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The evolution of antibiotic resistance

Craig MacLean, Professor of Evolution and Microbiology at Oxford's Department of Zoology, explains how evolutionary biology can help us to get rid of antibiotic resistant bacteria.

Bacteria are tiny single cell organisms, invisible to the naked eye, that live in essentially every possible habitat on our planet. Plants and animals are covered with microorganisms, the soil and the oceans are teaming with bacteria, and it is estimated that bacterial cells actually outnumber human cells in the body by a factor of 10-100:1. The overwhelming majority of bacteria are completely harmless, but a small minority of pathogenic bacteria can cause infections in humans. For most of human history, bacterial pathogens have been a major cause of disease and mortality. For example, the plagues that ravaged Europe in the middle ages were caused by the bacterium Yersinia pestis, and tuberculosis, and cholera outbreaks are caused by the bacterium Vibrio cholera.

The development of antibiotics in the 1940s provided a simple and effective treatment for many bacterial infections; for example, antibiotics decreased the mortality rate associated with serious cases of pneumonia from 90% to 10%. Given these stunning results, many prominent members of the medical community, including the US Surgeon General, thought that antibiotics would effectively make bacterial disease a thing of the past. Against this background of boundless optimism, researchers had already discovered that bacteria could become resistant to antibiotics and Alexander Flemming, who led the team that discovered penicillin, warned that the misuse of antibiotics would lead to the rise of resistance, rendering antibiotics ineffective.

Antibiotics have now saved millions of lives, but the large-scale use of antibiotics has driven the spread of resistance, as predicted by Flemming. Pathogenic bacteria have evolved resistance to all of the main classes of antibiotics and pan resistant bacteria have caused untreatable infections. Resistance already imposes a substantial health and economic burden, and an influential report published by the O’Neill commission in 2016 predicted that resistant infections could cause 10 million deaths per year and impose a global financial cost of 100 Trillion USD by 2050 .Given this threat, resistance has been identified as one of the most important global challenges by organisations such as the United Nations, The G8 and even the International Monetary Fund.

The spread of antibiotic resistance in pathogenic bacteria is a simple and elegant example of evolutionary adaptation by natural selection. Bacteria can become resistant to antibiotics through mutations that alter the cellular targets of antibiotics or by acquiring dedicated resistance genes from other bacteria. The acquisition of resistance is a very rare event; for example, resistance mutations usually occur in less than 1 in a million bacteria. However, resistant bacteria can continue to grow and reproduce under antibiotic treatments that effectively paralyse or kill their antibiotic susceptible neighbours – this is Darwinian natural selection in its simplest and cruellest form. Rare resistant strains can rapidly come to dominate pathogen populations under antibiotic treatment, and, in a worst-case scenario, these resistant bacteria can then go on to infect other people.

This simple sketch shows how evolution drives the spread of resistance, but it leaves out many important details. Evolutionary biologists and microbiologists have become increasingly interested in understanding the processes driving the spread and maintenance of resistance. These studies have addressed a wide-range of important questions, such as: What limits the transmission of resistant bacteria between people? How does the strength of antibiotic treatment influence the likelihood of resistance emerging? Can antibiotic cocktails be used to suppress the evolutionary advantage of resistance? How do resistance genes move between bacteria? We now have quite a mature theoretical framework for thinking about these important questions. The problem, however, is that the largely theoretical approach the evolutionary biologists have taken to resistance is not very well connected to the reality of resistance in the clinic.

In the last 15 years, technological innovations have massively improved our ability to sequence the genetic code of all living organisms, especially bacteria. Sequencing the genomes of pathogenic bacteria isolated from infections has provided a much clearer picture of how resistance emerges and spreads, especially in hospitals. In many important human pathogens, the global increase in the prevalence of antibiotic resistance has been driven by the epidemic spread of a relatively small number of highly resistant ‘superbugs’ that transmit between people, such as MRSA Staphylococcus aureus and XDR Mycobacterium tuberculosis. If evolutionary biology is going to help contribute to stopping the spread of antibiotics resistance, the field is going to need to shift emphasis towards understanding the specific processes that have driven the emergence of the superbugs.

For more information, read: 'The evolution of antibiotic resistance' in Science.

The grooved Nepenthes peristome

By Jian Guan, Finn Box and Chris Thorogood

Our understanding of how to manipulate and control liquids in technology has been transformed by the functional surfaces evolved by living organisms to interact with their environment. Water-repellent lotus leaves, water-collecting wing-cases of desert beetles, and water-removing gecko skin are some of the many organisms that have inspired solutions to challenges in liquid manipulating technologies. The requirement for liquid-repellent surfaces infiltrates industries from architecture, to medical devices, and household products.

The carnivorous Nepenthes trapThe carnivorous Nepenthes trap
Lubricated surfaces in a technological context are referred to as Slippery Liquid-Infused Porous Surfaces (SLIPS). They lock in water and create a self-cleaning surface on metal, plastic and textiles to repel contaminants. Interestingly, SLIPS technology is inspired by the slippery surface of a carnivorous pitcher plant (Nepenthes). Pitcher plants produce pitfall traps, derived from leaves, to attract, capture, retain, kill and digest animal prey (usually insects) to enable them to survive in nutrient-poor environments. A key trapping feature of the pitcher is the peristome, which has sloping, macroscopic ridges, in turn made up of microscopic ridges. When wetted, the peristome becomes highly slippery which leads insects to slide off it, into the trap, where they become broken down within a pool of digestive juices, releasing nutrients for the plant.  

A shortfall in SLIPS has been the lack of drop-solid interaction, which means that controlling the motion of liquid droplets upon their surfaces is inherently difficult. Importantly, this lack of controlled droplet transport has limited the application of these liquid-shedding surfaces in droplet-based technologies. Mechanisms for harnessing the directional transport of droplets will be important for informing the design of synthetic surfaces that transport droplets in a controlled way. Such mechanisms could be applied to technologies such as rainwater harvesting and anti-fogging coatings, as well as to rapidly expanding new technologies such as Micro-Electro-Mechanical Systems (MEMS) and digital microfluidic devices.

Examining functional surfaces in nature may also offer insights into the evolution of natural systems. Whilst the trapping mechanism of carnivorous pitcher plants is well documented, the functionality of the grooves on the peristome surface remains relatively unexplored. In our recent paper, we show that capillary action pins droplets to the parallel, water-infused grooves, and directs their transport in a controlled way. This indicates that the ‘pitfall’ trapping mechanism is enhanced by the water-infused, grooves on the slippery peristome surface, which drive prey into the trap in a way that is more tightly controlled than considered previously, and avoid arbitrary slippage.

Based on our observations of ants, Drosophila flies, and droplets sliding on the slippery peristome, we created artificial surfaces, inspired by the plant, capable of trapping, retaining and directing the travel of liquid droplets. We created various models including steps and trenches, upon which we positioned liquid droplets and observed their behaviour. Droplets in contact with ‘features’ (analogous to the grooves on the natural peristome) became strongly adhered and would not detach easily, but were free to slide along the feature.

In other words, the features had a strong retention influence. They trapped and retained the droplets, even when held upside down, and controlled the direction of droplet travel. Furthermore, the droplets would slide along the grooves at remarkable shallow angles – even just a few degrees. These findings reveal a potential mechanism for developing systems in which the transport of droplets is guided by curved ‘energy railings’. These would provide a biomimetic means of transporting and sorting droplets that is straightforward to implement in droplet-based fluidic devices and could enable the efficient mass transport of liquids along pre-determined pathways.

Find out more about the work of Jian Guan.

Read the full paper in The Royal Society: 'Guided droplet transport on synthetic slippery surfaces inspired by a pitcher plant'.

Saiga

By Hunter Doughty

The saiga is a Star-Wars looking Critically Endangered antelope from Central Asia, whose horn is used in traditional Chinese medicines (TCM). Last month, a new ruling by the Convention on International Trade in Endangered Species of Wild Fauna and Flora strengthened trade regulations around saiga product exports. However, conservationists have argued (for numerous unsustainably used wildlife products, such as elephant ivory and rhino horn) that demand reduction and not just trade regulation, is vital to long-term, effective solutions. And unfortunately, this consumer-focused attention is still limited for many lesser known species, like the saiga, that are being impacted by poaching.

Saiga horn as medicinal remedySaiga horn sold as medicinal remedy

Saiga horn is mainly used to treat fever and heatiness (a TCM state of illness with symptoms like nasal congestion and sore throat). Poaching of saigas in the 1990s took out more than 95% of the population, and poaching still persists today, despite many policy and on-the-ground efforts from range states and international bodies. In addition to this hunting pressure, saigas have also been heavily impacted in recent years by mass bacterial and viral disease outbreaks.

To address the dire attention gap around saiga horn consumers, our work, published today in PLOS One, represents the most extensive research to date on a saiga consumer population. We conducted over 2200 consumer surveys in Singapore with members of the general Chinese Singaporean population. Singapore is recognised as a top saiga consumer country, and within the country, legal-with-permit saiga horn products are marketed most commonly as ling yang (羚羊), antelope’s horn, or "Cornu Saiga tataricae".

Through our work we found that 19% of respondents were high-level saiga horn users. This means that they consider saiga horn to be a product they use most often to treat heatiness or fever in themselves and others. Additionally, 47% of individuals who buy saiga horn for themselves were also buying it for someone else. We saw that saiga horn users were most likely to be middle-aged Buddhist or Taoists, however, horn use was seen across almost all demographic groups. 

Consumer research like this one is a first and neccesary step in demand reduction efforts. By thoroughly understanding a user group you can more accurately design behavioural interventions targeting unsustainable consumption, or really any undesirable behaviour. Such evidence-based interventions are being conducted every day in fields like public health and development, targeting behaviours that range from alcohohism, to poverty alleviation, and excessive meat consumption.

One key insight we found, for instance, is that TCM shopkeepers and an individual’s family are the most likely people to have recommended saiga horn to someone, thus these are the influencers that can be utilised in a behavioural intervention. Shopkeepers, for example, fill a similar role as a western pharmacist, and pharmacist-dessiminated health interventions are a common tool that a shopkeeper-disseminated intervention could be based on. 

We also found that saiga horn users had a greater overall propensity for perceiving animals that are used in TCM as being common in the wild (regardless of the animals’ actual conservation status), and that this difference was especially significant for saiga. Identifying an awareness gap like this one gives a clear possible angle for a future project message that strives to drive up conservation concern in a socially relevant way.

Saiga hornSaiga horns for sale
Lastly, given that there are many common alternatives to saiga within TCM, such as barley, honeysuckle, and goat’s horn, and that these options are readily available and afordable in Singapore, encouraging consumers to use more sustainable products is a viable option for demand reduction efforts.

Saiga horn use in Singapore is extensive, and non-negligible. And if attention remains solely on the supply-side of an unsustainable or illegal wildlife trade, then the root of the problem - consumer demand - will continue to drive poaching until there are no individuals left to poach.

Hunter Doughty is part of the Department of Zoology and this research features in the Oxford Martin Programme on the Illegal Wildlife Trade.

Read the full paper, 'Saiga horn user characteristics, motivations, and purchasing behaviour in Singapore'.

An sp-hybridized molecular carbon allotrope

By Katharina Kaiser, Fabian Schulz, and Leo Gross (IBM Research - Zurich); Lorel M. Scriven, Przemyslaw Gawel and Harry L. Anderson (Oxford University)

Carbon, one of the most abundant elements in the universe, can exist in different forms - called allotropes - giving it completely different properties from color to shape to hardness. For example, in a diamond every carbon atom is bonded to four neighboring carbons, whereas in graphite, every carbon atom is bonded to three neighboring carbons.

While these are well studied forms of carbon, there are lesser-known forms and one in particular has been elusive – cyclocarbons, where the carbon atoms have only two neighbors, arranged in the shape of a ring. Discussed for many years, their structure was unknown, and two possibilities were debated, either with all the bonds in the ring of the same length or with alternating shorter and longer bonds. Adding to the drama, evidence for their existence was published in the gas phase, but due to their high reactivity, they could not be isolated and characterized – that is until now.

Based on our previous successes in imaging molecules with atomic force microscopy (AFM) and creating molecules by atom manipulation, scientists from the University of Oxford's Department of Chemistry and IBM Research attempted to find the answer to this debate. Our goal was to synthesize, stabilize and characterize cyclocarbon.

And for the first time, we have succeeded in stabilizing and imaging a ring of 18 carbon atoms.

Our approach was to generate cyclocarbon by atom manipulation on an inert surface at low temperatures (5 K) and to investigate it with high-resolution AFM. We started the collaboration between the groups of Oxford and IBM three years ago with this goal. Initially, we focused on linear segments of two-fold coordinated carbons, exploring possible routes for creating such carbon-rich materials by atom manipulation. We triggered chemical reactions by applying voltage pulses with the tip of the atomic force microscope. We found that such segments could be formed on a copper substrate covered by a very thin layer of table salt. Because the salt layer is chemically very inert, the reactive molecules did not form covalent bonds to it.

After the successful creation of the linear carbon segments, we attempted to create cyclocarbon on the same surface. To this end, the Oxford group synthesized a precursor to cyclo[18]carbon that is a ring of 18 carbon atoms.

Future applications are suggested by the fact that we could fuse cyclocarbons and/or cyclic carbonoxides by atom manipulation. This possibility of forming larger carbon rich structures by fusing molecules with atom manipulation opens the way to create more sophisticated carbon-rich molecules and new carbon allotropes. Eventually, custom-made molecular structures might be used as elements for molecular electronics, based on single electron transfer.

Airplane taking off

By Professor David Banister

In the UK, there is a legal commitment to reducing the net carbon account for all six greenhouse gases by 80 per cent (1990-2050) under the Climate Change Act 2008, and recently this target has been raised to 100 per cent. By 2050 UK greenhouse gas emissions will be cut to net zero. At present the aviation sector has been allowed to set and deliver voluntary targets. As globalisation progresses, more goods and people are being transported further and more frequently at ever-increasing CO2 costs. The aviation sector accounts for 7.3 per cent of UK CO2 emissions, but by 2050, aviation may account for over 20 per cent of all UK CO2 emissions. This radically changing position is a combination of other sectors reducing their levels of CO2 emissions whilst international aviation’s share of the total continues to increase.

This pattern of growth in long distance travel is not just restricted to the UK, but it is characteristic of all developed and many emerging economies. Globalisation has shrunk the planet, and society is now dependent on long distance and high quality supply chains as continued specialisation and concentration of production has kept prices low. Business practices have been transformed, but it is for leisure activities, together with visiting friends and relatives, that are now the fastest growing sectors of international travel. Leisure travel and visiting friends and relatives now account for about 85 per cent of UK air travel.

International aviation cannot be excluded from making a substantial contribution to CO2 reduction, as many planes will still be in operation in 2050. Offsetting emissions is not a solution to the problem, as it only serves to delay having to make more fundamental decisions. Substantially increasing the costs of flying through taxation on aviation fuel and through charging VAT on tickets, together with appropriate measures to account of the emissions at high altitude, will all help. But the only means to significantly reduce aviation CO2 emissions levels is to fly less.

The options available to reduce emissions for aviation are very limited, with some scope for electric or hybrid planes, alternative fuels (e.g. biofuels), lighter-weight materials, innovative design, improved fuel efficiency, and more efficient air traffic control and routing. But the main problem is the scale of change required and the time frame needed for effective action. The aviation industry has failed to address the climate crisis in terms of new aircraft or its operating practices.

Globally, this inaction is compounded by more aviation capacity is being constructed. The third runway at London Heathrow is currently going through its final stages of approval, and this will increase the number of annual flights from 473,000 to 740,000 (+56 per cent) and passenger numbers from 78m to 130m (+67 per cent). Currently London Heathrow produces 20.83 Mt CO2e each year, about 95 per cent of which can be attributed to flights (PEIR, 2019), and that with the expected growth in travel CO2 emissions will increase by about a half, even with optimistic assumptions on the introduction of technological innovations. Expansion on this scale at one major airport makes the UK net zero target unachievable.

Heathrow will offset all increases in CO2 emissions thought the UN Corsia scheme that is being introduced as a pilot scheme in 2021, with the voluntary first stage starting in 2024, and a subsequent mandatory phase in 2027, prior to a review in 2032. Yet there is very little detail on the exact rules to be followed, on eligible offset projects, and on the links with the existing EU Emissions Trading System. The International Coalition for Sustainable Aviation have calculated that only 6 per cent of all projected CO2 emissions from international aviation (2015-2050) will be covered. Such an imprecisely specified scheme will have no real impact for at least 10 years, and by that time projected CO2 emissions from aviation could have doubled.

There are huge inconsistencies between the rhetoric and the reality. It is hard enough to set the targets for reductions in CO2 emissions, but decisions are still being made to increase capacity. Such a strategy is entirely at odds with the net zero emissions targets. It is no longer only a matter of economics, but one of societal values, social pressure and personal choice. It is ultimately one about the quality of the life now and in the future, and the consequences of not addressing the climate crisis in a connected and holistic way that accepts the complexities and interactions between all decisions made.

David Banister is an Emeritus Professor of Transport Studies at the School of Geography and the Environment, University of Oxford.