the fun of being gay [was that] you didn’t have to worry about birth control. Condoms were birth control, not STI control,” says King. “[But] as the years passed and you get into the 90s and we know how HIV is transmitted, to get gonorrhoea is shameful because it means that you’ve been taking risks that could transmit HIV. “Suddenly gonorrhoea became this really shameful thing because it means you’re not doing the right thing.” Move forward to today and HIV is no longer the death threat it once was. A strong civil society movement saw the disease get the political – and scientific – attention it warranted. The development of life-saving drugs means that those with HIV can live long, healthy lives. But as HIV treatment and prevention methods improve, people’s perception of risk may be changing. Pre-exposure prophylaxis (PrEP) is a daily pill for people who don’t have HIV but who are at substantial risk of getting it. It’s a powerful tool in the fight against HIV, it is argued. When taken every day, it’s up to 92 per cent effective in preventing infection. But with its development and uptake came alarm bells, with some warning that STI rates would increase among those who used PrEP. Some small studies have hinted that this may be happening. Not all experts agree with this. The data from these studies is ambiguous and cannot be generalised. And some say that regular testing regimes associated with PrEP prescriptions could prevent STIs spreading. However, just as with antibiotics, there are people using PrEP without getting it through official health outlets. A recent survey carried out across Europe by the HIV/AIDS advocacy group AIDES found that about 70 per cent of informal PrEP users were having no regular medical monitoring. King is one of many for whom concerns over STIs in the broader context of having the incredible ability to prevent HIV infection seems absurd. “PrEP opens the door for people to have sex without fear of HIV infection. The reaction is: yes, but what do we do about STIs? Oh my god, gonorrhoea and syphilis,” King says sarcastically. “People ask me, how does a person get HIV or gonorrhoea in this day and age? Well, let’s see: because they were horny, or they said yes when they should have said no, or they had too much to drink, or they fell in love, or they trusted the wrong person.” King’s words may resonate with many around the world. But WHO is focused on increasing condom use. Wi is particularly worried about the proliferation and popularity of dating apps among young people, which she believes are making no-strings-attached sex easier to obtain. “All of us need to be strong about condom use. All of us need to campaign for condom use,” Wi says.§
Looking ahead, at what point will it be more common to have a gonorrhoea infection that can’t be treated with antibiotics than one that can? The answer is difficult to predict, but it’s also a potential reality that isn’t far-fetched. “We are in a situation now where we are worryingly using the last line of antibiotics for many infections or seeing even resistance to these last-line antibiotics,” Balasegaram says. But as GARDP works to bring a new antibiotic to market, some countries are getting desperate as resistance to the available treatments continues to spread. Australia, which has recorded widespread resistance to azithromycin, is considering going back to an old drug called spectinomycin. Spectinomycin involves a painful muscular injection and has been linked to toxicity and a range of side-effects. Another concern is that it’s in short supply because it’s rarely used around the world any more. To this end, R&D for new antibiotics is urgent. But antibiotic drug development is prohibitively expensive and not attractive to the pharmaceutical industry – even more so when it’s for an STI. In response, GARDP has partnered with Entasis Therapeutics, a US biotech company, to accelerate the development of a new antibiotic that will be produced specifically to target drug-resistant gonorrhoea. Zoliflodacin is a novel first-in-class oral antibiotic – in other words, a new and unique mechanism of potentially treating gonorrhoea – and is one of only three potential new antibiotic candidates currently undergoing trials. It had previously been put through clinical trials in 2015, but a lack of investment stopped the drug from progressing further. This year GARDP and Entasis will launch the last phase of trials of zoliflodacin, involving 650 people in Thailand, South Africa, the USA and parts of Europe. If the drug is approved by regulators, Entasis will permit GARDP to introduce it in 168 low- and middle-income countries. It’s hoping it will be registered by 2021 and available on the market by 2023. A major strength of the partnership between GARDP and Entasis is that it will be able to limit what infections zoliflodacin is used for. “We’re trying to focus this drug specifically on STIs – not other community infections where antibiotics are widely used,” Balasegaram says. “The aim is not to go beyond that because that’s how resistance starts.” To this end, initially the drug will be licensed only for use against gonorrhoea infections. If it proves to be effective against chlamydia and Mycoplasma genitalium (another bacterial STI), the GARDP and Entasis partnership could license it for those two infections as well, subject to clinical trials. “We will support clinical trials and registration and therefore we can play a big role in how it is responsibly introduced and used. That gives us more control in how the drug is introduced and marketed in the countries where we work,” says Balasegaram. Dunne is excited that Thailand will be part of the trials. “It is the underbelly of infections. It doesn’t get the attention it deserves and that is why this is exciting,” she says. A lot is riding on the success of the drug. Will zoliflodacin be successful in remaining effective for as long as possible? Or will it face the same fate as other antibiotics? Moreover, research is risky – there’s no guarantee the clinical trials will be successful. “We still don’t know whether this project will succeed or not,” says Balasegaram. “But it’s a project that we feel is extremely important and that we’re very committed to.” The development of new antibiotics raises myriad questions: How can we ensure they are used appropriately so we can preserve their effectiveness? And how can we ensure those who really need the drugs get them? One way would be a point-of-care rapid diagnostic test – ideally one that could predict which antibiotics will work on a particular infection and that could be used in settings around the world. Balasegaram says they’ve been looking for a simple diagnostic tool like this but haven’t yet found one. Diagnostic tools aside, the responsible use of new antibiotics also relies on robust national and international treatment guidelines and strong regulatory authorities to guide and monitor antibiotic use. “If you have developed an antibiotic for narrow use, you have to think about how to market the drug. We do not want to drop large quantities of it around the world. But we also want to make sure those who need it get it,” he says. This is where strong surveillance programmes, like Thailand’s, are critical. But it’s inevitable that bugs will develop resistance to the next antibiotic and then the next. So Balasegaram wants more investment in R&D that focuses not only on new antibiotics but also on alternative ways to treat bacterial infections. “We have to continue to do R&D into… therapeutic ways to treat these infections differently,” he says. “This may include novel and non-conventional approaches. I think that is a job that is going to last decades.” What that might look like is complex. It may include designing antibodies that specifically target bacteria or using bacteriophages – viruses that infect bacteria – as a replacement for antibiotics. Either way, many feel that the end of the antibiotic era is near and that the transition from antibiotics to non-traditional treatments poses major challenges that won’t be easy to solve. “It’s worth bearing in mind that bacteria can evolve to different approaches we develop,” says Balasegaram. “I don’t think we will see a magic bullet solution soon that will definitively solve the issue.” It’s a frightening thought. Mark King has had the clap so many times he’s renamed it ‘the applause’. The first time King had gonorrhoea, he was a teenager in the late 1970s, growing up with his five siblings in Louisiana. He had the telltale signs: burning and discomfort when he urinated and a thick discharge that left a stain in his underwear. King visited a clinic and gave a fake name and phone number. He was treated quickly with antibiotics and sent on his way. A few years later, the same symptoms reappeared. By this time, the 22-year-old was living in West Hollywood, hoping to launch his acting career. While King had come out to his parents, being gay in Louisiana was poles apart from being gay in Los Angeles. For one, homosexuality was illegal in Louisiana until 2003, whereas California had legalised it in 1976. In Los Angeles there was a thriving a gay scene where King, for the first time, could embrace his sexuality freely. He frequented bathhouses and also met men in dance clubs and along the bustling sidewalks. There was lots of sex to be had. “The fact that we weren’t a fully formed culture beyond those spaces… was what brought us together as people. Sex was the only expression we had to claim ourselves as LGBT people,” King says. When he stepped into the brick clinic just a few strides away from the heart of the city’s gay nightlife in Santa Monica, King, with his thick sandy blond hair with a tinge of red through it, looked around the room. It was filled with other gay men. “What do you do when you’re 22 and gay? You cruise other men. I remember sitting in the lobby cruising other men,” King recalls, laughing. “My Summer of Love was 1982. It was a playground. I was young and on the prowl.” Like a few years earlier, the doctor gave him a handful of antibiotics to take for a few days that would clear up the infection. It wasn’t a big deal. In fact, as King describes it, it was “simply an errand to run”. “It was the price of doing business and it wasn’t a high price at all.” But it was the calm before the storm, in more ways than one. When King picked up gonorrhoea again in the 1990s, he was greatly relieved that treatment was now just one dose. Penicillin was no longer effective, but ciprofloxacin was now the recommended treatment and it required only one dose. In King’s eyes, getting gonorrhoea was even less of a hassle. But this was actually a symptom of treatment regimens starting to fail. The bacteria Neisseria gonorrhoeae was on the way to developing resistance to nearly every drug ever used to treat it.§
Recent data collected by WHO examined trends in drug-resistant gonorrhoea in 77 countries – countries that are part of the health agency’s Gonococcal Antimicrobial Surveillance Programme (GASP), a global network of regional and subregional laboratories that track the emergence and spread of resistance. And the results are grim. More than 80 per cent of the countries that reported on azithromycin, a commonly prescribed antibiotic used to treat numerous common infections, including sexually transmitted infections (STIs), found resistance. Of greatest concern is that 66 per cent of countries surveyed have reported cases that resist last-resort antibiotics called extended-spectrum cephalosporins (ESCs). And as Wi points out, the real-world picture is undoubtedly far bleaker, because global surveillance for drug-resistant gonorrhoea is patchy and more frequently done in higher-income countries, which have greater resources. For example, of the 77 countries that were surveyed, few were in sub-Saharan Africa, a region where rates of gonorrhoea are high. “We’re only seeing half of the real picture. We need to prepare for the future when there’s no cure,” Wi says. But in a sign that time is running out, in March this year health experts’ worst fears were confirmed: a case of super-gonorrhoea, dubbed the world’s “worst ever” case, was found in a man who had attended a local sexual health clinic. He had reportedly had sexual contact with a woman in South-east Asia. Health officials said it was the first time this strain could not be cured with any of the antibiotics normally used to treat the disease. Although the patient has since responded to another antibiotic, doctors described him as “very lucky”. It’s an indication of a wider crisis – and one that knows no boundaries.§
Thailand is one country on the front line of the fight against antibiotic-resistant gonorrhoea. It’s a key destination for the sex tourism industry, where STIs like gonorrhoea can spread easily and quickly across borders and beyond. And like many other countries in the region, it has an over-the-counter culture of antibiotic access, which means patients put themselves at risk of being prescribed the wrong drugs – or even worse. I’m in a district close to Thailand’s capital, Bangkok, to meet Boontham, a pharmacist. We meet in the jam-packed stockroom of the herbal medicine company he also runs – a business that’s far more lucrative than his pharmacy. The stockroom is filled head to toe with boxes of tablets containing an array of funky herbs I’ve never heard of. The cost of visiting a doctor and the stigma surrounding STIs mean that many Thais rely on pharmacists like Boontham to cure their gonorrhoea. But he might be doing more harm than good. While Boontham has a degree in pharmacology and has been a pharmacist for more than 30 years, he has no idea of Thailand’s treatment guidelines for gonorrhoea. In fact, he’s more than a decade out of date. And he can’t, of course, diagnose patients accurately, particularly because gonorrhoea has similar symptoms to chlamydia. “If you’ve been doing this for a long time, you just do what you have to, and that’s an educated guess.” “As of now I use ciprofloxacin [to treat gonorrhoea],” he says. “If that doesn’t work, then I guess it’s chlamydia.” I tell him, however, that gonorrhoea in Thailand, as in many other countries, has shown widespread resistance to ciprofloxacin – and that his country actually stopped recommending it more than a decade ago. “It’s not resistant, even doctors use it,” he says. “I prescribe it because it’s cheap. In hospitals they prescribe newer antibiotics that are more effective, but they’re more expensive.” In countries where antibiotics are sold over the counter, research shows people are far more likely to visit pharmacists than a doctor. But while experts acknowledge that restricting the sale of antibiotics – particularly in rural and remote areas where there are few, if any, proper doctors – isn’t the answer, this still presents a major challenge in the fight against drug-resistant infections. “The problem is that when you go to a pharmacist and take antibiotics, maybe… your symptoms have disappeared, but in fact you still have the infection. That means you can transmit the infection and cause more resistance,” Wi says. I ask Boontham whether he’s concerned about resistance – if he’s worried that the people he’s treated for gonorrhoea aren’t cured. “Resistance to medication is a doctor’s job, not a pharmacist’s,” he says. The casual handing out of antibiotics without a prescription is not only confined to Thailand. It’s a huge concern across the rest of the region and in other parts of the world, with no clear vision of how to tackle this growing problem. Handing out antibiotics that likely no longer work for people with gonorrhoea has also been happening in high-income countries – countries that might be expected to have stricter treatment guidelines. In fact, a study published in the BMJ in 2015 found that many GPs in England were prescribing ciprofloxacin, even though it hasn’t been recommended for treating gonorrhoea since 2005. In 2007, ciprofloxacin still made up almost half of prescriptions for gonorrhoea. As recently as 2011, GPs still prescribed it in 20 per cent of cases.§
On a balmy afternoon in bustling Bangkok, I visit Silom Community Clinic @ TropMed, an STI clinic north-east of the city centre dedicated to men who have sex with men (MSM) and transgender women who have sex with men. Located on the 12th floor of the Hospital for Tropical Diseases, the clinic is spotlessly clean, with bright purple walls, rainbow flags and a sign that immediately catches my eye, which reads “Suck, F*ck, Test, Repeat”. Off the main corridor is a microbiology lab that is doing critical and urgent work in the fight against antibiotic-resistant gonorrhoea. In fact, the lab may be the best way Thailand can protect itself from this growing threat. Dr Eileen Dunne is an American epidemiologist and the head of the behavioural and clinical research section of the HIV/STI programme here, which is run as part of a collaboration between Thailand’s Ministry of Public Health (MOPH) and the US Centers for Disease Control and Prevention (CDC). She, along with her Thai staff, are Thailand’s best line of defence in slowing gonorrhoea resistance. In 2015, recognising the worldwide danger of increasingly difficult to treat gonorrhoea infections – and the specific threat they posed to Thailand – the US CDC, WHO and Thai MOPH joined forces to launch a programme to track and ultimately limit the spread of antibiotic-resistant gonorrhoea. The programme is an enhanced local version of the WHO’s GASP and is the first of its kind in the world. It’s called EGASP. It works like this. If a male patient comes into one of its two clinics with the telltale symptoms of gonorrhoea, he will have a sample collected for analysis and will fill out a questionnaire, which contains questions such as: “Did you take antibiotics in the last two weeks?” To create an open environment, the clinics are anonymous and the questionnaire is done privately on a computer. Men are the target group in the programme, Dunne explains, because the yield for isolating N. gonorrhoeae is very high among men who have urethritis compared with women and those who are asymptomatic. MSM are an important population, she adds, because research shows they are likelier to develop resistance earlier than the general population, for reasons that aren’t precisely known. She and the laboratory staff take me to see if there are any samples being cultured from swabs taken from patients’ penises. Inside the incubator, where the samples are kept in Petri dishes at 36 degrees Celsius with 5 per cent carbon dioxide to promote bacteria growth, there are three. The stench of agar, a brown gelatinous medium that provides nutrients and a stable environment for bacteria to grow, is overwhelming. One Petri dish contains a cluster of bubbly white dots, signalling that the patient does indeed have gonorrhoea. The next step is antibiotic susceptibility testing (AST) at a lab downstairs. The isolate will be measured for resistance to five antibiotics, including ciprofloxacin and the last-resort drugs cefixime and ceftriaxone. It’s resistance to these latter two which is of greatest concern. From the beginning of EGASP until 20 October 2017, of the 845 confirmed diagnoses of gonorrhoea that underwent AST, almost all isolates had widespread resistance to ciprofloxacin, as in many other countries. But encouragingly, none have shown resistance to the last-line drugs. That’s a relief for Thailand, but in no way an indication that Dunne and her team’s alacrity should wane. “People are surprised and have asked, ‘Oh, why are you doing this if you don’t show resistance?’,” Dunne says. “It’s actually good to do surveillance and not be detecting resistance yet. It means that we’re early enough to be prepared… and [to] have a plan of response. “Having strong surveillance activity in a region in which this is likely to emerge is important so we can detect it early.” Thailand’s neighbours, specifically Myanmar, India, Indonesia and China, have recorded a significantly higher percentage of gonorrhoea isolates that are resistant to last-line treatments compared to Thailand. With the increasing movement of people around the world and Thailand’s popularity for sex tourism, I can see just how rapidly this threat could have far-reaching consequences. “I think it’s really important to detect early, even one case, [because] it can be a harbinger for future developments of resistance. These bacteria are transmitted very rapidly between people. Being able to really find that one case early means that special steps can be in place to control transmission,” Dunne says. I ask if the focus on MSM means other groups might be being missed. What about women, who are more likely than men to not experience any gonorrhoea symptoms? Or itinerant sex workers from across the border in Myanmar and Cambodia? I wonder if, among this high-risk group, EGASP is missing some of Thailand’s most vulnerable. I ask if there’s potential for the programme to extend its work to include these people and their partners. Dunne agrees it’s a good idea. “This targeted approach in men with symptoms is purposeful but may not be generalisable to the whole population. It’s the tip of the iceberg.” But it’s early on in the programme, and she and the team have to start somewhere. “We need more time,” she says. But no one is really sure how much time Thailand – and the rest of the world – has.§
The number of people infected with gonorrhoea has risen rapidly in recent years. Australia has seen a 63 per cent increase in the number of reported gonorrhoea cases since 2012, with the fastest rate of increase being in young heterosexual urbanites. In England, gonorrhoea cases rose by 53 per cent between 2012 and 2015, led by young people, gay men and other MSM. Meanwhile, in the USA cases rose by nearly 50 per cent between 2009 and 2016. And according to some experts, one of science’s greatest achievements in the fight against HIV could be a factor. Like many, Mark King’s nonchalant attitude towards sex had come to a halt when the HIV epidemic hit the gay community in the USA. No longer was gonorrhoea simply seen as a small, insignificant price to pay for a night of fun. “Half the fun of being gay [was that] you didn’t have to worry about birth control. Condoms were birth control, not STI control,” says King. “[But] as the years passed and you get into the 90s and we know how HIV is transmitted, to get gonorrhoea is shameful because it means that you’ve been taking risks that could transmit HIV. “Suddenly gonorrhoea became this really shameful thing because it means you’re not doing the right thing.” Move forward to today and HIV is no longer the death threat it once was. A strong civil society movement saw the disease get the political – and scientific – attention it warranted. The development of life-saving drugs means that those with HIV can live long, healthy lives. But as HIV treatment and prevention methods improve, people’s perception of risk may be changing. Pre-exposure prophylaxis (PrEP) is a daily pill for people who don’t have HIV but who are at substantial risk of getting it. It’s a powerful tool in the fight against HIV, it is argued. When taken every day, it’s up to 92 per cent effective in preventing infection. But with its development and uptake came alarm bells, with some warning that STI rates would increase among those who used PrEP. Some small studies have hinted that this may be happening. Not all experts agree with this. The data from these studies is ambiguous and cannot be generalised. And some say that regular testing regimes associated with PrEP prescriptions could prevent STIs spreading. However, just as with antibiotics, there are people using PrEP without getting it through official health outlets. A recent survey carried out across Europe by the HIV/AIDS advocacy group AIDES found that about 70 per cent of informal PrEP users were having no regular medical monitoring. King is one of many for whom concerns over STIs in the broader context of having the incredible ability to prevent HIV infection seems absurd. “PrEP opens the door for people to have sex without fear of HIV infection. The reaction is: yes, but what do we do about STIs? Oh my god, gonorrhoea and syphilis,” King says sarcastically. “People ask me, how does a person get HIV or gonorrhoea in this day and age? Well, let’s see: because they were horny, or they said yes when they should have said no, or they had too much to drink, or they fell in love, or they trusted the wrong person.” King’s words may resonate with many around the world. But WHO is focused on increasing condom use. Wi is particularly worried about the proliferation and popularity of dating apps among young people, which she believes are making no-strings-attached sex easier to obtain. “All of us need to be strong about condom use. All of us need to campaign for condom use,” Wi says.§
Looking ahead, at what point will it be more common to have a gonorrhoea infection that can’t be treated with antibiotics than one that can? The answer is difficult to predict, but it’s also a potential reality that isn’t far-fetched. “We are in a situation now where we are worryingly using the last line of antibiotics for many infections or seeing even resistance to these last-line antibiotics,” Balasegaram says. But as GARDP works to bring a new antibiotic to market, some countries are getting desperate as resistance to the available treatments continues to spread. Australia, which has recorded widespread resistance to azithromycin, is considering going back to an old drug called spectinomycin. Spectinomycin involves a painful muscular injection and has been linked to toxicity and a range of side-effects. Another concern is that it’s in short supply because it’s rarely used around the world any more. To this end, R&D for new antibiotics is urgent. But antibiotic drug development is prohibitively expensive and not attractive to the pharmaceutical industry – even more so when it’s for an STI. In response, GARDP has partnered with Entasis Therapeutics, a US biotech company, to accelerate the development of a new antibiotic that will be produced specifically to target drug-resistant gonorrhoea. Zoliflodacin is a novel first-in-class oral antibiotic – in other words, a new and unique mechanism of potentially treating gonorrhoea – and is one of only three potential new antibiotic candidates currently undergoing trials. It had previously been put through clinical trials in 2015, but a lack of investment stopped the drug from progressing further. This year GARDP and Entasis will launch the last phase of trials of zoliflodacin, involving 650 people in Thailand, South Africa, the USA and parts of Europe. If the drug is approved by regulators, Entasis will permit GARDP to introduce it in 168 low- and middle-income countries. It’s hoping it will be registered by 2021 and available on the market by 2023. A major strength of the partnership between GARDP and Entasis is that it will be able to limit what infections zoliflodacin is used for. “We’re trying to focus this drug specifically on STIs – not other community infections where antibiotics are widely used,” Balasegaram says. “The aim is not to go beyond that because that’s how resistance starts.” To this end, initially the drug will be licensed only for use against gonorrhoea infections. If it proves to be effective against chlamydia and Mycoplasma genitalium (another bacterial STI), the GARDP and Entasis partnership could license it for those two infections as well, subject to clinical trials. “We will support clinical trials and registration and therefore we can play a big role in how it is responsibly introduced and used. That gives us more control in how the drug is introduced and marketed in the countries where we work,” says Balasegaram. Dunne is excited that Thailand will be part of the trials. “It is the underbelly of infections. It doesn’t get the attention it deserves and that is why this is exciting,” she says. A lot is riding on the success of the drug. Will zoliflodacin be successful in remaining effective for as long as possible? Or will it face the same fate as other antibiotics? Moreover, research is risky – there’s no guarantee the clinical trials will be successful. “We still don’t know whether this project will succeed or not,” says Balasegaram. “But it’s a project that we feel is extremely important and that we’re very committed to.” The development of new antibiotics raises myriad questions: How can we ensure they are used appropriately so we can preserve their effectiveness? And how can we ensure those who really need the drugs get them? One way would be a point-of-care rapid diagnostic test – ideally one that could predict which antibiotics will work on a particular infection and that could be used in settings around the world. Balasegaram says they’ve been looking for a simple diagnostic tool like this but haven’t yet found one. Diagnostic tools aside, the responsible use of new antibiotics also relies on robust national and international treatment guidelines and strong regulatory authorities to guide and monitor antibiotic use. “If you have developed an antibiotic for narrow use, you have to think about how to market the drug. We do not want to drop large quantities of it around the world. But we also want to make sure those who need it get it,” he says. This is where strong surveillance programmes, like Thailand’s, are critical. But it’s inevitable that bugs will develop resistance to the next antibiotic and then the next. So Balasegaram wants more investment in R&D that focuses not only on new antibiotics but also on alternative ways to treat bacterial infections. “We have to continue to do R&D into… therapeutic ways to treat these infections differently,” he says. “This may include novel and non-conventional approaches. I think that is a job that is going to last decades.” What that might look like is complex. It may include designing antibodies that specifically target bacteria or using bacteriophages – viruses that infect bacteria – as a replacement for antibiotics. Either way, many feel that the end of the antibiotic era is near and that the transition from antibiotics to non-traditional treatments poses major challenges that won’t be easy to solve. “It’s worth bearing in mind that bacteria can evolve to different approaches we develop,” says Balasegaram. “I don’t think we will see a magic bullet solution soon that will definitively solve the issue.” It’s a frightening thought. This article first appeared on Mosaic and is republished here under a Creative Commons licence.
