Antibiotic resistance: a challenge to rival climate change

Dr Clare Sansom, Senior Associate Lecturer in Birkbeck’s Department of Biological Sciences reports on a recent, international capacity-building workshop to tackle antimicrobial resistance and accelerate new antibiotic discovery, sponsored by the global challenges research fund (GCRF). 

Credit: Mr Harish Patel

Antibiotic resistance is one of the most serious threats to global health: some commentators have even rated it as important as climate change. It is, however, one that the research community – particularly in the academic and not-for-profit sectors – is finally investing serious resources in tackling. Research into novel antibiotic targets and the compounds that can interact with them is burgeoning throughout the world. At Birkbeck, research in the ISMB-Microbiology Research Unit, headed by Professor Sanjib Bhakta focuses on tackling antibiotic resistance in priority bacterial pathogens, the causative agent of a number of global infectious diseases.

In July 2019 Prof Bhakta invited his collaborators in the UK and overseas to a workshop at Birkbeck to discuss ways of tackling drug resistance. This was funded through the UK’s Grand Challenges Research Fund (GCRF), an initiative to promote the welfare of developing countries through international research. Delegates were welcomed by Birkbeck’s Pro-Vice-Master for internationalism, Professor Kevin Ibeh, and then heard brief presentations from Dr Sarah Lee on the place of the GCRF in Birkbeck’s research portfolio and Dr Ana Antunes-Martins on the mission of the neighbouring London International Development Centre. This combines the resources of seven University of London institutions in the Bloomsbury area, including Birkbeck, to support interdisciplinary research, capacity building and public engagement for international development.

In an intense scientific session, the first researcher to speak was Professor Nicholas Keep, Executive Dean of the School of Science at Birkbeck and a structural biologist. He presented some structures of Mycobacterium tuberculosis proteins known or believed to be novel prospective therapeutic targets that had been solved at Birkbeck or UCL using the three main techniques of structural biology: X-ray crystallography, nuclear magnetic resonance (NMR) and electron microscopy (EM). These included a small enzyme called resuscitation-promoting factor, which is necessary for the bacteria to emerge from their dormant state, and a rather larger one that synthesises an important component of the cell wall. This work is enabled by excellent local facilities including a new Titan Krios microscope in Professor Helen Saibil’s EM lab, and even more powerful national and international ones.

Beta-lactamase enzymes, which inactivate drugs in the penicillin family, are one of the most common antibiotic resistance mechanisms, but they are not as well understood in mycobacteria as they are in some other human pathogens. Prof Anindya S. Ghosh from the Indian Institute of technology in Kharagpur – incidentally, the speaker who had travelled the furthest – described his group’s work in collaboration with Prof Bhakta and Prof Tabor’s lab (funded by a Newton-Bhabha international fellowship to Sarmistha Biswal at Birkbeck this year) in designing inhibitors for beta-lactamases and other proteins that interact with penicillins and prevent their antibiotic action. He set out several more opportunities for collaborative research, including finding molecules that prevent the formation of drug-resistant microbial biofilms.

The next two speakers came from continental Europe, and both described novel natural sources of potential anti-infective drugs. Prof Franz Bucar from the University of Graz, Austria focused on drugs from plant and fungal sources, including an intriguingly named flavonoid, skullcapflavone II (derived from the poisonous skullcap mushroom). This and other recently discovered natural products were also highlighted on a poster by Prof Bucar’s doctoral student, Julie Solnier.  Prof Ester Boix from Universitat Autònoma de Barcelona in Spain described how the antimicrobial peptides that we synthesise as a defence against bacteria might be harnessed as drugs. Her group has used the HT-SPOTi assay developed in Prof Bhakta’s group at Birkbeck to screen human ribonuclease peptides against macrophages infected with Mycobacterium tuberculosis.

Dr Jody Phelan and Prof Taane Clark from the London School of Hygiene and Tropical Medicine asked – and answered – the question ‘What can the M. tuberculosis genome tell us about drug resistance in TB?” This bacterial genome contains over 4 million base pairs of DNA and about 4,000 genes, compared to the 3.3 billion base pairs and 20,000 genes of the human genome. Resistance to any of the over 10 drugs currently used to treat the disease arises largely when treatment is irregular or stopped too soon, and the genetic changes responsible for each type of resistance can be identified rapidly using whole genome sequencing. It is now possible to use this in clinical practice to predict which drugs a given strain is most likely to be resistant to, and thence to recommend a personalised course of treatment for an individual patient.

Dr Simon Waddell from the University of Sussex in Brighton described how the RNA molecules transcribed from the M. tuberculosis genome change during the lifecycle and with the environment of the bacterium, and how this analysis, known as transcriptomics or RNA profiling, can both track and predict responses to drug therapy. One new compound, a benzothiazinone discovered through a high-throughput screen, was found to induce transcription from the same set of genes as cell-wall synthesis inhibitors, suggesting that it is likely to act against the bacterium through the same or a similar mechanism.

These two ‘omics talks were followed by two extremely short ones by scientists based in the Department of Chemistry at University College London. Dr Rachael Dickman (from Prof Alethea Tabor’s lab in UCL) is developing potential antibacterial agents based on a complex amino acid, lanthionine. These ‘lantibiotics’ bind to Lipid II, which is formed during cell wall synthesis, and therefore act as inhibitors of that synthesis. Professor Helen Hailes described the antimicrobial properties of a series of isoquinolines that selectively inhibit slow-growing mycobacteria and that may also potentiate the activity of other drugs by preventing their efflux from bacterial cells.

With the last talk, by Prof Matthew Todd of the UCL School of Pharmacy, the workshop moved from pure science to begin to discuss the economics of drug discovery. Prof Todd’s open source drug discovery work, which began with a project on malaria, is completely open: all the data is freely available, all ideas are shared, no results are ‘owned’ by any of the researchers and there will be no patents. It is a timely approach and one that can involve anyone – Prof Todd has recently been awarded a grant by the Royal Society to work with teenagers at Sevenoaks School to develop new antifungals – and one that might, perhaps, help any of the academic groups represented at the workshop turn their novel ideas into drugs that are useful against the killer disease.

The final networking session was accompanied by an engaging talk by me, Dr Clare Sansom, about the important issue of communicating the challenge of antimicrobial resistance to non-scientists. This was illustrated with frightening scenes from fictional accounts of possible post-antibiotic futures and included a quiz that many of the experts present found surprisingly challenging. This workshop was organised in collaboration with the Commonwealth Scholarships Commission, UK and approved by the Royal Society of Biology for continual professional development credit.

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Science Week 2019: engineering a dinosaur

Dr Clare Sansom, Senior Associate Lecturer in Birkbeck’s Department of Biological Sciences reports on the 2019 Rosalind Franklin Memorial Lecture, delivered by Professor Emily Rayfield on how computational tools are reshaping our understanding of form and function in fossil animals.

Since 2016, the School of Science at Birkbeck has held an annual lecture named for one of its most distinguished alumni, Rosalind Franklin. This lecture, which is always given by a notable woman scientist, forms part of the school’s Athena SWAN programme. Each Rosalind Franklin lecturer’s research field is closely aligned to one of the three departments that make up the School, Biological Sciences, Earth and Planetary Sciences, and Psychological Sciences. This was the year of the earth sciences, and the lecturer, Emily Rayfield, was a professor of paleobiology at the University of Bristol. She gave an engaging talk about how computer modelling is helping us understand the biology and behaviour of fossil animals, beginning with the dinosaurs.

Emily drew a contrast between the techniques used to study living animals and prehistoric ones. With living animals, there is a chance, at least, that we will be able to observe their behaviour, but with prehistoric ones all we have to go on is the fossils they leave behind. So how can we approach a question such as, what – and how – did dinosaurs eat? We can begin to understand this problem by relating the skulls, and particularly the jawbones, of living animals to their diets. Plotting the measured bite force of reptiles’ jaws, including those of the closest living relatives of dinosaurs, the crocodiles and alligators, against the size of those jaws, and then scaling up to the size of dinosaur jaw bones has suggested that the largest would have had a bite force of over 10 tonnes.

It is possible to get some idea of what fossil animals ate by, literally, looking at their dung. Fossilised faeces, or coprolites, are frequently found, and geologists can estimate the size of the creatures that produced them, as well as finding clues to their diets. The largest that have been seen are likely to have come from Tyrannosaurus rex. This monster, one of the largest land-dwelling carnivores that ever lived, measured over 40’ from nose to tail and stood about 12’ tall at the hips. Skeletal fragments found in dinosaur coprolites include those from some of the first birds. Fossilised bite marks and teeth, which differ in shape and size between herbivorous and carnivorous animals, can also fill gaps in the picture of dinosaur diets.

Feeding is only one aspect of animal behaviour, although an important one. Emily opened out her question to ask what the shape of an extinct animal’s bones can tell scientists about its behaviour more generally. Bones all respond to externally applied forces of stress (load per unit area) and strain (stretch per unit length). Wolff’s Law, which dates from 1892, states that any change in the function of bones, and therefore in the stresses and strains that they are exposed to, is directly followed by changes in their shape. In human terms, if an individual overloads his or her bones by, for example, taking up a strenuous sport, the bones will gain mass, whereas disuse will cause bone loss in astronauts exposed to low gravity as well as the chronically sick.  Mechanical loads experienced in utero affect the shape of the developing embryo and, going back to the example of feeding, animals that experience different diets develop different-shaped jaws. This can be observed in individuals of the same species, with mice raised on only soft food developing less efficient jaws than those raised on hard pellets. It is also reflected in species differences in both living and extinct animals: animals and their environments may have changed dramatically since ‘deep time’, but the laws of physics – and the basic structure of the cells and tissues they operate on – have not.

It is, of course, impossible to measure the stresses and strains that a dinosaur bone will have been subjected to, but it is not impossible to deduce them. This is where computers come in, via a mathematical technique known as finite element analysis.  In this, a complex structure is broken down into a number of simple shapes. A force is applied to each element and a computer program is used to estimate how it moves and changes shape.

To apply this technique to a fossil, you need to start with a digital model of that fossil, and this can now be done quite easily using a CAT scanner similar to those used in medicine. The model is then completed by adding any bones missing from that specimen. The model is combined with information from living relatives to estimate the stresses and strains on the bones.

Professor Emily Rayfield

Armed with all this data on the forms of, and loads experienced by, dinosaur skulls, it is possible to ask complex questions about their mechanics and evolution. It is now quite well known that modern birds evolved from a group of dinosaurs, and this begs the question of how they evolved their characteristic, but extremely diverse, beaks. Some herbivorous dinosaurs in the group known as the theropods (three-toed) had beaks and comparing models of similar sized dinosaur skulls with and without beaks has suggested that a beak reduced stress and strain during feeding. Large theropods were found to have experienced proportionally lower stress during feeding than smaller ones, with the exception of Spinosaurus, which had much higher stress than expected for its size.

At the end of the lecture, Emily moved on from the largest land-based fossils to look at some of the smallest: a group of primitive shrew-like mammals known as the ‘Jurassic fissure mammals’ that lived in crevices between rocks some 200 million years ago. Working with Pamela Gill, an expert on the anatomy of these creatures, Emily examined the fossilised jaws and teeth of two species and predicted differences in the speed and strength of their bites. Comparing patterns of wear on the teeth of these mammals with modern bats suggested a similar range of insect diets. This implies that, even at the very beginning of the mammalian radiation, species that occupied similar niches were beginning to diversify their diets; and it provides another example of how studies of the mechanics of fossil bones can lead to insights into the lives of animals from hundreds of millions of years ago.

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Science Week 2019: Synthesising Life

Dr Clare Sansom, Senior Associate Lecturer in Birkbeck’s Department of Biological Sciences reports on Dr Salvador Tomas’ talk, which explored the hypothesis of abiogenesis, which assumes life arose spontaneously from non-living matter, a few billion years ago. The talk focused on research directed to the development of protocells, which are produced in the laboratory as plausible ancestors of living cells, and can be used as models to study abiogenesis. In the future, scientists may be able to use this knowledge to create programmable, cell-like robots.

Tekno the Robotic Puppy, credit: Toyloverz

Birkbeck Science Week 2019 kicked off with a talk by Dr Salvador Tomas of the Department of Biological Sciences, intriguingly titled ‘Synthesising Life’. Introducing Salvador, the Executive Dean of the School of Science at Birkbeck, Nicholas Keep, explained that he had taken both his degrees at the Universitat de les Illes Balears in his native Balearic Islands. He moved to Birkbeck to set up his lab in 2006 following postdoctoral study in Sheffield, and he now holds the position of Senior Lecturer in Chemical Biology.

His lecture was every bit as engaging as its title suggests. He started by asking the question ‘what is life?’ and illustrated the answer by comparing a ‘cyberdog’ with the common-or-garden variety. At a basic level, both dog and cyberdog can be thought of as a network of transistors or cells that responds to input signals in different ways, but while the cyberdog is programmed to carry out whatever (presumably) menial tasks its owner demands, the dog is programmed for survival. This led to a formalised definition of ‘life’, as ‘a self-sustained chemical system capable of undergoing Darwinian evolution’.  Furthermore, if you zoom in hundreds of millions of times, the dog’s equivalent of the cyberdog’s uniform network of transistors is the bewildering complexity of ‘molecular machines’ inside every living cell.

The question of ‘how life came to be’ is perhaps almost as old as humanity itself. A few centuries ago speculations centred on the idea of ‘spontaneous generation’, suggesting that (for example) fish might have arisen directly from water or mice from hay. The development of pasteurisation in the mid-nineteenth century helped disprove this theory. We now understand that all living (and extinct) organisms evolved from a simple organism known as LUCA – short for the Last Universal Common Ancestor – but this begs the question: where did LUCA come from? To answer this question, you need to go back to the kind of conditions that scientists believe to have existed on an early Earth: a chemically rich ‘warm puddle’ of liquid in an oxygen-poor environment, much like those found in underwater volcanoes today.

LUCA would have been a single-celled organism containing a minimum set of biomolecules necessary for life, all coded for by a minimal segment of DNA, and, self-evidently, all its precursors must have been non-living. For decades, scientists have been trying to recreate the process of ‘abiogenesis’ by providing simple molecules with energy in a similar environment and investigating whether more complex molecules, the ‘building blocks’ for LUCA’s DNA and proteins, might be able to form. So far, it has proved possible to make the basic building blocks of proteins, the amino acids, and even, in some circumstances, to join several amino acids into a short chain, but not to connect hundreds of them to form a complete protein. Nucleic acids, the building blocks of DNA, are proving even more intractable.

Building blocks become biomolecules through a process in which each two units – amino acids or nucleotides – are joined together with the loss of a water molecule. This process requires energy, but the opposite one, in which the bond between the units is broken, can be spontaneous. Salvador used a set of simple blocks to illustrate how populations change over time, as combinations such as ‘AB’ are ‘born’ and ‘die’. If AB, for example, is made ‘sticky’ so it attracts more copies of A and B, it becomes ‘autocatalytic’ (that is, it helps form itself) and the AB population burgeons. Or at least, it does so until A or B is depleted, when an ‘extinction event’ occurs. The system becomes more complex with the addition of an energy supply and further building blocks, and it becomes possible to see how collections of units with specialist functions could evolve. Some types would specialise in storing information (the ancestors of DNA) and others in promoting bond formation (the ancestors of proteins).

This would be a resourceful molecular system, capable of building its own building blocks, but it would have one major disadvantage: its survival would depend on the proximity of different types of molecule. If it were in the ‘warm puddle’ of the early Earth, a single rainstorm could blow it away. Keeping the components together requires a third type of biomolecule. Lipids are molecules with a long ‘water-hating’ tail and a short ‘water-loving’ head, and in water they form double layers with the tails pointing towards each other. These lipid bilayers often form spherical vesicles, and any primitive biomolecules trapped inside such a vesicle will stay together come what may.

Vesicles containing both ‘DNA-like’ and ‘protein-like’ molecules can be thought of as ‘protocells’: or, if you like, putative ancestors of the ancestors of LUCA. Salvador explained that his own contribution to the evolving story of synthesising life was in exploring the chemistry inside such protocells. Something like a protocell is almost certain to have existed, and this will have evolved to be better programmed for survival through developing more efficient chemical ways of making use of resources, storing and using energy, and responding to stimuli. Reproducing this process by adding molecular machines and efficient, specialist switches to a blank vesicle or protocell can generate cell-like robots. Initially, these are likely to have a variety of useful but quite mundane functions in, for example, targeted drug delivery, but eventually they might do more: ‘life, but not as we know it’, perhaps?

Salvador ended by asking two questions: can we synthesise life, and if so, should we? Most of his audience agreed with him that the first was ‘not done yet, but seems likely in the near future’. Interestingly, however, a majority thought that it might be too risky to take very far.

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Postguerres: what follows war?

Dr Fernando Gómez Herrero, Honorary Fellow in Birkbeck’s Department of Cultures and Languages, reports back from an international conference in Barcelona which focused mainly on the contemporary history of the Spanish Civil War and World War II.

Pablo Picasso’s ‘Guernica’ (1937). The artwork illustrates the violence and chaos of the Spanish Civil War and brought worldwide attention to the conflict.

Inside graffitied buildings at the University of Barcelona by the elegant Las Ramblas, I addressed the topic of intellectual life and the aftermaths of war in relation to three noted figures, mostly in the second half of the twentieth century. I brought “Dos Carlos,” so to speak, to the small-space of the Iberian peninsula, mostly during the Franco Regime but also after. Does any of this conservative and authoritarian thought, in complicity with early Nazism, remain alive today vis-à-vis the still prevailing orthodoxy of the “liberal West”? Symptoms of the loosening of the “liberal order” are easy to detect in different institutions, politics, university and mass media to name a few inside disparate national climates such as Brexit vis-à-vis the European Union, Trump America, etc. This international conference had three languages in unequal relationship (Catalan, Spanish and English) and the focus was mostly on the contemporary history coming out of the Spanish Civil War and World War II. Are we witnessing a turn to the Right, a revolt of the masses, even a Right-bound populism (what some authors call the “great Regression,” H Heiselberger for example)? Can we learn anything from the geopolitical situation of the following three figures of uneven visibility and uncertain impact?

These figures are: Carl Schmitt (1888-1985), Enrique Tierno Galván (1918-1986) and Camilo Barcia Trelles (1888-1977), not to be mistaken with his brother Augusto Barcia Trelles (1881-1961), also an interesting figure for another time and place. I addressed internationalism in relation to big-spaces and small-spaces, Grossraum and Reich, legal order and disorderly war, vis-à-vis the legacy of the Monroe Doctrine and the rise of the universalist-liberal ideology denounced as imperialist already by 1939 by Schmitt, sitting uncomfortably on the side of Nazi Germany losing WWII. This ineluctably dangerous thought emerges from the demise of imperial European hegemony, whilst marking differences from the Anglophone world and always keeping distance from the Left tradition emanating from Soviet Russia. Schmitt had plenty of (intellectual) life in him after such defeat finding refuge in the Iberian peninsula for four decades. This presentation developed the significance of such small-space for the historical geopolitics emerging from the middle of the twentieth century (we can think of the scale that goes from city of Barcelona, Catalonia, Spain, Europe, the West, etc.).

What are we to understand by the ominous sign of “war”? A permanent condition of being? Severe, harrowing test indeed big-time-big-space form of politics? Is there a way out of such politics? Law? Peace? What follows “total war”? Is international law the next chapter of significant difference? Or the first chapter that will be inevitably followed by disorder? What notions of “space” do we see emerging in between 1939 & 1945 and after? Schmitt’s spatialization of social energies: still convincing or useful methodology? What is missing? What is not to be touched with a ten-foot pole? What is the Spanish rendering of the alleged German scholar? What are the differences among these three European authors? Who are they turning to, conversing with? Their blind spots? Where is this Europe –and the liberal West with it– going in the 1950s between the two superpowers (U.S. and USSR)? Towards an inevitable debilitation? This presentation handled some of these burning issues. I played off the contrast with Anglophone environments.

L-R: Giovanni Cattini (Universitat de Barcelona), Fernando Gómez Herrero (Birkbeck and University of Birmingham, U.K.), Marcio Orozco (Universidad Panamericana, Mexico), Nick Sharman (University of Nottingham, U.K.).

Schmitt’s are strong words about the obfuscation and the falsification of the original Monroe Doctrine, also about the opportunistic use of messy geography emerging, the thinness of content and the doctrinal incongruence mobilized by the victors of WWI. There is insistence on the extension of the rule of the exception also in international law, that is nonetheless still monopolized by the Anglo Zone and paraded as triumphant narrative in the liberal West. Schmitt speaks of the universalist-imperialist principle of expansion in the Anglo Zone, the Americans picking up the legacy of the British Empire. Yet, international law will fly low in the United Nations in the following decades. There are also eerie sections about the elimination of the minority law in Schmitt, and we all know what that meant. His rejection of the ideals of assimilation, absorption and melting pots is blunt (it is important to remember contemporaneous Latin American thought experiments about “cosmic race” (Vasconcelos) and “transculturation” (F. Ortiz)). How did the Spaniards receive this profoundly uncomfortable thought in the 1950s and beyond?

It turned out that “Don Carlos” found refuge and community, circulation and outlet, even admiration in the Iberian peninsula, particularly Spain, in the final four decades of his long life. His daughter Anima Schmitt de Otero, who settled down in Franco Spain, acting as translator, representative and connector with several authorities and colleagues in legal and international studies. The Instituto de Estudios Políticos, Madrid gave him accolades. Manuel Fraga Iribarne (1922-2012) was among those “friends,” yet kept the figure of German intellectual at some distance. Among these “friends,” we have to include Tierno Galván whose article “Benito Cereno and the myth of Europe,” published in Spanish in 1952, recreates Schmittian’s Melville novel of a decrepit Europe giving way to some type of liberal American barbarism. What do we make of this article now 50 years after the publication of Sociología y Situación? There will be progressive distancing between Tierno Galván and Schmitt, as registered in Mehring’s extensive biography of the German intellectual. How are we to interpret today the gesture of the sociologist? Is the former Socialist Major of Madrid in the early moments of Spanish Democracy holding his own? The presentation answered some of these questions.

There is a second line of thought, which we may wish to call the Catholic international relations soon after WWII. Barcia Trelles, international-relations expert, managed to transition from Spanish-Republic and stay publicly active in the Franco Regime. He played a stellar role in the XIX World Congress “Pax Romana” (Spain, June-July 1946), event satirized by the English Catholic and conservative novelist Evelyn Waugh in his novel Scott King’s Modern Europe (1947), in honour of Francisco de Vitoria (1483-1546). What do we make of such initiatives in our own times? This paper contextualized and presented highlights of Barcia Trelles asking whether his vast scholarship remains of interest. Is this a third way? How are we to take the Catholic claims of a certain internationalism theoretically neither West nor East? Do we buy them? Schmitt praised Barcia Trelles’s formulations of land and sea in his magnus opus Nomos of the Earth. Is there evidence of a correspondence? American internationalist James Brown Scott (1866-1942) is in identical Vitoria circle in Spain bringing such legacy closer to the liberalism Schmitt denigrated. What do we make of it?  Where to stand? Does law follow war, or is it the other way round? Isn’t it true that we live now in low-standing moments of international law in our convulsive times and foggy wars of uncertain end?

Schmitt has been a strong point of reference among social scientists and “humanists” from the Right and the Left in the two-to-three decades, at least in continental Europe, including to a lesser degree Britain, and U.S. foreign-affairs circles, expansively the Anglo-dominated North Atlantic. I am insisting on this visibility three decades after his demise. I took into consideration Writings on War (Polity, 2011) edited by Timothy Nunan, spanning 1939-1945. I took into account Tierno Galván’s article on Melville’s Benito Cereno and a selection of texts by Barcia Trelles in the 1930-50s located at the British Library. I was fortunate enough to find a rare book in the Ramblas during my visit: Cardinal Points of International Relations of Spain (1939), which will be incorporated in future works. I said a few words about the said Pax Romana conference. I quickly included references to Miguel Saralegui’s Carl Schmitt, pensador español (Trotta, 2016) and the monumental work of Reinahrd Mehring, Carl Schmitt: A Biography (Polity, 2014). The Spaniards also deserve a place at the discussion table. Reconstruction of their intellectual efforts also interrogates our moments of insights and persistent blindness.

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