Science Week 2017: Resistance – film screening and panel discussion

Dr Clare Sansom, Senior Associate Lecturer in Biological Sciences, writes on the screening of Resistance: not all germs are created equal and panel discussion on antibiotic resistance, which took place as part of Science Week 2017

resistance_panel-disc-3Antibiotic resistance is one of the most crucial issues facing humanity in the early 21st century, with some commentators even suggesting that it poses as serious a threat to civilization as climate change. It was therefore timely that one of Birkbeck Department of Biological Sciences’ contributions to Science Week 2017, with its strapline ‘Microbes in the Real World’, should tackle the issue. This took the form of a screening of an award-winning feature film from 2014, Resistance (subtitle: Not all germs are created equal) followed by an extensive and lively panel discussion. The four panellists were scientists from the department whose research is geared to the development of antimicrobial drugs: Dr Sanjib Bhakta, a Reader in microbiology; Professor Nicholas Keep, Executive Dean of the School of Science and a structural biologist; and two promising students from Dr Bhakta’s lab: PhD student Arundhati Maitra and MRes student Alina Chrzastek.

Not surprisingly, given the timeliness of the issue and (it has to be admitted) the size of the venue – the tiny Birkbeck Cinema in Gordon Square – the session was over-subscribed. After a short introduction by Dr Bhakta, who used his own research field of tuberculosis to set out the ‘global threat’ of drug resistance, the packed audience were treated to 70 minutes of engaging and at times chilling documentary. The film, by US producers Ernie Park and Michael Graziano or, collectively, Uji Films, uses a combination of archive footage, animation, interviews and personal stories to explain how we have arrived at a point where antibiotics are failing and what we need to do to ‘save antibiotics in order to save ourselves’. Although the film was made in the US and focuses on US policies and case studies, the problem it describes is a global one and it would not have been difficult to find equivalent examples in the UK.

The producers weaved three case studies of patients who had suffered antibiotic-resistant infections engagingly through the footage. We were introduced to a teenage lad who had been exceptionally lucky to survive drug-resistant pneumonia with some disability; a fit, middle-aged man who picked up methicillin-resistant Staphylococcus aureus (MRSA) while surfing and is now seriously disabled; and, most harrowingly, a mother whose 18-month-old baby picked up a new strain of MRSA and died within 24 hours.

The film’s narrators explained that all antibiotics are ‘poisons that kill bacteria but not us’; if they don’t kill the bacteria they make them stronger. Using antibiotics in such a way as to promote this rapidly sets up a ‘Darwinian battleground’ in which weak bacteria are knocked out but strong ones survive. This can happen very quickly because bacteria grow and divide so fast. In the words of scientist and author Maryn McKenna, we had the only effective way of killing bacterial pathogens and squandered it. And we have done this in three main ways: by over-use in the environment, in agriculture and in medicine.

The first two of these are particularly prevalent in the US and some Asian countries and less of a problem in Europe, where regulation is stronger. In the US, antimicrobials are used in everyday household products, sprayed on everything from fruit trees to kitchen counters. And once farmers had realised that constant small doses of antibiotics made livestock grow faster and fatter, even in crowded, unsanitary conditions, they were determined to keep doing so even though it ‘makes as much sense as sprinkling antibiotics on your children’s cereal’. Most US-produced meat and poultry is now contaminated with resistant bacteria, and occasionally this is multi-drug resistant. A Danish hog farmer, Kaj Munck, explained the sensible approach taken in Denmark where antibiotic growth promoters in animal feed were banned in 1995 following an extensive public debate. The Danish pig industry is still profitable, producing 28 million a year: about the same as the state of Iowa.

The beginning of the antibiotic era in human medicine coincided with World War II, when it was seen as a ‘miracle drug’ for curing infected wounds. Over-use, however, started very soon: penicillin was given to overseas sex workers, not to protect them from infection but to prevent their US military clients from becoming infected. The danger of resistance was known as early as 1945, when Sir Alexander Fleming told the New York Times that “in such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection.” Doctors who prescribe antibiotics inappropriately are often not morally wrong, or even thoughtless, but over-anxious to avoid mistakes when the chance of an infection being bacterial is low but not vanishingly so. Readily available, rapid diagnostic tests would go a long way towards preventing this type pf misuse.

It would not matter as much if antibiotics became ineffective if there were other molecules ready to take their places. However, the current antibiotic pipeline is weak, with few drugs coming through. Pharma companies can spend at least a decade and a billion dollars on developing a single drug, so it makes more sense to work on drugs like statins that patients must take every day. We must begin to encourage and reward companies that bring forward antibiotic ‘drugs of last resort’ rather than best-sellers. In short, the film concluded, the problem of antibiotic misuse is a classic example of ‘the tragedy of the commons’; one individual’s over-use of antibiotics may be neutral or even beneficial, but if everyone does it there will be a huge problem. To win the arms race against bacteria we may need to redesign all the processes through which we discover, use and protect antibiotics, and to ‘use our wits to keep up with their genes’.

Bhakta introduced the panel discussion with a short explanation of the molecular mechanisms through which bacteria acquire resistance to antibiotics. Bacteria evolve quickly, and almost all have acquired some resistance either intrinsically, through mutations, or by acquiring resistance genes directly from other species. This is an inevitable process but we have some control over how quickly it occurs: good antibiotic stewardship is as important as innovative science for winning the ‘arms race’ described in the film.

Bhakta’s group at Birkbeck is interested in tackling the problem of resistance through discovering new compounds with novel modes of action and by aiming to ‘re-purpose’ some over-the-counter medicines that are already in use for other indications. Drugs in this category will have already been shown to be safe and are therefore quicker and cheaper to develop. Keep summarised the role of structural biology in antibiotic discovery as one of determining the structure of bacterial proteins that might be vulnerable to attack by drugs and identifying compounds that can bind to and inhibit them. We are now often able to see directly how these structures are changed by mutations that increase (or decrease) resistance.

Bhakta chaired the discussion that followed, which was extensive and wide-ranging, taking in politics and economics as well as science and medicine. Several questions touched on the role and responsibilities of the pharmaceutical industry, which is reluctant to invest in drugs that will only be used for short periods. More drug discovery than ever before is taking place in academic labs and small companies, often working together; Maitra, whose Birkbeck Anniversary PhD studentship is part-funded by Wellcome, highlighted the role of the Trust in promoting links with industry. Re-purposing drugs that have already been used clinically is much cheaper than developing a molecule from scratch. MRes students in Bhakta’s lab, including Chrzastek, are testing common anti-inflammatory drugs against Mycobacterium tuberculosis and have found some potentially useful activity although the mechanism of action is still to be explored.

Other questions focused on the need for strict antibiotic control measures. In many European countries, including the UK, antibiotics are only available on prescription and cannot be used as growth promoters in animal feed. This ‘best practice’ needs to be replicated worldwide, but it will be an uphill struggle. Bhakta told the audience that he often visits countries in south and east Asia where resistance is prevalent and has seen antibiotics available over the counter there. In countries without strong, publicly-funded healthcare systems there are often incentives for doctors to over-prescribe drugs including antibiotics. And even where this is not an issue, patients need to be educated to think of antibiotics as drugs of last resort rather than demanding them for every upper respiratory tract infection.

It was perhaps inevitable that someone would ask the ‘Brexit question’: in this case, is there a danger that we would reverse some of our ‘best practices’ when we are no longer bound by EU regulations? Encouragingly, Bhakta doubted that anyone would want to get rid of rules with such clear benefits. He felt that the now inevitable move of the European Medicines Agency, which regulates all medicines marketed in the European Economic Area, from London – and the confusion about how the UK drug market will be regulated – does present a danger, to our strong research base. And however the politics develops the international collaborations that UK-based doctors, scientists and entrepreneurs have built up over decades must be maintained.

Other Science Week 2017 events:

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The Many Uses of Bioinformatics

This post was contributed by Dr Clare Sansom, Senior Associate Lecturer in Birkbeck’s Department of Biological Sciences

Dame Janet Thornton

Dame Janet Thornton

Every year, Birkbeck hosts a lecture by a distinguished scientist to honour the memory of the founder of its Crystallography Department, J.D. Bernal. “Sage” as he was called by all who worked with him had an enormous range of research interests spanning both science and society; he is widely considered one of the most brilliant scientists never to have won a Nobel Prize. The 2014 Bernal Lecture, held on March 27, was given by Professor Janet Thornton, the director of the European Bioinformatics Institute (EBI) at Hinxton near Cambridge.

Introducing the lecture Professor David Latchman, Master of Birkbeck, described it as a unique occasion: the only time he has introduced as a guest lecturer someone who he had interviewed for a job. Thornton includes both Birkbeck and UCL on her CV: appropriately, her last post in London was that of Bernal Professor, held jointly at both colleges. She moved on to “even greater heights” as director of one of Europe’s top bioinformatics institutions in 2003.

Thornton began her lecture with a quote from Bernal: “We [academics] can go on being useless up to a point, with confidence that sooner or later some use will be found for our studies”. That quote is of particular relevance to the subject that she has made her own: bioinformatics. She had already begun her research career in 1977, when Fred Sanger invented the process that was used to obtain the DNA sequence of the human genome. That endeavour, which was completed in 2003, took over ten years and cost billions of dollars. Sequencing a human-sized genome, which has about 3 billion base pairs of DNA, now takes maybe 10 minutes and costs about a thousand dollars. While a decade ago we had one “Human Genome”, we now have lots. Mega-sequencing projects already planned or in progress include projects to sequence about 8,000 Finns, and the entire 50,000 population of the Faeroe Islands; one to sequence paired tumour and normal genomes from 20,000 cancer patients; and the UK10K project, which is investigating the genetic causes of rare diseases.

It is now almost extraordinarily simple and cheap to obtain genomic data, but real challenges remain in interpreting and understanding it so that it can be used in medicine. This is the province of bioinformatics, and Thornton devoted much of her presentation to explaining five ways in which gene (and protein) sequence information is being applied to both basic and clinical medical research:

1)      Understanding the molecular basis of disease

2)      Investigating differences in disease risk caused by human genetic variation

3)      Understanding the genomics of cancer

4)      Developing drugs for infectious diseases, including neglected diseases

5)      Investigating susceptibility to infectious disease

There are rather more than 20,000 genes in the human genome, far fewer than were originally predicted. Tiny differences between individuals in many of these either directly cause a genetic disorder or confer an increased – or in some cases decreased – risk of developing a disease. The genetic causes of some diseases, such as the bleeding disorder haemophilia, were known many years before the “genome era”: others have been discovered more recently. Mapping known mutations onto the structure of the enzyme copper, zinc superoxide dismutase has revealed the cause of the inherited disorder amyotrophic lateral sclerosis, a form of motor neurone disease. And knowing the genome sequence has already made an enormous contribution to our understanding of the mechanisms of disease development, contributing to improvements in diagnosis and the design of novel drugs.

We now understand that cancer is a genetic disease: it arises when mutations in a group of cells cause them to grow and divide excessively. A cancer is no longer classified just by its location (for example, a breast or lung cancer) but by the particular spectrum of genetic variations in its cells. About 500 different genes are known to be mutated in cancer, some much more often than others. For example, about 60% of cases of melanoma, a type of skin cancer, contain one specific mutation in the gene BRAF. This codes for a protein that can direct cells to grow and divide, and the cancer-causing mutation sticks this protein into the ON position, so this signal is always sent. Scientists in a company called Plexxicon used their knowledge of this mutation and the structure of the protein to design a drug, vemurafenib, which prevents the BRAF protein from signalling. This can cause a dramatic, if short-term improvement in melanoma patients, but, crucially, it only works in patients whose cancers carry this mutation. It is one of the first developed examples of a “personalised medicine” that is only used alongside a diagnostic test for a genetic variation. There will soon be many more.

Genomics is also proving very useful in the fight against infectious disease. Antibiotic resistance is one of the greatest emerging threats to human health, and scientists have to use all the tools at their disposal, including genomics and bioinformatics, as they try to stay one step ahead of rapidly mutating pathogens. Sequencing is widely used to track the sources of outbreaks of infection and of resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) in hospitals, and it is the only way of determining the exact nature of an infection.  One of the most dramatic examples of the use of genomics in infectious disease control occurred in 2011, when a novel strain of E. coli O104 caused about 4,000 cases of serious food-borne illness and 50 deaths in Germany. This was originally linked to cucumbers imported from Spain but a global effort to trace its specific sequence variants proved that the source of the infection was beansprouts grown on a farm near Hamburg.

There was much more to Thornton’s wide-ranging lecture than simply bioinformatics and medicine: more, indeed, than it is possible to do justice to in a single blog post. She went on to describe some of the benefits of genomics for agriculture and food security. These included designing new strategies for controlling pests and diseases, maximising the efficiency of biomass processing, and even managing biodiversity. It is necessary to measure biodiversity in order to manage it properly; it is now possible to define a short stretch of DNA sequence that fully identifies a species or sub-species (a so-called “DNA barcode”) and these are beginning to be used to track some very diverse organisms, including the 400,000 known species of beetle.

The lecture ended with a short discussion of some of the challenges facing bioinformatics and genomics in the second decade of this century, largely relating to difficulties with storing, manipulating and understanding the enormous quantity of data that is being generated. Mining this data mountain for the benefit of mankind is a task that is beyond either the academic community or the biotech industry alone. It will require novel ways of doing science that involve governments and charities as well as academia and industry. The new Centre for Therapeutic Target Validation, launched at Hinxton on the same day as Thornton’s Bernal Lecture, is a pioneering example of such a partnership. It has been set up by the EBI, the Sanger Institute where a third of the original human genome sequence was obtained, and pharmaceutical giant GSK, and its scientists aim to use the whole range of available genomic data to select and evaluate new targets for novel drugs.

A podcast of the 2014 Bernal Lecture is available now.

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Birkbeck Commemorates World TB Day by Discussing Drugs from Plants

This post was contributed by Clare Sansom, a part-time lecturer in Birkbeck’s Department of Biological Sciences, and a freelance consultant and science journalist.

World TB Day is held on 24 March every year, to mark the day in 1882 when Robert Koch, one of the fathers of microbiology, first announced that he had discovered the cause of tuberculosis (TB) – the bacterium now known as Mycobacterium tuberculosis. Over 125 years since its discovery, and despite billions of dollars of investment in drug discovery, this bacterium is still a killer. The World Health Organisation estimates that about two billion people are infected with latent tuberculosis; in 2010, the last year for which full figures are available, over eight million people became ill with active tuberculosis, and 1.4 million people died from the disease. Two factors help make TB particularly deadly: it often occurs in people infected with the HIV virus, where it is one of the major causes of death, and drug resistant forms are becoming more common. In January 2012, Nature reported the identification in India of so-called “totally drug resistant” (TDR) tuberculosis, resistant to all anti-TB drugs in general use.

In 2012 at Birkbeck, World TB Day coincided with the start of the College’s annual Science Week. Dr Sanjib Bhakta, head of the Mycobacteria Research Laboratory in the Department of Biological Sciences, organised a well-attended symposium on tuberculosis and its treatment. Besides two scientific presentations, the symposium featured a short video, Tuberculosis: The Real Story, highlighting the views of people affected by TB in the UK, and a panel discussion led by the grassroots volunteer organisation Results UK on some of the political challenges raised by tuberculosis. 

Both science lectures focused on plants as a source of potential new drugs for tuberculosis. Professor Franz Bucar from the University of Graz in Austria highlighted the extreme chemical diversity of compounds that could be extracted from plants, particularly as compared to those found in the average synthetic compound library. Plants have always existed alongside their own microbial pathogens and have evolved natural antibiotics to protect themselves. Our ancestors, before the dawn of scientific medicine, used plant extracts to treat infectious disease, often quite successfully. The sub-discipline of ethnomedicine involves “mining” these traditional or historical remedies for pure chemicals that can be developed as, or modified into, drugs.

Bucar described a European herb, elecampane or Inula helenium, which is known to have been used to treat lung disease in the sixteenth century. He explained how a complex mixture of natural products derived from this plant had been tested against mycobacteria. Compounds found to have anti-mycobacterial activity were extracted and purified. Other plants have also yielded useful lead compounds; extracts of bark from a small tree with the Latin name of Berchemia discolor have even been shown to inhibit multi-drug resistant strains of Mycobacterium tuberculosis at useful concentrations.

Discovering antibacterial products in plant extracts, however, is only a first step towards drug discovery. Even when natural products like these compounds are found to be selective for bacterial over human cells, it is necessary to discover their mechanism of action; to modify them to optimize their activity; and, since plant sources are often scarce and extraction processes costly, to determine methods of synthesizing them in the laboratory.

The second scientific presentation was given by Dr. Bhakta himself and described current work in Birkbeck’s Mycobacteria Research Laboratory in searching for potential drugs for TB. These are needed not only to combat resistant forms of the bacteria but to improve current treatment regimens for “standard”, drug-sensitive TB. This requires a combination of four drugs to be taken for two months followed by two drugs for another four months, and many patients, particularly poorer and less well educated ones, fail to complete such a long and complex regimen. This in turn can lead to the development of further resistant strains.

Ideally, new drugs are required that target proteins not targeted by existing drugs, as resistance will be harder to develop. Mycobacteria have extremely complex cell walls, unlike those of other types of bacteria; they are essential for the bacteria to survive, and the enzymes used to synthesise them have no equivalents in mammalian genomes. These enzymes, therefore, have many of the characteristics of excellent drug targets.  Bhakta and his group have been exploring ways to inhibit the synthesis of the peptidoglycan that is one of the most important constituents of that cell wall. This molecule has been described as the bacterium’s “Achilles heel”, but no drugs targeting its synthesis have yet entered the clinic.

Mycobacteria synthesise peptidoglycan via a series of enzymes known as ligases, each of which adds a new link to the growing peptidoglycan chain. Bhaka’s group has focused on one of these ligases, termed MurE. This enzyme is essential for the bacterium to survive and it is conserved in all Mycobacterium tuberculosis strains. Working in collaboration with Professor Nick Keep, also in the Department of Biology, Bhakta solved the structure of MurE and showed it to have an active site that could in theory, at least, be occupied, and blocked, by a relatively small, “drug-like” molecule. He and his co-workers are now searching libraries of natural products for compounds that might inhibit this enzyme. They have identified promising MurE inhibitors from plants endemic to both Colombia and China, and are synthesizing analogues of these compounds for further testing.

It is unlikely that the next generation of anti-tuberculosis drugs will include any unchanged natural products. It is extremely likely, however, that natural products will yield the “scaffolds” on which these desperately needed drugs may be built, and perhaps one of these will be generated from within Bucar’s or Bhakta’s groups.

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