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NOVEMBERDECEMBER2018
News • biodigestables • Antibiotic Research • FINANCE AND FUNDING • CANCER RESEARCH • Parasitic Diseases • INTELLECTUAL PROPERTY
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Welcome Reflecting on the past Ellen Rossiter Editor in chief
Editor Ellen Rossiter ellen.rossiter@distinctivepublishing.co.uk
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2018 has been a year of anniversaries which hold great resonance, both for us as individuals and collectively. Just before we go to print, Remembrance Day and the 100th anniversary of the signing of the Armistice are marked by numerous commemorative events. As peace was restored across Europe and the guns fell silent – another threat was taking hold – Spanish Flu. Today, it is estimated that between 50-100 million people died in this pandemic. A new exhibition at the Florence Nightingale Museum explores the influenza outbreak, examining, amongst other things, how the spread of the virus was exacerbated and illustrating the global impact of the pandemic. Satellite exhibitions around the UK take up the tale too. Ten years after the First World War ended, a physician and research scientist stepped out of his laboratory to go on holiday, returning sometime later to find a petri dish he’d left by the window contained a bacteria-killing mould. You know the story, his name was Sir Alexander Fleming and his discovery marked one of the most significant breakthroughs in medical history. Work continued to develop antibiotics, with Sir Ernst Boris Chain, Sir Edward Abraham, Norman Heatley and others taking up the gauntlet. By 1943, enough antibiotics were being produced to have an impact on the war, meaning infection was no longer the greatest killer in the conflict. Infections that had once proved fatal, could now be treated.
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Few of us can have been unaffected in one way or another by these events, whether we lost family members or indeed have been helped by the discovery of penicillin. Antibiotics have been described as both a ‘miracle medication’ and a ‘magic bullet’, capable of extending life and treating an array of infections, yet in this issue, we also hear about the ‘time-bomb of antibiotic resistance’.
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As early as 1945, shortly after receiving the Nobel Prize for Medicine, Fleming warned of the problem posed by antibiotic resistance. 90 years on from Fleming’s discovery, we reflect on his achievement, speaking to Sarah Whitlow about her Grandfather, his work and how it has felt to see his discovery in action during her career. We find out how Fleming’s ‘inquisitiveness’ and ‘sense of service’ steered his work, remaining an inspiration and example to us today. As Professor Colin Garner explains, we can learn from his ethos, championing the cause of finding the cures we desperately need, including prioritising the search for a solution to antibiotic resistance. As we are preparing this issue, a new Public Health England Campaign is launched, alerting us to the risks of antibiotic resistance, highlighting how surgeries and treatments we’ve come to rely on could become life-threatening without antibiotics. ‘Keep Antibiotics Working’ raises awareness of why antibiotics should not be seen as a ‘catch-all’ cure, why we should always seek the advice of a healthcare professional before taking them and only take them when necessary. Elsewhere in this issue, we take a look at the work of Professor Mathew Upton to find new antimicrobials and learn how sponges from the depths of the ocean are central to research ongoing to find new solutions. Parasitic diseases represent another huge global health challenge - with hundreds of millions of people infected, and many millions more affected by the impact of diseases such as malaria and schistosomiasis. So in this issue, we speak to Professor Jonathan Cooper about how a humble piece of paper - not too dissimilar to this page here – has a huge role to play in saving lives - turn the page to find out more.
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features
Cutting to the chase - how a folded piece of paper is saving lives
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24 90 years since Sir Alexander Fleming’s penicillin discovery changed antibiotic treatment Supercharged natural killer cells may hold promise for cancer
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contents www.biosciencetoday.co.uk / issue 15 /november•december 2018
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Introduction/Foreword
4-5
Contents
6-7
Industry Contributors
8-9 Biodigestables 10-19 News
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20-23
24-29
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30-33 34-39
40-45
46-53
Biomedical Research
Simplicity is all Artificial Neural Networks working with Image Guided Therapies to improve heart disease treatment
Antibiotic Research
90 years since Sir Alexander Fleming’s penicillin discovery changed antibiotic treatment
Intellectual Property
The IP journey and risk mitigation
Cancer Research
Stanford shows that breast cancers punch tunnels into neighbouring tissue Supercharged natural killer cells may hold promise for cancer How chromosomes find a happy medium
Finance and Funding
Having access to finance is an essential ingredient to grow and prosper
Combat and Control of Parasitic Diseases
Regulator protein key to malaria parasite’s lifecycle New type of bed net could help fight against malaria Discovery aids disease elimination efforts
54-55 Training 56-63
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Discovery helps fight against drug-resistant tuberculosis
Antimicrobial Solutions
Biological engineers discover new antibiotic candidates Discovery helps fight against drug-resistant Tuberculosis UK-led study marks shift towards genetic era in tackling TB
Biopharmaceutical Manufacturing
A new way to manufacture small batches of biopharmaceuticals on demand Making pharmaceuticals person specific
70-72 Excipients
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Sabrina Richards Staff writer at Fred Hutchinson Cancer Research Center
Sarah Whitlow Paternal granddaughter of Sir Alexander Fleming, the discoverer of penicillin.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University.
Trained at the West Suffolk Hospital, Sarah has been at the Swan Surgery in Bury St Edmunds since 1990 and is a practice nurse. That means she has seen her grandfather’s discovery in action.
Paul Storer Senior Policy Adviser in the Business Support Policy Team at the IPO
Sarah is a supporter of the Antibiotic Research UK (ANTRUK) charity and has been helping them recently to mark the 90th anniversary of the discovery of penicillin.
Graeme Fisher Managing Director for Communications and Policy at British Business Bank
The team develops and delivers policies which help to ensure that innovative businesses can maximise the value of their IP Assets. He was previously a policy advisor in the Legal Framework Team where he was a lead on reform of the Patents County Court.
Graeme Fisher is responsible for the British Business Bank’s policy and communications team, leading interactions with the government and other stakeholders and efforts to explain and raise the profile of the Bank’s work.
Professor Colin Garner Founder and chief executive of Antibiotic Research UK (ANTRUK)
Professor Mathew Upton Chair of Medical Microbiology, University of Plymouth
ANTRUK is the world’s first charity to fight bacterial antibiotic resistant infections. ANTRUK aims to raise sufficient funds over the next few years to bring at least one new antibiotic therapy to market by the early 2020’s.
Mathew’s work is focused on finding new antibiotics that work in different ways to conventional antibiotics, he is currently searching for new antimicrobials produced by the microbiome of sponges. In 2008, he discovered epidermicin, whilst working at the University of Manchester.
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Professor Kawal Rhode Professor at King’s College London School of Biomedical Engineering and Imaging Sciences
Doctor Rashed Karim Research Fellow at King’s College London School of Biomedical Engineering and Imaging Sciences
Kawal Rhode is Professor of Biomedical Engineering. His research interests include image-guided medical interventions, medical robotics and healthcare education. He works closely with clinicians and industry to develop novel healthcare technologies.
During his PhD, he studied deep exploration of 3D medical imaging data and now uses his expertise to gain new insights from cardiac imaging. He received the highly cited research award from JACC Journal of Cardiovascular Imaging and is an honorary lecturer at Imperial College London.
Professor Steve Lindsay Professor in the Department of Biosciences at Durham University
Gillian Burgess Vice President, Head of Research, Vertex
Professor Parastou Donyai Professor of Social and Cognitive Pharmacy
Gillian Burgess joined Vertex in 2016 as Vice President, Site Head and Head of Research at Vertex’s Oxford Research Site in the UK. Dr Burgess is a member of the MRC DPFS Translational Panel, the MRC Translational Oversight Group and the Wellcome Trust Grant Interview Panel. She is also a member of the British Pharmacological Society Industry committee.
Director of Pharmacy Practice at the University of Reading, and Admissions Tutor for the Pharmacy Degree programme, Parastou examines the psychology of medication usage and patient-professional interactions, and works with colleagues to educate the next generation of pharmacists to combine their scientific knowledge with patient-centred care.
Julie Barrett-Major Consulting Attorney, AA Thornton
Bruce Davis Co-Founder and Joint Managing Director of Abundance Investment
Professor Steve Lindsay is a public health entomologist with a passion for studying some of the world’s most important vector-borne diseases, including malaria, lymphatic filariasis, dengue and trachoma. He has considerable experience in medical entomology, parasitology, ecology and clinical epidemiology
Dr Mohammed Maniruzzaman Lecturer in Pharmaceutics and Drug Delivery, University of Sussex Mohammed’s work focuses on developing biopharmaceutical manufacturing systems, including continuous manufacturing platforms and person specific biopharmaceutical manufacturing systems, bridging the gap between what people need and what is available.
Julie is our Consulting Attorney, based in our Chemistry, Biotechnology and Pharmaceuticals team. She has spent decades in-house, especially in international pharmaceutical companies. She therefore brings a strong strategic focus to the whole gamut of IP, including in the establishment and maintenance of IP portfolios to fit business objectives. As a European Patent Attorney, she also enjoys working on developments such as personalised medicine, cosmeceuticals and AI.
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David Horn Professor of Parasite Molecular Biology at the Wellcome Centre for Anti-Infectives Research (WCAIR), University of Dundee David Horn is Professor of Parasite Molecular Biology at the Wellcome Centre for AntiInfectives Research (WCAIR), University of Dundee. His research focuses on understanding mechanisms of gene expression control in trypanosomes. His lab also seeks to understand drug action and resistance.
Bruce Davis is cofounder and joint managing director of Abundance Investment. He was a founding director of the UKCFA. He is Visiting Research Fellow at the Bauman Institute, Leeds University and a Trustee of the Finance Innovation Lab. Prior to founding Abundance, Bruce was a member of the founding team that created Zopa.com and has worked extensively researching money and financial innovations for institutions in the UK and across Europe.
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BIODIGESTABLES
Nobel prize in Physiology or Medicine
The Nobel Prize in Chemistry
The Nobel Prize in Physics
Two immunologists, American James P Allison and Japanese Tasuku Honjo, have won the Nobel prize in Physiology or Medicine for discovering a form of cancer therapy.
The Royal Swedish Academy of Sciences has awarded the Nobel Prize in Chemistry 2018 with one half to Frances H. Arnold, California Institute of Technology, Pasadena, USA “for the directed evolution of enzymes” and the other half jointly to George P. Smith, University of Missouri, Columbia, USA and Sir Gregory P. Winter, MRC Laboratory of Molecular Biology, Cambridge, UK “for the phage display of peptides and antibodies.
The Royal Swedish Academy of Sciences has awarded the Nobel Prize in Physics 2018 “for ground-breaking inventions in the field of laser physics”:
The ¾ million pound prize, announced by the Nobel Assembly of Sweden’s Karolinska Institute, captures the increasing role of immunology in medical research and treatment. The Institute chose the winners for their discovery of cancer therapy by inhibition of negative immune regulation.
One half has been awarded to Arthur Ashkin, Bell Laboratories, Holmdel, USA “for the optical tweezers and their application to biological systems”. The other half jointly to Gérard Mourou, École Polytechnique, Palaiseau, France and University of Michigan, Ann Arbor, USA and Donna Strickland, University of Waterloo, Canada “for their method of generating high-intensity, ultrashort optical pulses.”
Understanding pandemic Hereditary angioedema – Non-dystrophic myotonia influenza new medicine hope – first treatment Researchers at the University of Cambridge and the University of Oxford have discovered a new molecule that plays a key role in the immune response that is triggered by influenza infections. The molecule, a so-called mini viral RNA, is capable of inducing inflammation and cell death, and was produced at high levels by the 1918 pandemic influenza virus. The findings appeared in Nature Microbiology.
The European Medicines Agency has recommended granting a marketing authorisation for Takhzyro (lanadelumab), the first monoclonal antibody therapy for the prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older. HAE is a long-term debilitating disease characterised by attacks of swelling beneath the skin that can occur anywhere in the body, such as in the face, limbs, gut and larynx. It is caused by abnormalities in the gene responsible for the production of C1 esterase inhibitor.
The European Medicines Agency has recommended granting a marketing authorisation for Namuscla (mexiletine hydrochloride) for the treatment of adult patients with non-dystrophic myotonia, a group of inherited muscle disorders where muscles are slow to relax after contraction. These disorders are chronic life-long debilitating conditions characterised by pain, fatigue, and muscle stiffness, resulting in frequent falls and disability.
£8 million EPSRC support $5 million grant
Spanish Flu Exhibition
A new £8 million capital investment in research equipment has been announced by the Engineering and Physical Sciences Research Council (EPSRC), which is part of UK Research and Innovation (UKRI).
An exhibition has opened at the Florence Nightingale Museum, St Thomas’ Hospital, commemorating the hundredth anniversary of the Spanish Flu pandemic.
The series of capital awards will go to 36 institutions across the UK to support Early Career Researchers undertaking new research and enhance their career development prospects.
Using a new Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society, a team from Baylor College of Medicine and the Center for Cell and Gene Therapy at Baylor, Houston Methodist Hospital and Texas Children’s Hospital will work to develop more widely applicable targeted cellular therapies for leukemia and lymphoma.
The total value of the investment is over £8 million and forms part of EPSRC’s World Class Labs investment.
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Running until the 16 June 2019, the exhibition explores six key themes including the global impact of the pandemic, what it was really like to have Spanish Flu, the experiences of professional nurses, the role of casual nurses in the home, Spanish Flu in popular culture and the contemporary relevance of the 1918 pandemic.
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BIODIGESTABLES
How superbugs rapidly evolve?
Dandelion seeds’ natural flight
Paleontologists discover baby sea monster
A scientific breakthrough has revealed a new way that bacteria evolves, thought to be at least 1,000 times more efficient than any currently known mechanism. The insights will help scientists to better understand how superbugs can rapidly evolve and become increasingly antibiotic resistant.
The extraordinary flying ability of dandelion seeds is possible thanks to a form of flight that has not been seen before in nature, research has revealed.
Scientists have discovered an ancient baby sea monster in Kansas, United States. The newborn Tylosaurus fossil is approximately 85 million years old, and its discovery was aided by University of Alberta paleontologists and alumni.
The research, led by the University of Glasgow and the National University of Singapore and published in Science, has found a previously unknown method of genetic transduction – the process through which bacteria begins to evolve into potentially deadly superbugs.
First vaccine for prevention of dengue The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation for Dengvaxia (dengue tetravalent vaccine (live, attenuated), for the prevention of dengue caused by dengue virus serotypes 1, 2, 3 and 4 in people who are between 9 and 45 years old, live in an endemic area and already had a prior dengue virus infection.
Researchers from the University of Edinburgh carried out experiments to better understand why dandelion seeds fly so well, despite their parachute structure being largely made up of empty space. Their study revealed that a ringshaped air bubble forms as air moves through the bristles, enhancing the drag that slows each seed’s descent to the ground.
The Tylosaurus specimen died shortly after it was born, making the fossil extremely difficult to identify, as it had not yet developed the characteristic snout and teeth of adult Tylosaurus. As adults, the predatory reptiles could grow up to 13 metres in length with powerful jaws and large teeth – not yet developed in the newborn fossil specimen.
Src regulates mTOR
A dose of strong cocoa?
A team of researchers at Baylor College of Medicine and Texas Children’s Hospital has revealed a connection between mTORC1 and Src, two proteins known to be hyperactive in cancer. The study, published in the journal Nature Communications, shows that Src is necessary and sufficient to activate mTORC1 and offers the possibility to develop novel approaches to control cancer growth.
People with the circulation condition called Primary Raynaud’s are being asked to help researchers at the University of Nottingham find out whether antioxidant compounds in cocoa can help alleviate symptoms. The research team at the University’s School of Life Sciences are looking for otherwise healthy volunteers with Primary Raynaud’s to help them examine the effects of antioxidant compounds known as flavanols that are found in cocoa.
Nurse-led care more Sugarcane waste to be successful in treating gout put to good use
Short story or article to share?
Providing nurse-led care for people suffering with the painful, long-term condition gout could lead to an increase in the number of patients sticking to a beneficial treatment plan, a clinical trial has revealed.
Send them to our Editor, Ellen Rossiter, at ellen.rossiter@distinctivepublishing.co.uk
The study, which was funded by the charity Versus Arthritis, highlights the importance of individualised patient education and engagement to treat the condition.
BIOREVIEW is a £1.99M Newton Bhabha Fund Industrial Waste Challenge project, a collaboration of scientific research and business from India and the UK in order to create innovative solutions to global challenges.
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BIO
SCIENCETODAY
The research, led by academics at the University of Nottingham and published in The Lancet, has shown that keeping patients fully informed and involving them in decisions about their care can be more successful in managing gout.
A new collaborative research project between the UK and India led by Aberystwyth University, aims to transform waste streams from the Indian sugarcane industry into a range of valuable new products that can address tooth decay, obesity and diabetes.
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Patients lives to be greatly improved by technology revolutions in healthcare Winners announced to receive funding that could revolutionise healthcare
new discoveries and technologies to diagnose illnesses earlier that could lead to more lives being saved.”
The projects include developing artificial intelligence for bed availability in hospitals, 3D printing to create tablets and smart phone applications to improve the treatment of complex wounds
The funding, through the Industrial Strategy Challenge Fund managed by UK Research and Innovation, will also support efforts to enable antibodies to be taken orally rather than through invasive injections and increasing the range of medicines that can be delivered through skin patches.
Technology can transform health and social care, improving treatment and deliver better care for patients Breakthrough technologies to revolutionise UK healthcare get a step closer to becoming reality following a government competition. A GPS app to track where porters and available beds are in hospitals, 3D printing technology for tablets and smartphone apps to monitor and improve treatment of long-term complex wounds are just some of the things being developed by the businesses and academics. The projects that are collectively to receive over £17 million funding to develop their innovations are based throughout the UK, including Devon, Cumbria, Edinburgh, Glasgow, Cardiff, Manchester, Oxford, Cambridge and London highlighting the breadth of strengths in addressing new and emerging issues in our world-leading healthcare industry. Business Secretary Greg Clark said: “Technology is revolutionising industries across our economy, and new innovations play a key role in advancing our healthcare sector to make sure people are living longer, healthier and happier lives. “By pooling the expertise of the public and private sectors, as highlighted through the Life Sciences Sector Deal and the modern Industrial Strategy, we are making every opportunity to reach our full potential in finding
Ian Campbell, Executive Chair of Innovate UK, for UK Research and Innovation said: “The projects we have funded today aim to make a real difference for patients and clinicians. They represent the very best of British innovation, focussing on improved patient outcomes and driving efficiency. The UK health sector is thriving, with SMEs playing a crucial role. By supporting this sector, as part of the government’s modern industrial strategy, we can ensure we remain global leaders in health innovation and create the jobs of tomorrow.” The development of new and innovative technologies is changing the economy. Through the modern Industrial Strategy the government is committed to embracing emerging technology to transform industries and increase productivity, create new highly skilled jobs and improve living standards. Matt Hancock, the Secretary of State of Health and Social Care, said: “Innovative technology has the potential to truly transform healthcare for patients and staff. From artificial intelligence to VR to live tracking of hospital beds and equipment, there are so many ways in which the NHS is embracing tech. We are determined to make the NHS the most technologically advanced healthcare system in the world and today’s prizes will help progress towards that goal.”
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Genetic tool to predict adult heart attack risk in childhood Powerful technology paves way for early interventions to prevent heart attacks. People at high risk of a heart attack in adulthood could be spotted much earlier in life with a one-off DNA test, according to new research part-funded by the British Heart Foundation and published in the Journal of the American College of Cardiology. An international team led by researchers from the University of Leicester, University of Cambridge and the Baker Heart and Diabetes Institute in Australia used UK Biobank data to develop and test a powerful scoring system, called a Genomic Risk Score (GRS) which can identify people who are at risk of developing coronary heart disease prematurely because of their genetics. Genetic factors have long been known to be major contributors of someone’s risk of developing coronary heart disease – the leading cause of heart attacks. Currently to identify those at risk doctors use scores based on lifestyle and clinical conditions associated with coronary heart disease such as cholesterol level, blood pressure, diabetes and smoking. But these scores are imprecise, age-dependent and miss a large proportion of people who appear ‘healthy’, but will still develop the disease. The ‘big-data’ GRS technique takes into account 1.7 million genetic variants in a person’s DNA to calculate their underlying genetic risk for coronary heart disease. The team analysed genomic data of nearly half a million people from the UK Biobank research project aged between 40-69 years. This included over 22,000 people who had coronary heart disease. The GRS was better at predicting someone’s risk of developing heart disease than each of the classic risk factors for coronary heart disease alone. The ability of the GRS to predict coronary heart disease was also largely independent of these known risk factors. This showed that the genes which increase the risk of coronary heart disease don’t simply work by elevating blood pressure or cholesterol, for example. People with a genomic risk score in the top 20 per cent of the population were over four-times more likely to develop coronary heart disease than someone with a genomic risk score in the bottom 20 per cent. In fact, men who appeared healthy by current NHS health check standards but had a high GRS were just as likely to develop coronary heart disease as someone with a low GRS
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and two conventional risk factors such as high cholesterol or high blood pressure. These findings help to explain why people with healthy lifestyles and no conventional risk factors can still be struck by a devastating heart attack. Crucially, the GRS can be measured at any age including childhood as your DNA does not change. This means that those at high risk can be identified much earlier than is possible through current methods and can be targeted for prevention with lifestyle changes and, where necessary, medicines. The GRS is also a one-time test and with the cost of genotyping to calculate the GRS now less than £40 GBP ($50 USD) it is within the capability of many health services to provide. Senior author Professor Sir Nilesh Samani, Professor of Cardiology at the University of Leicester and Medical Director at the British Heart Foundation said: “At the moment we assess people for their risk of coronary heart disease in their 40’s through NHS health checks. But we know this is imprecise and also that coronary heart disease starts much earlier, several decades before symptoms develop. Therefore if we are going to do true prevention, we need to identify those at increased risk much earlier. “This study shows that the GRS can now identify such individuals. Applying it could provide a most cost effective way of preventing the enormous burden of coronary heart disease, by helping doctors select patients who would most benefit from interventions and avoiding unnecessary screening and treatments for those unlikely to benefit.” Lead author Dr Michael Inouye, of the Baker Heart and Diabetes Institute and University of Cambridge said: “The completion of the first human genome was only 15 years ago. Today, the combination of data science and massivescale genomic cohorts has now greatly expanded the potential of healthcare. “While genetics is not destiny for coronary heart disease, advances in genomic prediction have brought the long history of heart disease risk screening to a critical juncture, where we may now be able to predict, plan for, and possibly avoid a disease with substantial morbidity and mortality.” This study was supported by funding from the British Heart Foundation, National Health and Medical Research Council (NHMRC, Australia), the Victorian Government and the Australian Heart Foundation.
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Maggots and rotting food waste: a new recipe for sustainable fish and animal feed In a warehouse to the northeast of Cambridge are shelves upon shelves of trays teeming with maggots, munching their way through a meal of rotting fruit and vegetables. This may sound stomach-churning, but these insects could become the sustainable food of the future – at least for fish and animals – helping reduce the reliance on resource intensive proteins such as fishmeal and soy, while also mitigating the use of antibiotics in the food chain, one of the causes of the increase in drug-resistant bacteria. The company behind this idea is Entomics Biosystems. It was set up in 2015 by a group of students from the University of Cambridge, with support from the Cambridge Judge Entrepreneurship Centre’s ‘Accelerate Cambridge’ programme. “It’s one of those stories where we came together in a pub over a pint, talking about weird ideas,” explains its CEO and co-founder Matt McLaren. “The team has members from the Department of Biochemistry, from Engineering, from the [Judge] Business School, so it really is a diverse skill set.” According to the company, each year over 1.3 billion tonnes of food are wasted globally – equating to around US$1 trillion of lost value. With an increasing population and modern lifestyles, the burden of food waste on society and the environment is set to increase in the future. Entomics focuses on ‘insect biomass conversion’. Larvae of the black soldier fly chew their way through several tonnes of food waste collected from local supermarkets and food processing plants. The insects are fed different ‘recipes’ under controlled conditions to see how these affect growth rates and nutritional profiles. They metabolise the food waste into fats and proteins, growing to around 5,000 times their body weight within just a couple of weeks. As McLaren, explains, these fats and proteins “are great sources of nutrition for salmon and poultry – in fact, insects are part of their natural diet”. Entomics is currently working with partners including the University of Stirling, who are world-leading salmon aquaculture experts, to validate and test their products in the field. “Farmed salmon in Scotland are currently fed on fishmeal which comes from wild-caught anchovies from as far away as Chile and Peru, which are then shipped across the world to Scotland,” he explains. “Insects provide a nice, sustainable solution.” With support including from Innovate UK and the European Institute of Technology (via EIT FoodKIC),
Entomics is using a novel bioprocessing technique to boost the nutritional and functional benefits of these insectderived feeds, using a microbial fermentation technology they have termed ‘Metamorphosis’. Essentially, these specialised feeds represent a sustainable, holistic approach to improving overall fish health and welfare. “There are several benefits to this process,” explains Miha Pipan, Chief Scientific Officer and fellow co-founder, “from affecting the gut’s microbiome and trying to preserve a healthier bacterial community there, to training immune systems to make livestock more resistant to disease challenges and at the same time reduce the need for veterinary medicines, antibiotics and vaccines.” “The world’s looking for more sustainable sources of feed and I think increasingly there’s a recognition that it’s not just about basic nutrition, but it’s about overall health,” says McLaren. “We’re trying to take a promising, sustainable ingredient of the future – these insect-derived feeds – and trying to add a bit of biotechnology or science focus to it, to really enhance what the effect is in the end application and reduce reliance on traditional antibiotics and veterinary medicines.” There is endless potential for innovation in the emerging insect industry in general, and the Entomics team is also working on an engineering project to build a smart, modular system for insect production in the future. This includes developing computer vision algorithms to understand and monitor insect behaviour during the production process – for example, the insects’ growth and health. McLaren is grateful of the support that the company received from the Cambridge Judge Business School to get itself off the ground. “The mentorship and coaching provided by the Accelerate Cambridge programme in particular has been vital to getting our business to its current stage, and the credibility of the Cambridge brand has allowed us to engage with some great academic and commercial partners.”
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AvantiCell hepatic organoids
Ayrshire Life Science Company launch advanced scientific technology to support successful drug development AvantiCell Science is a life science company based in Ayr, with a mission to provide leadingedge ethical tools which offer the prospect of faster, more efficient progress towards better drugs, safer chemotherapy, and improved healthcare. An important preclinical test of drug safety is to evaluate their effect on the liver, and drug-induced liver injury (DILI) remains a major health concern. It contributes to over 50% of acute liver failure and is the leading cause of drug removal from the market. DILI occurs when the toxic properties of medicines damage the cells of the liver, resulting in their reduced function and ultimately their death. Individual liver cell death can lead to a cascade of clinical symptoms, from fatigue and abdominal pain to jaundice. The incidence of DILI could be lowered with more effective preclinical testing of medicines to monitor their toxic effects. Existing methods for preclinical testing have, of course, served their purpose (otherwise we wouldn’t have the life-saving drugs that we have!) but with more than 90% of potential drugs failing clinical trials due to inadequate safety and efficacy responses, there is a responsibility within the
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scientific life science community to make improvements, which is where AvantiCell Science’s exclusive organoid technology comes in. “Organoids” are miniaturized and simplified organs, grown in three-dimension in the lab, to study disease and therapeutics. AvantiCell’s Human Hepatic Organoids are derived from human adult stem cells of the liver, using donated tissue from liver biopsies as an ethical alternative to animal use. When grown under the right conditions, these cells mimic how they would behave in the body, giving more relevant responses to drugs, which then allows more informed selection of drug candidates for clinical testing, and a lower likelihood that the candidate will fail after enormous financial investment. From early-stage discovery to late-stage quality control of production, and even in basic academic research, AvantiCell’s Human Hepatic Organoids can be valuable, and their use could prevent an immense amount of money being wasted every year on inefficient or unsuccessful drug development. For more information on AvantiCell Science and their expertise in primary cells and cell-based assays, please visit www.avanticell.com, call 01292 521 060 or email sales@avanticell.com
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Reducing the risk of bio-contamination in gene, cell and CAR-T therapy Bioquell’s Dr Rolf Hansen examines how the latest isolator systems create aseptic working conditions for reducing risk and keeping gene, cell and CAR-T therapies efficient, compliant and accurate, whilst also supporting biologics manufacturing expansion and enabling more patients to be treated at the same time. Gene, cell and CAR-T therapies are the latest techniques that use genes to treat or prevent diseases such as inherited disorders and some types of cancer and viral infections. In the future, it is likely this rapidly emerging process will allow the medical profession to treat a variety of conditions by inserting a gene into a patient’s cells instead of using conventional drugs or surgery. Although a promising treatment option for certain diseases, gene therapy is a delicate process and is still being researched to ensure it is safe and effective. Bio-contamination found in critical zones within the gene, cell and CAR-T cleanroom environment can put successful patient outcomes at risk, and also have serious financial consequences and a detrimental impact on operational resources. The critical nature of gene therapy means it is essential to keep cells free from contamination by microorganisms such as bacteria, fungi and viruses. The risk of microbial contamination is exceptionally high during the complex cell production procedure which typically comprises multiple stages, all demanding accuracy and the highest standards of quality control. As a result, regulators are increasingly specifying that Good Manufacturing Practice (GMP) biologics facilities be more proactive in providing an aseptic environment with sterile work areas, reagents, media and handling. To ensure GMP compliance for stringent aseptic techniques, cell therapy companies, hospitals and service providers are choosing the latest isolator systems for containing the cell manipulation process. Advanced isolator technology is ideal for the critical nature of gene, cell and CAR-T therapy, helping to reduce the risk of contamination by microorganisms or another patient’s cells through product handling and environmental exposure. Offering space and energy saving benefits, isolators allow cells with limited exposure times to be quickly handled under controlled aseptic conditions and worked on with fully decontaminated tools. Bioquell has developed the Qube work station for the aseptic processing and transfer applications widely used in gene, cell and CAR-T therapy applications. It is the only modular isolator in the world to offer Bioquell’s built in Hydrogen Peroxide Vapour technology for rapid decontamination, reduced risk and major cost benefits. Traditional cell therapy processes require an array of bulky equipment and repeated measures to mitigate risk exposure between transfers and manipulations. The Bioquell Qube far outperforms traditional isolators for decontamination, providing an effective aseptic environment from R&D through to the manufacturing process. Bioquell’s Qube workstation offers a guaranteed safe and productive ISO 5/EU Grade A environment for GMP compliance, providing an added level of protection from costly and hazardous bio-contamination.
Used with the Qube aseptic workstation, Bioquell’s Hydrogen Peroxide Vapour achieves more in less time by starting the decontamination cycle immediately. It eliminates the need to reach temperature or humidity levels to begin the process with the Hydrogen Peroxide Vapour providing sporicidal for a 6-log kill over every exposed surface. It is also fully compliant with the European Biocidal products regulation (528 / 2012). Both modular and adaptable, the Qube offers up to three Bioquell Qube aseptic workstation chambers (two gloves in each) with optional material passthroughs and Rapid Transfer Ports (RTP) designed to meet workflow needs. It enables decontamination of materials in one chamber whilst operatives work in another, and offers aseptic-hold retention for typically seven days depending on protocols. With most organisations starting with one system, Bioquell offers the option to add chambers at a later date to suit capacity requirements. Each Qube hosts a chamber integrated with a Bioquell vaporiser module. Operators can choose to decontaminate within this workspace only or open connecting pathways to decontaminate adjacent chambers. With peace of mind that the Qube is implementing thorough decontamination, operators can focus on the job in hand. Available with four levels of environmental monitoring for all viable and nonviable particle needs, the Qube has ability to incorporate the Merck Millipore Sigma Symbio Flex Sterility Pump and other distinctive options to ensure maximum efficiencies. The Bioquell Qube is simple to install, does not require ventilation, can switch between negative and positive pressure and uses a standard outlet so electrical work is rarely needed. Optional accessories such as sterility test pumps, environmental monitoring and racking options can be incorporated within the isolator. Bioquell’s advanced isolator manufacturing process ensures product consistency, increased production efficiencies and shorter lead times. Without a doubt, today’s modern Isolator solutions for gene, cell and CAR-T therapies create aseptic working conditions that keep this valuable, life-saving work efficient, compliant and accurate. www.bioquell.com
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Risk Reduction Solutions for Pharmaceutical, Life Sciences & Healthcare Trusted and Effective Biodecontamination Solutions using our unique Hydrogen Peroxide Vapour technology
Bioquell | Qube The unique, adaptable isolator system with integrated Hydrogen Peroxide Vapour technology applied for gene and cell therapy. Integrated with Bioquell’s Hydrogen Peroxide Vapour Technology 2, 4, or 6 glove isolators with optional RTP or material pass though endcaps Capable of decontamination cycles in nearly 20 minutes Ideal for time and/or heat sensitive processes Compliance Adherence include CMP, USP 797, USP 800 and more Manufactured, installed and validated in as fast as 12 weeks from order date Potential to decontaminate materials in one chamber while you work in another Aseptic-hold retention for typically seven days depending on your protocols No construction or electrical work required for installation typically
Bioquell | RBDS
Rapid Bio Decontamination Service
From the smallest enclosure to a large building, our skilled personnel provide the customised treatment you require, whether scheduled or emergency.
To find out more information T: +44 (0)1264 835 835
E: enquiries@bioquell.com
W: www.bioquell.com
| news |
| BIOSCIENCE TODAY |
New bacterial strain named after Cornish discovery A new bacterial strain will be named after Cornwall following its identification from a skin infection. Staphylococcus cornubiensis, named after the medieval name for Cornwall, Cornubia, was isolated from a sample submitted to the laboratory by a local GP. Cornwall-based researchers at the University of Exeter Medical School and the Department of Clinical Microbiology at the Royal Cornwall Hospital in Truro, investigated its similarity to known related bacteria. They found that the strain was unique and likely belonged to the Staphylococcus intermedius group (SIG), a group of bacteria that is also associated with pets. The work was in part funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC) and is published in the International Journal for Systematic and Evolutionary Microbiology. Dr Michiel Vos, principal investigator on the study at the University of Exeter Medical School said: “Routine hospital microbiology procedures focus on the isolation of well recognised infective species. However, although bacteria on agar plates can look deceptively similar, they often represent a rich genetic diversity, with substantial variation in infectivity and susceptibility to treatments, including antibiotics. “By improving detection methods, we were able to distinguish this species from related species. Sequencing the entire genome, we could confirm it to be genetically unique.”
Lead author Dr Aimee Murray added: “We now need to know how prevalent this new species is in human infections. As some related species are transferred from pets to humans, we also would like to find out whether owning pets, or any other potential risk factors, increase the chance of infection.” John Lee and Richard Bendall of the Royal Cornwall Hospital explained that the new species was discovered during a project to increase recognition and detection of SIG bacteria in the diagnostic laboratory. Dr Bendall said: “Discovering a new species was an unexpected benefit of our efforts to improve the routine work of the department.” The full list of authors is as follows: Aimee K. Murray, John Lee, Richard Bendall, Lihong Zhang, Marianne Sunde, Jannice Schau Slettemeås, William Gaze, Andrew J. Page, Michiel Vos.
“By improving detection methods, we were able to distinguish this species from related species. Sequencing the entire genome, we could confirm it to be genetically unique.” 16
| BIOSCIENCE TODAY |
| news |
Making a difference to patients with debilitating conditions – new Healthcare Technologies Institute opened A new Institute where research will look into improving healing and make a difference to patients with debilitating conditions has opened at the University of Birmingham. The Healthcare Technologies Institute (HTI) will strive to advance new technologies and treatments that encourage better tissue healing, quicker detection of diseases, and better outcomes for patients. The Institute will take research from the laboratory through to clinical trials, where researchers are: developing new technologies that will minimise the impact of scarring on the skin and the eyes discovering rapid, real-time chemical and biological detection methods for diseases to improve long-term outcomes creating better, longer-lasting prosthetics that will allow patients to return to full function earlier finding new ways to combat antibiotic resistance to fight infections globally developing new technologies to help repair bone, teeth and cartilage discovering new technologies for future transplantation and bone defect replacement The HTI will bring together leading experts from a variety of disciplines across the University of Birmingham, including chemical engineering, biomedical science, computer science, applied mathematics, chemistry and physics. Researchers across campus will work collaboratively to speed up the translation of new discoveries into health applications. The Institute will also host the Centre for Custom Medical Devices in collaboration with Renishaw, one of the world’s leading engineering and scientific technology companies with expertise in precision measurement and healthcare. The centre will bring together multidisciplinary expertise to explore the full potential of additive manufacturing, otherwise known as 3D printing, in the healthcare sector, driving innovation at all stages of the medical device supply chain, from implant simulation through to manufacturing prosthetics that overcome healthcare challenges such as infection. Professor Liam Grover, Director of the HTI, University of Birmingham, said: “There is an increasing demand to deliver new technologies that allow us to more rapidly diagnose and better treat patients. Advances in medicine mean we are living longer than ever before, alongside our chances of survival following devastating, life-changing events. However, these successes lead to major challenges - we’ve extended life expectation, but there is no commensurate improvement in quality of life. This demand has led to a rapid increase in the amount of research needed to be undertaken to develop new healthcare technologies.
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“Through our research at the HTI, we will aid healing and make a difference to patients with debilitating conditions to ensure people are able to live longer, healthier and happier lives.” Dr Sophie Cox, from the University of Birmingham’s Centre for Custom Medical Devices, said: “3D metal printing, also known as additive manufacturing, is a healthcare revolution. It removes many of the limitations seen in more traditional manufacturing methods, and opens up the possibilities for innovations that are both structurally and medicinally customised to the patient. For example, we are changing implant design so that we may incorporate antimicrobials either on the surface or within the device itself. This will enable local therapeutic delivery which is known to be more effective at treating implant infections. In the long term we are also looking at how we can change these devices to prevent infections.”
| news |
| BIOSCIENCE TODAY |
This artist’s concept shows a very young star encircled by a disk of gas and dust, the raw materials from which rocky planets such as Earth are thought to form. Image Credit: NASA/JPL-Caltech
Watery Earth mystery solved by dust Scientists at the University of St Andrews may have helped solve the mystery of why there is so much water on planet Earth. An international team of researchers has discovered that small dust grains (no bigger than a millimetre) can accumulate substantial amounts of water from the surrounding gas and ice before they start to collide, stick and form the Earth with enough water to explain the Earth’s oceans. Researchers from St Andrews, with colleagues from the Max Planck Institute for Extraterrestrial Physics in Germany and the University of Groningen, Delft University of Technology and Tilburg University in the Netherlands, concluded that this process takes only one million years, which is enough time, according to common evolutionary scenarios, for star and planet formation. The water-rich dust grains clump together to form first pebbles, then kilometre-sized boulders and, eventually, Earth. The research is published in the journal Astronomy and Astrophysics.
Dr Peter Woitke, of the Centre of Exoplanet Science at the University of St Andrews, said: “The mystery as to why Earth has so much water has previously baffled. One theory suggested that the water was delivered by icy comets and asteroids that hit the Earth. A second scenario suggests the Earth was born ‘wet’ with the water already present inside ten-kilometre-wide boulders from which the planet was built. However, the amount of water that these large boulders can contain is disputed.” This latest research calculated a variant of the boulderwith-water scenario. The most common materials the dust grains and boulders are made of are silicates of various types, some of them similar to sand on the beach. These silicates have been shown to be capable of hosting water molecules in their lattice structure, the co-called ‘wet silicates’. The new journal article shows that these wet silicates form naturally in space already below about 150°C, if time permits.
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| BIOSCIENCE TODAY |
| news |
Gene therapy breakthrough in treating rare form of blindness The positive results of the world’s first gene therapy trial for a genetic cause of blindness known as choroideremia have been reported in Nature Medicine. The trial involved 14 patients receiving a single injection into the back of the eye of a virus containing the missing gene and began in 2011 at the Oxford Eye Hospital - part of the Oxford University Hospitals NHS Foundation Trust. By the end of the study there was a significant gain in vision across the group of patients as a whole. Furthermore, of the 12 patients who received the treatment without any complications, 100% either gained or maintained vision in their treated eyes, which was sustained for up to 5 years at the last follow up. During this time only 25% of the untreated eyes which acted as controls maintained vision. The gene therapy treatment was generally well tolerated and there were no significant safety concerns.
Professor Robert MacLaren the ophthalmologist who led the trial said: “The early results of vision improvement we saw have been sustained for as long as we have been following up these patients and in several the gene therapy injection was over 5 years ago. The trial has made a big difference to their lives.” The success of the Oxford study has since led to a much larger international gene therapy trial involving over 100 patients across nine countries in the EU and in North America. It is now led by Nightstar Therapeutics, a gene therapy spin-out company established by the University of Oxford and Syncona to develop the treatment further. If successful the follow on trial could result in the gene therapy treatment being formally approved by the relevant regulatory bodies worldwide. Overall gene therapy is a new treatment that is currently being developed in several trials for a variety of diseases. The concept of gene therapy is to alter or correct inherited diseases at the level of the DNA and if successful, a single treatment might have life-long effects. These early results support the notion that a single gene correction can have long-lasting beneficial effects on nerve cells of the retina to prevent blindness. Choroideremia is one disease in a spectrum of inherited eye diseases sometimes referred to as ‘retinitis pigmentosa’ and which have now become the most common cause of untreatable blindness in young people. Last month, the European Medicines Agency formally approved its first gene therapy treatment for a different eye disease. Experts predict that other currently incurable diseases are likely to follow and will have approved gene therapy treatments in future years. Dr Neil Ebenezer, Director of Research, Policy and Innovation at Fight for Sight, said: “All research breakthroughs are made by standing on the shoulders of others. Our mission is to fund research that will stop sight loss and we’re delighted to have been part of this breakthrough which will have huge benefits for the future. This technique could transform how we treat diseases and could have broad applicability to a range of other conditions.” Chris Hollowood, Chief Investment Officer at Syncona, commented: “Nature Medicine’s publication of the findings of the first choroideremia gene therapy trial is a great endorsement of the work by Professor Robert Maclaren and the team and validation of the early results that encouraged Syncona to partner with Robert to found and build Nightstar. Since then, Nightstar has advanced the therapy to a pivotal Phase 3 trial. We look forward to continuing our support of Robert and Nightstar as we seek to bring transformational treatments to patients.”
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| biomedical research |
| BIOSCIENCE TODAY |
Simplicity is In this issue of BioScience Today, Ellen Rossiter speaks to Professor Kawal Rhode about his work in the realm of biomedical engineering, his inspiration, motivation and why simplicity is all. “Way back in school, we were taught science in a very thorough way, spending at least a day a week in the lab, which sparked my interest. I initially studied medicine at Guy’s and St Thomas’ NHS Foundation Trust and during the course, I had the opportunity to study medical imaging for a year – this was really when my research career started.
“She came up with a simple solution which involved taking 3D images of their ribs before surgery, then building a 3D model of the ribs, before reconstructing them using bone cement. It is a simple modelling procedure from a cast which we are performing on a patient for the first time in the next few weeks.
“I was fortunate that the hospitals had a pioneering course in imaging sciences and I got to work with some of the greatest in that field including Professor Raymond Gosling, who actually took the famous image known as ‘Photograph 51’.
“At the other end of the spectrum, we have a team of ten people working on a robot that can take multiple ultrasound scans, which will takes about 3-4 years to build. But very often simplicity results in the most purposeful thing.
“Under the tutelage of his research team, I built software that enabled measurements to be made of the stiffness of the aorta in patients with diabetes – enabling the progression of vascular diseases to be monitored, so from an early stage, I was involved in projects that were highly translational. This project proved to be a turning point – it was then that I realised that I wanted to be a research scientist rather than a clinical doctor. “Later, I studied for my PhD in the Department of Radiological Sciences at King’s College London and at the Department of Surgery at University College London, looking at x-ray images of the coronary arteries and trying to work out how to quantify the passage of contrast material when it had been injected into patients – which consolidated my career in biomedical engineering. “The most surprising thing that I’ve found in my career is that despite the sophistication of the tools and systems at our disposal, in the real world, simplicity is all powerful. Some of the simplest things have a huge impact on care pathways for patients. “A recent example is an undergraduate student of mine who noticed the problems encountered by patients undergoing surgery to remove lung cancer, whose ribs were often irreparably damaged during the process.
“Bringing people together and getting the best out of them is the most impactful part of the job. Mine is a peoplecentred role; it is as much about the way you work with others than your own capabilities. “A little bit of freedom can be extremely valuable in a research setting, we respect everyone’s capabilities, giving them the freedom to be creative, so they can extend their skills and we can grow together as a team. “The focus of the School of Biomedical Engineering and Imaging Sciences is to develop things that can be translated so that they solve real-world problems. Once, when visiting Dallas Children’s Hospital, I saw a navigation system being used to repair a child’s heart which had been built by my team in partnership with Philips Healthcare - it was quite emotional. It is moments like this which make it all worthwhile and you know that your work is making a difference. “Having an engineering department in a hospital is extremely advantageous, clinicians can visit us and discuss the problems they are encountering so that we can work on a solution. Once a clinical colleague walked into the department and discussed the challenges of passing tubes into patients’ stomachs, within a short time we anticipate having a solution that will make the process more comfortable and successful.
“We are living in difficult times, we’ve got a lot of problems in the western world, including dealing with an ageing population – which is increasing the burden of disease. Biomedical engineering has a large part to play in solving this crisis, so it is a very worthwhile branch of engineering in which to be working and one of the major motivators in my life is to build the engineers of the future.” 20
| BIOSCIENCE TODAY |
| biomedical research |
all Professor Kawal Rhode “It is essential that the engineering department is multidisciplinary, as it affects the scale of things we can achieve and the scale of the problems we can take on. The end game is to see the equipment we’ve developed being used on patients. “We’ve got lots of projects going on at the moment, but one of the largescale projects, which is funded by the Wellcome Trust, is aimed at improving the diagnosis of foetal abnormalities at the 20- week scan. “When we looked at the national statistics we realised that these scans had a detection rate of only 50%, meaning that one in two failed to detect serious abnormalities. However, this average figure hides a huge variability around the country with some scans having an accuracy rate of 95%, whilst others were as low as 30%. “We are building a robot with the hope of making these scan results more consistent, it won’t perform the scan as well as the best person, but it will do them better than average. Overall, the robot will help raise the accuracy rate, enabling parents to make more informed decisions and in some cases enable in utero treatments to be performed, so the impact of this project is potentially huge. “As long as we know they can do what we say they can do, using robots in the healthcare environment is an effective way to put resources where they are most needed, meaning doctors can spend more time with patients seeing how their treatment is progressing and utilising the people skills that can’t ever be replaced by a robot.
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“We are living in difficult times, we’ve got a lot of problems in the western world, including dealing with an ageing population – which is increasing the burden of disease. Biomedical engineering has a large part to play in solving this crisis, so it is a very worthwhile branch of engineering in which to be working and one of the major motivators in my life is to build the engineers of the future. “Here at King’s College London, we are at the forefront of tackling these long term issues. Our vision is to make the world a better place and our next steps are to get a lot of good projects translated into the clinical environment. “Connectivity has opened up research possibilities, our work is global rather than local, with partners all around the world, it is now much easier to know what research is going on and progress is being made at a much faster pace. “The materials we need are more easily available now and at a lower cost too, so that when I need a piece of equipment I can get it almost immediately, all of which means the research cycle has become much quicker and we can get things out into practice sooner. “Research in the UK is booming and being a research scientist here is a wonderful career – it is a very satisfying job as you are developing yourself whilst also having an impact on society, plus the research world is much more diverse and inclusive than was once the case. “The UK is a world leader in research, with some of the topranked research universities based here and as a research scientist you are addressing real problems and you can make a difference.”
| biomedical research |
| BIOSCIENCE TODAY |
Artificial Neural Networks working with Image Guided Therapies to improve heart disease treatment It’s exciting to envisage that future treatments for cardiovascular disease will be supported by intelligent systems and devices. At the NIHR Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London we are constantly looking at using the latest technologies to enhance and support quicker, more efficient diagnosis and more accurate treatments for patients with cardiovascular disease.
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| BIOSCIENCE TODAY |
| biomedical research |
By Rashed Karim
Research Fellow at King’s College London School of Biomedical Engineering and Imaging Sciences The burden of cardiovascular disease on the NHS and patients is significant. In the UK alone, 7 million people are affected by cardiovascular disease at any one time. Most common conditions include heart attack, coronary heart disease, heart failure and atrial fibrillation. The total annual healthcare cost of cardiovascular disease is £9 billion a year, with an estimated disease cost of £19 billion to the UK’s economy. We think that using machine learning in the field of imaging could be a game-changer for these conditions. Currently imaging is a vital tool in diagnosing and treating heart disease – since the heart is buried deep in a patient’s chest, imaging helps clinicians to understand a patient’s condition and plan their treatment. But analysing images takes up vast amounts of clinicians’ time. If we could use machine learning to do some of this work, this could allow us to start patients’ treatment sooner and therefore improve success rates. Another benefit would be freeing up time that clinicians currently spend analysing scans and therefore reducing costs for the NHS.
CAN WE TEACH MACHINES TO READ HEARTS? We have focused our research on using machine learning to diagnose and treat Atrial Fibrillation (AFib). AFib, when the heartbeat is irregular and often abnormally fast, is one of the most common forms of abnormal heart rhythm and a major cause of stroke. There are 1.3 million people diagnosed with the condition in the UK, with a further 500,000 estimated to be living with undiagnosed AFib. Most patients with symptoms of AFib are diagnosed via Magnetic Resonance Imaging (MRI) - a 3D scan of the heart. These images are complex, showing the muscle tissue of the heart, its chambers and the special muscle bundle network that tell the heart when to beat. To create these 3D pictures, hundreds of images are taken and put together. Because of this, the volume of data acquired during these scans is vast, in the region of gigabytes. Processing all of this data in a timely manner has become a real challenge. Usually the first step in analysing a 3D cardiac MRI scan is segmenting and classifying important information within an image. In AFib, the left atrium, which is a complex upper chamber of the heart, needs to be identified and outlined by a radiologist before it can be fully appreciated in 3D. This can take a very long time and sometimes a second type of scan is necessary to get enough information to plan treatment. If the atrium can be outlined from just one scan, clinicians can put together a treatment plan sooner, deliver it to patients quicker, and with fewer hospital visits. We have been working to develop more efficient ways to read these scans, using machine learning and application of computing systems known as artificial neural networks (ANNs). ANNs are inspired by the biological neural networks that make up the brain. This means they could ‘learn’ how to read the images just like an expert radiologist. But they could read these images far more quickly and around the clock. Humans need to sleep and eat occasionally, but machines don’t. We have used a special type of an ANN which can learn the anatomy of cardiac chambers from hundreds of MRI scans that have been manually annotated by consultant clinicians. The entire network can be trained on thousands of manually annotated images in less than half a day. Once trained, it can help us segment an MRI image in less than a minute.
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Using these imaging techniques and machine learning will assist clinicians in detecting cardiac conditions with greater accuracy over the currently applied diagnostic tools and approaches, and in a fraction of the time. The more accurately and quickly we can understand patients’ conditions, the more likely it is that our treatment will be successful.
GUIDING TREATMENT WITH IMAGES After they have been diagnosed with heart failure, part of treatment for many patients is to undergo cardiac resynchronization therapy (CRT), where a cardiac pacemaker is implanted. Pacemakers are small, creditcard sized electrical devices that are implanted in patients’ hearts to regulate their heart beat if it is too fast, too slow, or irregular. CRT pacemakers have three electrode leads which are implanted into the heart tissue – they sense the heart’s beat, and send electrical signals to stimulate a regular heartbeat. 25,000 people a year in the UK have a pacemaker fitted to treat a variety of heart conditions, including heart failure. This number has increased over the last 30 years. Statistics show that with current diagnostic and treatment methods, 30-50% of patients do not benefit from pacemake implants, with many patients requiring a repeat procedure. One key factor for success is placing the pacemaker and the leads in the optimal place, and the best site is specific to each patient. Most surgeons, however, place the lead in the same location for every patient. Our hypothesis is that if we can find areas of the heart that will respond to the pacemaker poorly and ensure the electrodes are not implanted in these areas, we can increase the chance of the treatment being successful the first time, and reduce the number of patients having to have repeat procedures. For instance, one region we know has a poor response rate is scar tissue from previous heart attacks. We aim to make the implantation of a pacemaker more tailored to each patient by using image technology to guide therapy. Working in collaboration with Siemens, we have developed a technique to identify regions within the heart that respond best to signals from a pacemaker. These regions are automatically identified by a computer algorithm and classified into varying degrees of responsiveness. The computer algorithm analyses the MRI images and makes detailed measurements of various properties of the heart muscle tissue. Together these measurements can help clinicians identify the best place for a pacemaker in each individual patient. The use of intelligent systems and technical innovations like artificial neural networks and image guided therapies have the potential to significantly improve outcomes for patients, while reducing the cost of cardiovascular disease for the NHS.
Most common conditions include heart attack, coronary heart disease, heart failure and atrial fibrillation. The total annual healthcare cost of cardiovascular disease is £9 billion a year, with an estimated disease cost of £19 billion to the UK’s economy.
90 years
| antibiotic research |
since Sir Alexander Fleming’s penicillin discovery changed antibiotic treatment the first time it really hit home. It was then that I really learned the importance of who he was and what he had done.”
DID YOU REALISE HOW SIGNIFICANT HIS DISCOVERY OF PENICILLIN WAS? “When I started to look into nursing as a career, I saw the big picture. A lot of what we talked about at home was just family stories, when we went to visit my grandfather’s birthplace, when we were on holiday. I was really awestruck when I went to St Paul’s Cathedral and went down to the crypt where his ashes are interred and I looked at all the names of all the famous people around, such as Wellington and Nelson. Attending the opening of the Sir Alexander Fleming building at Imperial College London, and meeting Her Majesty The Queen also gave me a huge sense of pride.”
DO YOU KNOW WHAT MOTIVATED THE DISCOVERY OF PENICILLIN?
“My name is Sarah Whitlow and my paternal grandfather was Sir Alexander Fleming, who discovered penicillin. I have worked as a practice nurse at the Swan Surgery in Bury St Edmunds, Suffolk, since 1990, training as a staff nurse at the West Suffolk Hospital before that. I am proud to say I was born a Fleming!” WHEN DID YOU FIRST BECOME AWARE OF YOUR GRANDFATHER’S WORK? “My grandfather died before I was born but through our family memories, we have always remained amazingly proud of him. The first time I really twigged who grandfather was, was when I was about ten-years-old and there was a programme on the television about him. The actor Bill Owen was playing my grandfather, and we were invited up to the television studios at Wood Lane in London. My father was there as an advisor and that was
“Inoculations were where his work was mainly focused initially, but during the First World War he became an acknowledged expert in the bacteriology of wound infection through the terrible wounds that he saw. He discovered Lysozyme, the body’s natural antiseptic, this he considered his best work as a scientist. Before he died he was looking into vaccinations into polio and other diseases. He was always reading and had such an inquisitive mind, always questioning, and instead of finding a bit of mould and throwing it away he said: “ah, that’s interesting!” I have been reading a lot about him and it’s scary because I find myself saying: “I do that!””
CAN YOU OFFER US ANY OTHER INSIGHTS INTO FLEMING THE MAN? “When people say “Who would you have as an ideal guest at an imaginary dinner party?” it would be him. I would’ve loved to have met him. I re-read a few of his letters recently. He was very much a family man and his nieces and nephews thought he was great fun. My grandmother would throw him and my father out of the house on a Sunday and they would do a few things in the lab and then go off together to get lunch, or go to Regent’s Park, go on the river. When the accolades started coming in, my grandfather was a bit overwhelmed, but in the end he started to quite
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| BIOSCIENCE TODAY |
| BIOSCIENCE TODAY |
| antibiotic research |
“I was really awestruck when I went to St Paul’s Cathedral and went down to the crypt where his ashes are interred and I looked at all the names of all the famous people around, such as Wellington and Nelson.” enjoy it! People would invite him to events all over the world and he met the famous people of the time. Though he remained quite a private man.”
tonsillitis she had medicine discovered by my gramps. If that had been one hundred years ago, she would have been a very, very sick little girl.”
HAS BEING FLEMING’S GRANDDAUGHTER ALWAYS BEEN A POSITIVE THING?
FLEMING FAMOUSLY PREDICTED THE RISE OF ANTIBIOTIC RESISTANT INFECTIONS
“At school, it was always “you should be able to do that” because of who my grandfather was. They would say “You are from an intelligent family” and I knew I had a lot to live up to, here.
“We’re human beings and say to ourselves “we will worry about that tomorrow and anyway, antibiotics are so available”. The problem is in other parts of the world you can buy them over the counter, people don’t complete the courses prescribed to them and they are misused in farming. My grandfather suspected that was going to happen and that was a risk.
I went into nursing because I liked biology and was inquisitive as to how the body works. Our family has always believed in service too. It is quite amazing when you think of what a change his discovery made to the lives of people. It was such a positive contribution and because of it, so many other things have been learned but also new treatments and operations have become possible.”
Since my grandfather’s day people have become more frightened of illness. They won’t sit and wait to get better, they feel they must get rid of it. People say “I can’t be ill” and yet it is a normal fact of life.
AS A NURSE YOU MUST HAVE SEEN HIS DISCOVERY IN ACTION
I think now is the time to find new treatments to replace our current antibiotics and that is why I am supporting Antibiotic Research UK (ANTRUK).
“I see patients all the time who benefit from antibiotics – and sometimes I let them know who my grandfather was! Health would’ve been a disaster without his discovery. I told one of my granddaughter’s (aged 6) recently that he was a very important man and that when she had
My grandfather was always optimistic and would have been similarly so about finding a solution to antibiotic resistant infections. As he said in his lifetime: “There’s never been a better time for humanity, despite the hydrogen bomb.”
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| antibiotic research |
| BIOSCIENCE TODAY |
90 years on, the time-bomb of antibiotic resistance By Professor Colin Garner The events of 28 September 1928 could justifiably lay claim to being called the most significant breakthrough in medical history. With typical ingenuity and a quantity of genius, Sir Alexander Fleming discovered bacterial-killing mould in a petri dish he had left by a window before going off on his holiday. Thus was penicillin discovered, Fleming’s legacy established and the treatment of bacterial infections revolutionised forever. Antibiotics were a miracle medication, extending life expectancy, treating blood, lung, skin and kidney infections, their potency being displayed at the Normandy Landings, where their use saved thousands of lives. And yet upon receiving the Nobel Prize in Physiology and Medicine in 1945, Fleming used an interview with the New York Times to warn that one day “misuse of the drug could result in selection for resistant bacteria.” Ninety years after his discovery, that nightmare vision is coming true. In August this year, the US Centre for Disease Control and Prevention warned that gonorrhoea could soon become resistant to antibiotic treatment. Meanwhile, a report by the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) showed that one in three (34%) of the urinary tract infection samples they had analysed were found to be resistant to an antibiotic called trimethoprim, compared to 29.1% in 2015. Then there are the 700,000 deaths globally from antibiotic resistant bacterial infections each year. Now we have a situation where antibiotics, because of poor stewardship, have got everywhere in our environment, our water and our food. Set against this background, the consumption of antibiotics has grown by 65% between 2000 and 2015. Despite some efforts to reduce needless antibiotic usage in livestock, reports by organisations such as the US Food Safety Inspection Service (FSIS) have shown that they are still being utilised in unacceptable quantities. Prescribers – including here in the UK – are still dishing out too many antibiotics and the internet has given rise to online buying, a truly dangerous pursuit. Governments meanwhile, pay mere lip service but do little else to ease what has been described as the “biggest health problem humankind faces”, while big pharma is closing down its research and development into new antibiotics because there isn’t enough money to be made from the production of these new antibiotics. Today there are only four large pharmaceutical companies researching into new antibiotic therapies. And so 90 years on from Fleming’s discovery, we have reached a crisis point which could return us to a preantibiotic age where routine hospital operations are cancelled due to fear of infection, and people die of something as simple as an infected scratch.
Put simply, now is the pivotal time for action. Whether by incentive or taxation, large drug companies need to be persuaded to get back into developing new treatments. Their much-vaunted breakthroughs in areas such as cancer will mean nothing if a cancer patient treated with the newest breakthrough therapy then succumbs to a hospital acquired infection because we have run out of antibiotics. And those hospitals need to keep up their robust progress in infection control. The public should learn not to demand antibiotics as a silver-bullet cure-all and guidance around their prescribing ought to be clear. I am encouraged that so many medical and research charities are coming together to tackle the problem, but remain concerned that antibiotic resistance is perceived as a peripheral political issue. One of the joys of celebrating the 90th anniversary of penicillin has been to meet up with Fleming’s granddaughter, Sarah Whitlow. She revealed that Fleming was an inquisitive man, always learning, never dismissing and guided by a sense of service (late in his life he had been working on vaccinations). As scientists, we could learn from his ethos. As individuals we can champion the cause of finding the cures we desperately need to save lives. And as employees we should seek to sway decision makers to ensure finding a solution to antibiotic resistance is a top priority. The media has recently been full of stories of new antibiotics solutions being found in everything from soil to bear spit and platypus milk! It is easy to be dismissive. Now is a good time to remember that a single petri dish which became contaminated with mould has changed the world. We need inquisitive scientists who like Fleming will once again find the new breakthrough medicines so that the legacy of penicillin continues – we need resource and brainpower to help preserve the health of generations to come. Professor Colin Garner is the founder and chief executive of Antibiotic Research UK (ANTRUK), the world’s first charity to fight bacterial antibiotic resistant infections. ANTRUK aims to raise sufficient funds over the next few years to bring at least one new antibiotic therapy to market by the early 2020’s. To learn more about their work and donate to their cause, visit www.antibioticresearch.org.uk
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THE CONSUMPTION OF ANTIBIOTICS HAS GROWN BY 65% BETWEEN 2000 AND 2015
| BIOSCIENCE TODAY |
| antibiotic research |
Over three million surgical operations and cancer treatments a year in England may become life-threatening without antibiotics New data published by Public Health England (PHE) show that antibiotic resistant bloodstream infections continue to rise in England, with an estimated 35% increase from 2013 to 2017 (from 12,250 in 2013 to 16,504 in 2017) Antibiotics play a critical role in preventing infections that can be a consequence of surgery and cancer treatment Public Health England’s ‘Keep Antibiotics Working’ campaign returns to alert people to the risks of antibiotic resistance New data published shows that over three million surgeries and cancer treatments may become life threatening without antibiotics. The ‘Keep Antibiotics Working’ campaign returns to alert the public to the risks of antibiotic resistance, urging them to always take their doctor, nurse or healthcare professional’s advice on antibiotics. Antibiotics are a vital tool used to manage infections. PHE’s English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report, published today, highlights how more than three million common procedures such as caesarean sections and hip replacements could become life-threatening without them. Without antibiotics, infections related to surgery could double, putting people at risk of dangerous complications. Cancer patients are also much more vulnerable if antibiotics don’t work; both cancer and the treatment (chemotherapy) reduce the ability of the immune system to fight infections. Antibiotics are critical to both prevent and treat infections in these patients. Antibiotics are essential to treat serious bacterial infections, but they are frequently being used to treat illnesses such as coughs, earache and sore throats that can get better by themselves. Taking antibiotics encourages harmful bacteria that live inside you to become resistant. That means that antibiotics may not work when you really need them. The threat of antibiotic resistance continues to grow. Bloodstream infections have increased and the report shows that antibiotic resistant bloodstream infections rose by an estimated 35% between 2013 and 2017 [1]. Despite the risks of antibiotic resistance, research shows that 38% [3] of people still expect an antibiotic from a doctor’s surgery, NHS walk-in centre or ‘GP out of hours’ service when they visited with a cough, flu or a throat, ear, sinus or chest infection in 2017. The ‘Keep Antibiotics Working’ campaign educates the public about the risks of antibiotic resistance urging people to always take healthcare professional’s advice as to when they need antibiotics. The campaign also provides effective self-care advice to help individuals and their families feel better if they are not prescribed antibiotics. Professor Paul Cosford, Medical Director, Public Health England said: “Antibiotics are an essential part of modern medicine, keeping people safe from infection when they are at their most vulnerable. It’s concerning that, in the not too distant future, we may see more cancer patients, mothers who’ve had caesareans and patients who’ve had other surgery facing life threatening situations if antibiotics fail to ward off infections.
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“We need to preserve antibiotics for when we really need them and we are calling on the public to join us in tackling antibiotic resistance by listening to your GP, pharmacist or nurse’s advice and only taking antibiotics when necessary. Taking antibiotics just in case may seem like a harmless act but it can have grave consequences for you and your family’s health in future.” Professor Dame Sally Davies, Chief Medical Officer for England said: “The evidence is clear that without swift action to reduce infections, we are at risk of putting medicine back in the dark ages – to an age where common procedures we take for granted could become too dangerous to perform and treatable conditions become life threatening. “The UK has made great efforts in recent years to reduce prescribing rates of antibiotics, however there continues to be a real need to preserve the drugs we have so that they remain effective for those who really need them and prevent infections emerging in the first place. This is not just an issue for doctors and nurses, the public have a huge role to play – today’s data and the launch of the national ‘Keep Antibiotics Working’ campaign must be a further wake-up call to us all.” Professor Helen Stokes-Lampard, Chair of the Royal College of GPs, said: “GPs are already doing an excellent job at reducing antibiotics prescriptions, but we often come under considerable pressure from patients to prescribe them. “We need to get to a stage where antibiotics are not seen as a ‘catch all’ for every illness or a ‘just in case’ back-up option – and patients need to understand that if their doctor doesn’t prescribe antibiotics it’s because they genuinely believe they are not the most appropriate course of treatment. “It’s crucial that we continue to get this message out, which is why we’re pleased to support Public Health England’s Keep Antibiotics Working campaign to make sure we can carry on delivering safe, effective care to our patients both now and in the future.”
| antibiotic research |
| BIOSCIENCE TODAY |
Combatting antibiotic resistance In the UK alone, the government estimates there are currently 5,000 deaths each year because antibiotics no longer work for some infections. Worldwide, drug-resistant infections are set to kill more people than cancer and diabetes combined by 2050 – making antibiotic resistance one of the biggest threats to global human health.
company through which he is looking to develop a cream containing epidermicin.
It is against this backdrop that a biomedical scientist at the University of Plymouth is working on projects to develop a new class of antibiotic, and discover new antibiotics for use in the future.
On top of his work with epidermicin, Professor Upton is involved in another project identifying and developing potential new antimicrobials produced by the microbiome of sponges which live deep beneath the ocean surface. He is working alongside Dr Kerry Howell from the University of Plymouth Marine Institute to develop new methods of microbial cultivation, apply them to unique samples from a source rich in bioactive molecules, and identify urgently needed new antimicrobials.
Professor Mathew Upton, from the University’s Institute of Translational and Stratified Medicine, discovered epidermicin in 2008 when he was at the University of Manchester, and, working in collaboration with worldleading industrial biotechnology specialists Ingenza, he has been developing an efficient, scalable microbial production system. Epidermicin can rapidly kill harmful bacteria including MRSA (methicillin resistant Staphylococcus aureus), Streptococcus and Enterococcus at very low doses, even if they are resistant to other antibiotics. The antibiotic was initially recovered from a skin bacterium named Staphylococcus epidermidis, but can now be produced in a microbe suitable for industrial scale-up, using synthetic biology methods developed by Ingenza. In the form of a nasal ointment, epidermicin has delivered remarkable results in infection model trials, with a single dose proving as effective as six doses of the current standard clinical therapy. Now, working with University commercialisation partners Frontier IP, Professor Upton has launched his own spinout
Through the company, Amprologix, the next phase of development for epidermicin is pre-clinical trials, which, if successful, would pave the way for testing on human volunteers and ultimately the creation of a licensed drug within the next six years. The team is also researching alternative uses for the drug, such as investigating whether it is effective against superficial skin infections, like impetigo and acne.
The team is already making headway, as they have cultured more than 100 novel bacterial strains from deep-sea sponges, some of which have produced antimicrobials that can kill MRSA. As well as screening for potential antimicrobials, Professor Upton and Dr Howell are on the lookout for other potential applications in the areas of cancer, immune deficiency and wound healing. No new antibiotics have been introduced into clinical use for the past 30 years and, in 30 years’ time, resistance to existing remedies is set to be one of the biggest killers in the world. But, alongside a commitment to educating the public about the dangers of antimicrobial resistance through regularly speaking at local events, Professor Upton hopes to be part of the solution.
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NO NEW ANTIBIOTICS HAVE BEEN INTRODUCED INTO CLINICAL USE FOR THE PAST 30 YEARS AND, IN 30 YEARS’ TIME, RESISTANCE TO EXISTING REMEDIES IS SET TO BE ONE OF THE BIGGEST KILLERS IN THE WORLD.
| BIOSCIENCE TODAY |
| antibiotic research |
The search for new antimicrobials Few issues are more pressing than the global problem of antibiotic resistance, so we speak to Professor Mathew Upton, about his work searching for new antibiotics. “For so long now, antibiotics have been seen as a magic bullet capable of curing our ills and much of the medical system we’ve developed over the last 50 to 60 years is reliant on their use. “Yet as early as 1945, in his Nobel Prize lecture, Sir Alexander Fleming warned about the dangers of antibiotic resistance and today it represents one of the biggest threats to human health globally. “Many of the medical procedures and treatments that we take for granted, from hip replacements to caesarean sections and cancer therapy, are underpinned by the use of antibiotics to prevent the occurrence of infection. Yet all that we take for granted could be taken away. “In the last few years, since the O’Neill Review into Antibiotic Resistance, a lot of progress has been made in quantifying the extent of the risk; and we know the challenge has to be addressed on many fronts.” The O’Neill Review made a number of recommendations, including improved infection control, ensuring antibiotics are used appropriately in humans and animals; the research and development of new drugs and diagnostic tools; plus, adequately monitoring the prescription of antibiotics and the rise of resistance. “Efforts are focused on combatting antimicrobial resistance either through prevention with vaccines and improved hygiene or by developing new antibiotics,” explains Mathew. “Public engagement and awareness also have a huge role to play in changing behaviour and improving personal hygiene to reduce general levels of infection and minor illness. “Given viral infections are often followed by bacterial infections, washing your hands is crucial. If we pick up fewer viral infections, our immune systems will work better, and we’ll be less susceptible to bacterial infections reducing our need for antibiotics. “When we do catch a cold or have a sore throat, we are in many cases better off relieving the symptoms rather than reaching for antibiotics. We mustn’t take antibiotics for granted and when they are prescribed, it’s imperative that we take them as directed and that we use the whole course.” In addition to raising awareness, Mathew’s work focuses on finding new antibiotics that work in different ways to conventional antibiotics. He leads a team of researchers working in the field of antimicrobial resistance, discovering and developing new antimicrobials. “Bacteria evolve very quickly and have many resistance mechanisms, but in the last ten years, we’ve learnt a lot
Professor Mathew Upton about tracking and tracing this resistance. Now we are looking for novel antibiotics that work differently and are not threatened by these mechanisms. “Until recently, the technical methods used to discover new bacteria were similar to those used in the 1950’s and 60’s, but using these methods means that there is a risk that you find things you’ve seen before. “However, a few years ago, researchers at North Western University developed a new approach to growing bacteria from environmental samples, which was a really important step forward, meaning there is a whole new library of bacteria that we can start screening. “When you have a novel lead, you’re interested in getting to the point when you know it is new, but this takes quite a while and can be frustrating. However, new technology, like DNA sequencing analysis tools, enable you to get to this point a lot quicker by identifying the genes important for the production of novel antibiotics. “The formation of Amprologix is a huge step and I see it as accelerating future developments in which we hope to take some of these interesting antibiotic candidates through to clinical trials. “Suffice to say, any new antibiotics found will be used in a very different way to those we’ve relied on over the last 50 years and this should help ensure they remain useful for as long as possible.”
“as early as 1945, in his Nobel Prize lecture, Sir Alexander Fleming warned about the dangers of antibiotic resistance and today it represents one of the biggest threatS to human health globally.” 29
| intellectual property |
| BIOSCIENCE TODAY |
The IP journey and Paul Storer
Senior Policy Adviser in the Business Support Policy Team at the IPO
Resolving IP disputes can be costly and the Intellectual Property Office continues to seek to reduce costs for businesses, not only in relation to disputes but, at every stage of the IP journey. We have made some real progress in improving access to justice at proportionate cost for small firms involved in IP disputes. We have helped reform of the Patents County Court (now the Intellectual Property Enterprise Court [IPEC]1) and modernised the IPO Mediation Service.2 We have also worked with legal organisations like the Chartered Institute of Patent Attorneys to encourage the introduction of IP Pro Bono.3 Beyond the area of legal disputes we have focused our energies on improving the understanding and maximising the benefit of IP for growing companies. For instance, with our partners, we have introduced an IP Audit Scheme to help businesses to recognise and understand their intangible assets and to manage them more strategically. And our IP Finance Toolkit4 helps businesses, banks and investors speak the same language in relation to IP assets. We are working with the insurance market to raise awareness of, and provide access to, IP insurance specifically Before the Event Legal Expenses Insurance (BTE LEI) - as an option to transfer the risks of a costly IP dispute. Our interest in insurance is in its potential to deter wouldbe infringers (or at the very least bring parties to the table) and not to facilitate litigation. The capped scale of recoverable costs (maximum £50k) in the IPEC has brought some certainty around financial exposure for business (the loser pays in the UK). It has also presented an opportunity for insurers: indemnities could be lower which can result in lower premiums. Consequently, there are now far more affordable IP insurance products on the market, some of which are centred on IPEC. Of course, with all types of insurance the reality is that the higher the risk, the higher the premium. IP insurance is no different. In some cases, IP insurance premiums can climb quite steeply depending on sector and geographical cover. So, our advice is two-fold: to shop around for quotes and; where possible, take out cover as early as is practical.
You will find useful information on IP insurance providers and advice to help you to navigate the ins and outs of IP insurance5 on the IPO website. Aside from cost, the typical misconception around IP insurance is that ‘it doesn’t do what it says on the tin’. Like any insurance, it is important to understand clearly what the insurance does or does not cover – the T&Cs. Here it is crucial to consult a specialist insurance broker to avoid any surprises later - you will also find a list of IP brokers on our website. The IPO is working to improve commercial insurance brokers’ understanding of IP and IP issues around the country. We want to make sure that any business can access a specialist broker in its locality and build an understanding and relationship with them; the earlier the better. A well informed broker will advise on a strategy - for instance, taking out narrower geographical cover at the outset can mean the initial premiums are lower. Any decision whether to take out IP insurance cover or not, must be based on sound analysis and not on misconceptions around its cost and efficacy. Are intangibles at the heart of your products or services and business model? What is the risk to them of challenge from competitors? If you could not afford to assert them (or defend yourself against legal action) what impact would that have on the company? You should note that the transactional costs associated with an IP dispute are the most significant and can potentially be commercially terminal. It is curious that businesses insure against many risks, for regulatory and other reasons but key assets, the intangibles at the heart of the business, are often left exposed. It might be right to say that the imperative to consider the entire IP journey - from recognising and understanding the assets, appropriately protecting and commercialising them and, lastly, ensuring potential risks and threats are considered from day one - has never been greater. The government is supporting and encouraging UK businesses to drive sustainable international growth and to underpin its agenda for a global Britain. There are many uncertainties in making that move into other marketplaces but the right IP insurance cover may provide a business with some confidence to take the first step. 1. https://www.gov.uk/courts-tribunals/intellectual-property-enterprise-court 2. https://www.gov.uk/guidance/intellectual-property-mediation 3. http://www.ipprobono.org.uk 4. https://www.gov.uk/government/publications/banking-on-intellectualproperty-ip-finance-toolkit 5. https://www.gov.uk/guidance/intellectual-property-insurance
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| BIOSCIENCE TODAY |
| intellectual property |
risk mitigation Of course, with all types of insurance the reality is that the higher the risk, the higher the premium. IP insurance is no different. In some cases, IP insurance premiums can climb quite steeply depending on sector and geographical cover. So, our advice is two-fold: to shop around for quotes and; where possible, take out cover as early as is practical.
Intellectual Property Office is an operating name of the Patent Office
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| intellectual property |
| BIOSCIENCE TODAY |
Know your third party patent rights Jenny Vaughan
In the competitive world of the biosciences, third party patent rights (TPRs) can stand in the way of a planned course of action, even after significant investment has been made. Knowledge of such rights and potential rights at an early stage is invaluable.
Although proceedings for patent infringement cannot be brought until a patent is granted, and the scope of the patent is defined only by the granted claims, in certain circumstances pre-grant infringing actions can attract damages in post-grant proceedings. Thus, identification of potentially relevant TPRs at the patent application stage can help avoid problems and facilitate a proactive approach.
IDENTIFICATION OF THIRD PARTY PATENT RIGHTS Awareness is key to avoiding problems associated with TPRs. Patent searches, or ‘freedom to operate’ searches are useful tools for identifying potential TPRs of relevance, before significant investment is made. Patent watches can be put in place so that whenever a new patent application is published, it can be monitored and assessed.
A PRO-ACTIVE APPROACH BEFORE PATENT GRANT If a relevant patent application is identified, there is no need to merely observe its progress and wait for patent grant. A third party can take action while the application is pending.
Taking European patent applications as an example, it is possible to file formal third party observations (TPOs) on the patentability of the claimed invention. Strong, substantiated observations can alter the course of examination and even lead to refusal of the application, thus ensuring freedom to operate in the relevant area at an early stage. However, filing TPOs during examination will indicate to the applicant outside interest, potentially affecting the way any eventual patent is handled. Unsuccessful TPOs may affect the perception of the filed evidence if re-used in any subsequent action, such as in post-grant opposition proceedings. The decision as to whether to file TPOs while an application is pending is a strategic one.
EARLY ACTION AFTER PATENT GRANT In many cases a potentially relevant European patent application will just be monitored through to grant, when a formal opposition to the granting of the patent may be filed (within nine months of its grant). The opposition process involves the opponent(s) and the patentee and culminates in oral proceedings at which the patent will be maintained (as granted or in amended form) or revoked. The decision is open to appeal and the process can take a number of years. However, if successful, it will lead to central revocation of the patent, which would otherwise have to be litigated through the national courts. If you have any queries on this topic please contact Jenny Vaughan at jenny.vaughan@adamson-jones.co.uk.
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| BIOSCIENCE TODAY |
| intellectual property |
Patenting aerospace medicines – the final frontier? Julie Barrett-Major,
Consulting Attorney, AA Thornton Research and development (R&D) into aerospace medicine can be viewed as falling into one of two camps: that aimed at adapting an existing ‘terrestrial’ medicine for use in the aerospace environment; and that which is being newly developed for treating conditions that occur primarily or uniquely in aerospace. Adaptations of existing pharmaceutical formulations, delivery devices and packaging may, for example, have to account for differing temperature, pressure and other physical conditions of storage or use. If these developments are not only new but also overcome specific technical problems or provide unpredictable advantages, then they may well be protectable from copying or independent, later development by competitors. Specific patents covering these developments could be obtained, regardless of any patent protection already in place (or expired) on the existing medicine. Broader protection may be available for active ingredients (AI) newly-developed to treat unique, aerospace-related conditions. As well as the AI itself, manufacturing processes, pharmaceutical formulations and uses of the AI in general may be patentable. Alternatively, an existing drug could be trialled for such specific conditions, in which case, although the drug may be identical to one already having a marketing authorisation, its specific use or method for treating a particular condition in aerospace may be patentable.
PROTECTION AND ENFORCEMENT Patent protection and enforcement are subject to national or regional laws and procedures. For example, a UK patent on a medicine would not prevent its manufacture, sale or use in the USA; for this, a US patent would be required. The question then arises as to whether such patent laws apply in aerospace, for example, in the International Space Station (ISS). The modules of the ISS are each operated by one of the partner space agencies of Canada, Europe, Japan, Russia and the United States. The International Space Station Intergovernmental Agreement (IGA) now clarifies that the country in which a space object is registered retains control and jurisdiction (including for patents) over that space object. The main aim of the IGA is to mitigate the risk of potential infringement by each partner of each others’ intellectual property rights (IPRs), so they have agreed to create specific marking procedures to protect the ownership and confidentiality of each other’s data and goods, and those of relevant third parties (e.g. their contractors).
If an action for infringement were called for, this would have to be taken under national laws. Therefore, patent protection for aerospace medicines should be considered for each territory that has registered space objects (primarily ISS countries and China) . Innovators may also want to consider patenting in jurisdictions in which patentable medicines are likely to developed, manufactured and/or launched into space.
OWNERSHIP OF INVENTIONS MADE IN SPACE Not all aerospace medicines will be invented on Earth. The long-term presence of R&D teams in the unique environment of the ISS provides an opportunity for medical innovations eligible for patent protection (and use either in space or on Earth). However, the IGA only determines the country of inventorship (according to the ownership and registry of the ISS module in which the invention has taken place); it does not impact who owns the invention or where a patent for it can be filed. These matters are determined under the laws of the country concerned. However, special provisions apply to the European modules (e.g. the Columbus Laboratory): any European partner can elect to deem an activity to have occurred within its territory. Space activities are increasingly moving from being stateowned to private and commercial activities, or operate under international co-operation schemes governed by an international legal framework. ISS participants from industry or academia will have their ownership rights and obligations determined by their agreements with each other and/or the relevant partner agency.
CONCLUSION While the full panoply of IP protection and enforcement already familiar in the life sciences field is available to aerospace medicines, there are additional considerations to when ‘aerospace’ extends to space itself. Specific laws and regulations such as the IGA must be considered, especially for determining which terrestrial laws apply to protection, infringement and ownership of IPR. Furthermore, the complexity of inter-relationships and agreements governing space activities need careful analysis, particularly from an ownership perspective. If you have any queries regarding this topic, or other pharmaceutical or biotechnological matters, please contact Julie at jbm@aathornton.com or visit our website aathornton.com
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Trusted advice throughout your IP lifecycle
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| cancer research |
| BIOSCIENCE TODAY |
Stanford shows that breast cancers into neighbouring tissue “Showing how cells can physically invade the basement membrane suggests new therapeutic strategies for blocking invasion.� 34
| BIOSCIENCE TODAY |
| cancer research |
Stanford researchers have found that malignant breast cancer cells can extend protrusions known as invadopodia to dig escape tunnels through surrounding tissue, revealing a possible new target for therapies. Cancers pose the greatest danger when they become invasive and then spread from their originating tissues throughout the body. Although scientists have long known that cells have a chemical means of breaking free, Stanford researchers have discovered that breast cancer cells can also physically push their way out of their normal confines to become invasive tumors. The work could point to new ways of preventing cancers from spreading. The findings, published in Nature Communications, could also apply to prostate, liver, skin and many other cancers that arise from the epithelium, the thin layer of cells that lines the outer edge of many bodily organs. The epithelium is surrounded by a mesh-like structure known as the basement membrane, a thin matrix that encloses, protects and separates epithelial cells from the surrounding tissue. Ovijit Chaudhuri, the assistant professor of mechanical engineering who led the study, said the work reveals a previously unknown mechanism cancerous cells use to break through the basement membrane, allowing the tumor to become invasive.
NEW STRATEGY ROUTE “Showing how cells can physically invade the basement membrane suggests new therapeutic strategies for blocking invasion,” said Chaudhuri, who collaborated with a team of engineers and medical scientists on this interdisciplinary research. Previous research had shown that epithelial cancers use chemical tricks to invade nearby tissue. They do this by forming protrusions called invadopodia, which secrete chemicals that act like an acid to burn through the basement membrane. Katrina Wisdom, a graduate student in Chaudhuri’s lab and co-author on the paper, said the team’s work shows invadopodia can also use physical force to punch through the basement membrane rather than simply relying on chemicals, known as proteases. The group made its discovery by embedding breast cancer cells in a gelatin-like biogel that mimics the basement membrane – with one major exception. The biogel was not susceptible to protease secretions. Having nullified chemical action as an escape mechanism, the researchers used time-lapse microscopy to track the cancer cells and see whether they could move through the gel. If yes, the cells must have something other than just chemical means of escape. As it turned out, the cells could burrow through the gel. The time-lapse microscopy revealed how. Wisdom
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said the images show that cancer cells used their invadopodia like stiff arms to tear tiny holes in the biogel. Time and again the cancer cell formed and retracted its invadopodia until the repeated physical battering created an opening large enough for the entire cancer cell to scoot through.
PROCESS REVEALED Chaudhuri said the experiments revealed a previously unknown process because the biogel more accurately mimicked human tissue. It was based on the emerging idea that human tissue, especially cancerous tissue, can be somewhat malleable, like Silly Putty, rather than elastic like rubber bands. Force applied to malleable tissue imparts a permanent effect while elastic materials snap back into shape when force is released. In prior experiments predicated on the assumption of tissue elasticity, the tissue was not susceptible to breaching by a mere physical attack. But in Chaudhuri’s malleable biogel, invadopodia were able to punch out escape tunnels by brute force. Chaudhuri said the discovery of a physical role for invadopodia, independent of their previously known protease secretions, might explain why cancer drugs known as protease inhibitors haven’t been effective. After scientists discovered the chemical action of invadopodia, cancer researchers developed these drugs known to stanch protease activity. But Chaudhuri said clinical trials of those drugs proved disappointing. With the new findings about a physical means of escape, Chaudhuri is working with researchers at Stanford Medicine on strategies for blocking both the physical and chemical escape mechanisms, in the hopes that this will lead to new ways of preventing cancers from becoming dangerous. Ovijit Chaudhuri is a member of Stanford Bio-X and faculty fellow of Stanford ChEM-H. Katrina Wisdom is now a postdoctoral scholar at the University of Pennsylvania. Other authors include Robert West and Ninna Struck Rossen of Stanford Medicine; Marjan Rafat of Vanderbilt University; postdoctoral scholar Joanna Lee and doctoral candidates Kolade Adebowale, Julie Chang and Sungmin Nam of Stanford Engineering; Rajiv Desai of Harvard; and Louis Hodgson of Albert Einstein College of Medicine. The work was funded by the American Cancer Society, the National Institutes for Health and the National Cancer Institute.
| cancer research |
| BIOSCIENCE TODAY |
How chromosomes find a happy medium
By Sabrina Richards
Staff writer at Fred Hutchinson Cancer Research Center
Hutch scientists show how chromosomes communicate to balance crossovers during sexcell formation Scientists at Fred Hutchinson Cancer Research Center have worked out the molecular underpinnings of how chromosomes make the right number of crossovers – important links that make it possible for developing sex cells (eggs or sperm in humans) to sort those chromosomes properly. Crossovers are a little like Goldilocks’ porridge – they need to be just right. Too few or too many crossovers, and new cells end up with the wrong number of chromosomes, which can cause miscarriages or developmental disorders. It’s been known for 100 years that our chromosomes have a way of preventing too many crossovers along their length. What’s been missing all that time has been a working model that identifies the key molecules involved. In work published in the Proceedings of the National Academy of Sciences, Hutch molecular biologist Dr. Gerry
Smith and his team outline just such a model in yeast that explains how chromosomes find their happy medium during sex-cell formation. “What’s significant is that we’ve developed a molecular model of the proteins involved and how they work together to create crossover interference,” said Smith, the study’s senior author.
CHROMOSOMES NEED CROSSOVERS Creating a sperm or egg cell is an incredibly complex process. Among the many vital steps, genetic material packaged in chromosomes — half from mom and half from dad — must be faithfully copied and precisely parceled out to the new cells. Crossovers are needed during the parceling process. They occur when sections of the maternal and paternal versions of chromosomes overlap and connect. These connections create tension that helps chromosomes properly pull apart as the cell divides, ensuring each new cell ends up with exactly the right set of genetic material. So how do cells regulate this process to avoid too many, or too few, crossovers? A phenomenon called crossover interference, in which a crossover at one location along a chromosome reduces the
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| BIOSCIENCE TODAY |
| cancer research |
instances of another crossover nearby, was first observed in 1915, Smith said. It was discovered in fruit flies and then in most other organisms tested. But it wasn’t until 1990 that anyone proposed an idea of how it might work. “There was no molecular model,” he said. “No explanation of how the proteins involved would work together to create crossover interference.”
CLUSTERS EXPLAIN IT ALL Smith’s team unexpectedly came up with its solution to crossover interference while studying how the formation of DNA double-strand breaks (DSBs), the first step in crossover formation, are regulated. DNA is made up of two complementary strands of molecules, and a split in both strands is referred to as a DSB. Crossovers are formed when the broken end of a maternal chromosome links up with the broken end of its paternal counterpart. (This also allows maternal and paternal chromosomes to increase genetic diversity by swapping large segments.) Like crossovers, the frequency of DSBs is regulated during sex-cell formation. And both DSBs and crossovers occur at regularly spaced intervals along chromosomes, never getting too close together. To examine DSB formation, Smith and co–first authors Kyle Fowler, then a research scientist in the Smith Lab (now a graduate student at the University of California, San Francisco), and Smith Lab research scientist Randy Hyppa turned to the yeast species Schizosaccharomyces pombe. The team looked at sites in the yeast’s DNA that have higher than average numbers of DSBs, known as DSB hotspots. Hyppa and fellow author Dr. Gareth Cromie of the Pacific Northwest Research Institute found DSBs appear to “compete” with each other. If the researchers inserted into a chromosome a new DSB hotspot close to other hotspots, the frequency of DSBs at those other hotspots dropped. Conversely, removing a hotspot made the number of DSBs at nearby DSB hotspots increase. This DSB competition only reached a certain length along the chromosome. The team also looked at a related phenomenon called DSB interference. The team saw that one DSB interferes with, or prevents, the formation of another DSB on the same chromosome, so that two DSBs rarely occur close to each other on one DNA molecule. Remarkably, this DSB interference spanned the same chromosome length as DSB competition. An important clue to how competition and interference work came from looking closely at proteins called linear elements, which attach to chromosomes at hotspots. These proteins form distinct clumps when viewed under
“What’s significant is that we’ve developed a molecular model of the proteins involved and how they work together to create crossover interference.” 37
the microscope, and they must be present for DSBs to form at hotspots. Fowler found that the length of DNA in each cluster of linear elements roughly matched the distance over which DSB competition and interference act. “We think that these foci [clumps under the microscope] correspond to physical clusters of hotspots,” Smith said. Linear element proteins clustering hotspots together would explain how chromosomes “communicate” the presence of DSBs over long distances. Though hotspots are far apart along the 2D DNA molecule, gathering them together makes them near neighbors in 3D space. This means that what happens at one hotspot can easily influence the others that are now nearby. The researchers found that another protein, called Tel1, appears to take advantage of hotspot closeness to repress both crossovers and DSB formation at nearby hotspots. Without Tel1, two DSBs formed at nearby hotspots much more often than expected. The team saw a similar change in crossovers without Tel1. It appears that each cluster contains four to six hotspots (roughly the length over which DSB interference works). Smith theorizes that Tel1 senses the first DSB to form within a given cluster and likely (though this has yet to be shown) stems the tide of further breaks by turning off the activity of the proteins that create them. Based on these findings, Smith proposes that the phenomenon of crossover interference arises from DSB interference. “It just makes sense,” he said: Crossovers can’t form without a DSB, so molecular strategies that control how often (and where) DSBs form will likely also control how often (and where) crossovers form.
NEXT STEPS Smith’s team is currently delving deeper into the proteins involved in making the clusters and the nuances of crossover interference, including investigating what happens when the linear elements that create the hotspot clusters are removed. If these proteins are needed for crossover interference, then without them, the formation of one crossover should no longer interfere with the formation of others. Though predicted, it’s not yet been shown that the clusters the researchers see occur only along the maternal or paternal chromosome, or whether hotspots from both the maternal and paternal chromosomes can group into the same cluster. To help solve that mystery, Smith and his colleagues have turned to a particular yeast relative originally found in a bottle of fermented kombucha tea. When they cross this strain with their laboratory strain of S. pombe, slight variations in the kombucha-derived yeast’s DNA will help them trace the origin of each chromosome and their resulting clusters. Time will tell whether the basics of the clustering mechanism, and Tel1’s integral role, hold true in other species. Smith acknowledges that the work is a long way from solving the problem of miscarriage or other medical issues that stem from improperly sorted chromosomes. “But it does give a mechanism for how crossover interference is working. You can look through the history of medicine and see that knowing the mechanism of something is the first good step leading to either prevention or cure,” he said. The National Institutes of Health funded this work. www.fredhutch.org/en/news/center-news/2018/09/ molecular-model-crossover-interference-meiosis.html
| cancer research |
| BIOSCIENCE TODAY |
Supercharged natural killer
for cancer A type of ‘supercharged’ immune cell could be mass-produced to help fight cancer.
The researchers behind the early-stage finding, from Imperial College London, say the development could mark the next generation of cutting-edge immunotherapy treatments, called CAR-T therapies. These personalised treatments involve reprogramming immune cells to kill cancer. NHS England announced it would be making the first ever CAR therapy licensed for the treatment of lymphoma available to patients on the Cancer Drugs Fund. In the new study, funded by charity Bloodwise, the research team created a genetically engineered version of a cell called an invariant natural killer T-cell - CAR19-iNKT Current CAR-T therapies are very expensive (around £300,000 per patient), and tend to be tailor-made for each patient. However, scientists behind the current study say their newer CAR-T therapy has the potential to be ten-fold cheaper, and can be mass-produced to enable one batch to be used on multiple patients. The new research shows the CAR19-iNKT eliminated all cancer cells in 60 per cent of mice, with 90 per cent of animals surviving long-term. The scientists behind the study, published in the journal Cancer Cell, are now considering human trials. Professor Anastasios Karadimitris, senior author of the study from Imperial’s Department of Medicine, said: “These early findings suggest that a type of immune cell painstakingly engineered in the laboratory to be ‘supercharged’ holds promise as a new treatment for cancer patients.” CAR (chimeric antigen receptor) therapy is a new type of immunotherapy that involves removing a type of immune cell from a patient’s blood, and genetically altering it in the laboratory. This creates a type of supercharged immune cell primed to seek and destroy cancer cells. This new, altered cell is then multiplied in the lab, and an army of these cancer-fighting cells are placed back into the patient. This approach has been used to create new personalised treatment for leukemia and lymphoma, and resulted in up to one third of patients with no other therapeutic options going into long-term complete remission. “Cancer researchers and doctors are very excited about this therapy - it means that instead of talking to patients about a hospice, we can offer them a treatment that has a good chance of working,” explained Professor Karadimitris who is
based at Imperial’s Centre for Haematology
At the moment scientists use a type of immune cell called a T-cell to create CAR treatments called CAR-T. However, in the new study, the Imperial scientists used a slightly different type of immune cell called iNKT . Although these cells are much rarer in the body, the researchers found that CAR19-iNKT were more effective than CAR-T at eliminating cancer cells. When the team used the genetically engineered cells to treat mice with lymphoma (a type of cancer of the lymph system) they found that 90 per cent of animals treated with CAR19iNKT cells survived long term as compared to 60 per cent survival of mice treated with CAR-T cells. The researchers were surprised to see the genetically engineered cells could travel to the brain, and also tackle large tumours – raising the possibility the technology could one day be used for brain tumours, as well as other cancers such as prostate and ovarian. Dr Alasdair Rankin, Director of Research at the blood cancer research charity Bloodwise, said: “Current CAR-T therapies being approved for use on the NHS are effective for a significant amount of patients, but not everyone responds to these treatments and they are extremely expensive to make. “This very promising research is in the early stages, but it paints an exciting picture of what the future of this treatment could look like. The possibility of cheaply massproducing highly effective anti-cancer immune cells is in many ways the holy grail of CAR therapy. If successful, it would open up these life-saving treatments to many more patients.” Dr Antonia Rotolo, first author of the study explained: “The current methods of producing CAR-T cells use the patient’s own T cells. However iNKT-cells can be sourced from healthy individuals, and unlike T cells don’t need to be matched to the patient. This means CAR19-iNKT cell treatment can be used off-the-shelf.” She added that the next step for the technology is to test it in patients: “Our animal experiments have shown the approach can eliminate cancer cells, but we cannot predict potential side effects - we can only investigate this through patient trials. This is an option we’re now exploring.” The team are not yet recruiting for patients, but for further information on other clinical trials and patient support please visit Bloodwise.org.uk. For more information: www.imperial.ac.uk
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| BIOSCIENCE TODAY |
| cancer research |
cells may hold promise
“Cancer researchers and doctors are very excited about this therapy - it means that instead of talking to patients about a hospice, we can offer them a treatment that has a good chance of working.� 39
| finance and funding |
| BIOSCIENCE TODAY |
Having access to finance is an essential ingredient to grow and prosper SMEs said they were willing to forgo growth rather than borrow. Part of the underlying cause of these figures is that businesses are often unaware of the increasing range of finance options available to them. Just over half of smaller businesses considered only one provider when they last needed external finance – most often their current bank, although a bank loan might not always be the most suitable form of finance. Furthermore, over a quarter of businesses that did not get the finance they were looking for put their plans on hold or gave up altogether, meaning lost opportunities to create jobs, grow their business, increase their productivity and, ultimately, grow the UK economy.
Graeme Fisher
Managing Director for Communications and Policy at British Business Bank
Smaller businesses are a fundamental part of the UK economy, driving growth and employment creation. Those businesses categorised as small and medium-sized enterprises (SMEs) employ around two thirds of the private sector workforce and generate turnover almost equal to that generated by the country’s largest businesses. Enabling their success is therefore crucial to UK economic growth. Having access to the finance, and importantly of the right type, is an essential ingredient for these businesses to grow and prosper. In the fields of bioscience and research, startup and scale-up funding in particular can be critical to bring innovative products to market. However, according to British Business Bank research, their growth ambitions often aren’t realised because the financial landscape is complex, daunting and misunderstood. That is reflected in the findings of our research. The Bank’s 2018 Small Business Finance Markets report found reluctance to seek external finance. Less than half (43%) were confident they would get a loan if they applied - even though most new loan applications (72%) are approved – and over the last ten quarters, only 1.7% of smaller businesses sought new loans, a record low. Perhaps most strikingly, 70% of
British Business Bank, the Government owned economic development bank, was established in 2014 to help make finance markets work better for these businesses. We want to help smaller businesses understand the financial landscape and ultimately access the right finance for their growth potential. Because we see this as core to our mission, we have a specific objective to help meet that need. That’s why the Bank has launched the Finance Hub – a new interactive website, developed with a range of industry partners and business groups, dedicated to providing independent information on finance options for scale-up, high growth and potential high growth businesses to help them see what’s really possible. We also continue to work with the industry to provide clear information through resources such as our Business Finance Guide, which we developed with the ICAEW and 21 leading business organisations. Available from the Bank in hardcopy and as an online tool, it allows small businesses to easily navigate the range of finance options available. As well as raising awareness of the increasing range of finance options on the market, we are committed to diversifying the range of providers in the market thereby creating greater competition and choice. Greater choice for small businesses enables them to find the right finance for them to grow and succeed. We know that when we support a small business finance product or help an alternative provider, smaller businesses benefit from better choices and better terms that increased competition can deliver. This is why one of our stated aims is that more than 75% of our stock is delivered through providers outside the ‘Big Four’ banks – and we have exceeded this target for four consecutive years. Access to the right type of finance, whether that be debt or equity, opens up fantastic opportunities for businesses in any industry, and we are currently supporting finance to nearly 75,000 businesses across a range of sectors.
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| BIOSCIENCE TODAY |
| finance and funding |
The examples below that we have supported through our programmes show how the right finance at the right time helped businesses operating in the fields of bioscience and research to further success.
Dr Arash Bakhtyari
Fluidic Analytics
Olberon Medical Innovation
Based in Cambridge, Fluidic Analytics designs and manufactures special tools for protein characterisation (new techniques for studying protein structures) for applications in scientific research, clinical diagnostics and consumer healthcare.
Another great example is Nottingham-based Olberon Medical Innovation. Dr Arash Bakhtyari, a practicing doctor for 25 years, founded the company after he recognised the need for specialist medical devices that would improve intravenous accessibility and help with ear and nose procedures.
Fluidic Analytics secured £6.8m in equity finance over two rounds from six institutional investors. Initial financing of £1.7m received from IQ Capital, via the British Business Bank’s Enterprise Capital Fund, allowed Fluidic Analytics to transform their prototype products into a laboratory demo, and then to a market-ready product.
The business received a loan from Enterprise Loans, part of British Business Bank’s Midlands Engine Investment Fund, to support the manufacturing of their new Vacuderm™ – a single-use tourniquet which helps inflate the vein in cases where access is difficult – enabling them to go to market.
It has allowed the launch of their first model (the Flow Mk-1, released in August 2016) and to continue development of further products to bring to market. To continue to scale-up, their ambition is to secure further funding. This will allow them to create and manufacture a new generation of laboratory tools that will contribute to new scientific discoveries.
Fluidity One
Having access to clear and impartial information on finance options is a pre-requisite for ensuring that businesses obtain the right finance for their business needs. It is an essential first step in enabling them to shop around and get the best deal on the right kind of finance to help them grow and succeed. What is more, it drives competition and improves the way finance markets operate for all of us. If you are not clear on the full range of finance options available to your small business, you can learn about the
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The funding has enabled the company to send samples to distributors worldwide. They now have 25 distributors on board to bring their products into hospitals.
Vacuderm™
many choices available at www.thebusinessfinanceguide. co.uk/bbb or follow the guide on Facebook @ TheBusinessFinanceGuide. If you are a business looking to grow rapidly, you can access our new Finance Hub at www.british-business-bank.co.uk/finance-hub
| finance and funding |
| BIOSCIENCE TODAY |
21st century capital for startups and SMEs
Although Britain has long been recognised as a country of pioneering scientists, inventors and entrepreneurs, it has historically been poor at making sufficient capital available for this creativity to blossom fully to the UK’s economic benefit. However, the last 7 years have seen the concept of ‘crowdfunding’ taken well beyond its original roots to become a fully regulated and increasingly mainstream source of much needed capital to startups and smaller businesses. Although the major banks have only ever played a limited role in financing startups, they had previously been far more active in lending to SMEs than they are now, despite some cheesy advertising to the contrary. Crowdfunding has stepped in and now accounts for a growing percentage of the capital lent to small businesses.
SO WHAT IS CROWDFUNDING? Crowdfunding is a way of raising finance by asking a large number of people each for a small amount of money. Traditionally, financing a business, project or venture involved asking a few people for large sums of money. Crowdfunding switches this idea around, using the internet to talk to thousands – if not millions – of potential funders. Typically, those seeking funds will set up a pitch for their project or business on an online crowdfunding platform such as one of the members of the UK Crowdfunding Association.
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The project or business can then use social media, alongside traditional networks of friends, family and work acquaintances, to raise money. The crowdfunding platform chosen facilitates the investment, manages the whole process and does its own marketing to encourage the public to look at the investments it is offering. There are a number of distinct forms of crowdfunding, with the variations relevant to who it is appropriate for, both in terms of the ventures seeking funding, and the profile of the potential investors.
DONATION / REWARD CROWDFUNDING This is where the concept of crowdfunding started. People invest simply because they believe in the cause raising money. Returns from this kind of crowdfunding are considered intangible. Donors have a social or personal motivation for putting their money in and expect nothing back, except perhaps to feel good about helping the project. While the American ‘Kickstarter’ was the first platform to scale, UK sites include www.fundit.buzz, www.crowdfunder.co.uk, www.justgiving.com, www.pleasefund.us Rewards can be offered (leading to the name ‘reward crowdfunding’), such as acknowledgements on an album cover, tickets to an event, regular news updates, free gifts and so on.
| BIOSCIENCE TODAY |
DEBT CROWDFUNDING Investors receive their money back with interest. Also called Peer-to-Peer (p2p) lending, it allows for the lending of money while bypassing traditional banks. Returns are financial, but investors also have the benefit of having contributed to the success of an idea they believe in. In the case of microfinance, where very small sums of money are leant to the very poor, most often in developing countries, no interest is paid on the loan and the lender is rewarded by doing social good. Sites include: www.abundanceinvestment.com, www.simplecrowdfunding.co.uk, www.fundingknight.com, www.downingcrowd.co.uk
EQUITY CROWDFUNDING People invest in an opportunity in exchange for equity. Money is exchanged for shares, or a small stake in the business, project or venture. As with other types of shares, apart from community shares, if it is successful the value goes up. If not, the value goes down. Because so many startups do end up failing, this is considered the most risky form of crowdfunding from the investors point of view.
| finance and funding |
For scientists, inventors and entrepreneurs looking to start a new venture, equity crowdfunding is the most relevant. While wealthy ‘angel investors’ have long been a source of seed capital for startups in the UK, the success of equity crowdfunding has improved capital flow considerably, by making it feasible - for the first time - for less wealthy people to invest. Previously, the costs of access, legal services and administration meant it was hard to economically invest less than £10,000 in a single startup, making the diversification essential when investing in startups (because of the high risk) impossible for anyone with less than hundreds of thousands to spare. People can now invest as little as £10 per startup, making sensible diversification easy for a much wider cross section of the public. This ‘democratisation of investing’ is one of the major positive impacts of crowdfunding, and not just equity crowdfunding. Small investors interested in exploring new investment asset types now have a whole range available from the higher risk/potentially higher returns of shares in startups, right through to those looking for steadier, lower risk returns that still beat inflation from lending money via debentures in renewable energy projects. www.ukcfa.org.uk
Sites include: www.crowdcube.com, www.seedrs.com, www.propertypartner.co
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| your guide to r&d tax relief |
| BIOSCIENCE TODAY |
Could your accountant have made a mistake with your Research and Development Tax Relief claim? How would you know? What can you do about it? You could start by speaking with a specialist and even better someone who’s worked in a Top 5 CRO preparing claims for 6 years! Now I am not saying that every accountant that files an R&D Tax Relief claim for their clients is bad, far from it, but as a qualified ACCA accountant, who has made R&D Tax Relief his niche, I feel I am reasonably qualified to call out the profession for its blunders in this area. We have recently completed a claim for a startup medical device company. Their accountant had filed a claim for them, having told them he knew what he was doing, but somehow, he actually ended up making them pay more tax than they would have had to had they not “claimed”. This was by far and away the worst case of an accountant making an error in the preparation of a claim that we have seen, and we have seen a few. Somehow the accountant had managed to add back the enhanced R&D Tax Relief costs to the taxable profit, rather than deducting them. Whilst there was an error, the accountant does need to be congratulated for bringing up R&D Tax Relief in a conversation with their client, because, even 18 years after it’s introduction, a lot of accountants still don’t discuss this with their clients. The good news is if you think your accountant has made an error then you have until the second anniversary of the end of the tax period to correct that error. It should also be pointed out that sometimes we do actually recommend reducing the value of a claim because a cost has been incorrectly interpreted or a claim has been made for under the wrong scheme.
WHAT ARE THE COMMON ERRORS THAT WE SEE IN CLAIMS? Staff costs Incorrect or unreasonable apportionments of R&D made for members of staff Staff costs claimed exceed the actual salary cost Reimbursed out of pocket travel expenses on R&D activity have not been included ERs NI and ERs pension contributions have not been included Inconsistencies with the application of the Employers NI allowance
Connected subcontractors or staff providers incorrectly valued Overseas subcontractors not included or incorrectly included Material Costs Sometimes incorrectly treated as a subcontractor cost and vice versa Claiming under the wrong scheme Grant funding has been incorrectly reported and claims have been made under the SME Scheme when they should have been claimed under RDEC and under the RDEC scheme when some could have been claimed under the SME Scheme Working as Subcontractor for a Large Company has been incorrectly assessed when the nature of the contract is actually not one of Subcontracting Grant Funding Any costs covered by the grant qualify for RDEC, you don’t have to deduct the value of the grant from the costs incurred. Not all grants have an effect on your eligibility to claim R&D Tax Relief under the SME Scheme
SOME OTHER THINGS CAN BE CORRECTED BUT SOME CAN’T If you made a loss and decided to carry that loss forward, you can, within the second anniversary time frame, elect to surrender that loss for a 14.5% tax credit, what you can’t do is elect to surrender the loss for the 14.5% tax credit and then change your mind and carry the loss forward, the surrender is irrevocable. In summary, whatever you have or haven’t done in relation to your R&D Tax Relief claim you always have until the second anniversary of the end of the tax period to make a change, whether that is a new claim or amending an existing one. We can help you if you think there is a mistake with a claim with a proofreading and claim review service. If you’d like to know more about these or our full blown R&D Tax Relief claim service, why not contact Simon on 01424 225345 or e-mail info@coodentaxconsulting.co.uk to start the process. Remember we have a very strong clinical research/biotech background to the team!
Subcontractors and Externally Provided Workers Costs incorrectly allocated 65% apportionment not properly made
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| BIOSCIENCE TODAY |
| news |
Scientists praised for pulling plug on a drug In a novel twist for researchers who actively develop drugs to combat tropical diseases, a group of scientists at the University of Dundee have been honoured for putting an end to a promising piece of research. The Mode of Action team, based in the Wellcome Centre for Anti-infectives Research at the University’s School of Life Sciences, have been awarded the GlaxoSmithKline Scientific Termination of Projects (STOP) Award 2017 for pulling the plug on the development of compound series aimed at treating visceral leishmaniasis and Chagas’ diseases. Dr Susan Wyllie, who leads the team, explained, “Drug discovery is very expensive and has a high failure rate. Working out which compound series are likely to succeed and those likely to fail can be a very difficult process. One way to help differentiate series is to understand how compounds are killing the parasites that cause these disease, and this is the primary focus of our group. “We were excited to study the mode of action of this particular compound series because the compounds were
active against a number of parasites that cause neglected tropical diseases. “Investigating further we found that these compounds kill the parasites by a mechanism that also has the potential to damage human cells. Our research, recently published in the journal Antimicrobial Agents and Chemotherapy, was key in stopping the further development of this series. The Mode for Action team, funded by the Wellcome Trust, was formed three years ago and has determined the definitive mechanisms of action of 13 different compound series that may have potential to combat diseases such as visceral leishmaniasis and Chagas’ disease. The World Health Organisation (WHO) estimates that over 600 million people are at risk of visceral leishmaniasis. It is estimated that there are 50,000–90,000 new cases per year, giving rise to 20,000-40,000 deaths annually. Chagas’ disease affects around eight million people worldwide, based on recent reports from WHO. This disease is one of the leading causes of heart failure in Latin America as it is responsible for life-threatening heart damage, if not treated early.
“Although it sounds negative, it’s a huge positive because identifying compound series that are not likely to be successful in the drug discovery process means we can divert much-needed resources into the development of more promising compounds.”
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| combat and control of parasitic diseases |
| BIOSCIENCE TODAY |
Cutting to the chase - how a folded piece of paper is saving lives Around the world, many hundreds of millions of people are infected by parasitic diseases such as malaria and schistosomiasis. Many more millions of people are affected by the impact of these diseases with profound consequences in terms of education of children and economic sustainability of communities. Early, accurate diagnosis is paramount for effective treatment, so we thought it was time that Bioscience Today shone a light on work ongoing to develop accessible, affordable tests for parasitic diseases. We spoke to Professor Jonathan Cooper about a University of Glasgow-led project which is putting tests for parasitic diseases within easy reach of under-served communities in low and middle income countries. What may surprise you, is the material being harnessed to achieve this goal. Jonathan holds the Wolfson Chair of Bioengineering and is Vice Principal of International Knowledge Exchange, with a long track record of translatable research. Working with Dr Julien Reboud, who has been central to many of the innovations, this latest project, depends on a material
you may more readily associate with a craft project rather than the cutting edge of science – a folded piece of paper. Yet it is just what the doctor ordered, for Jon’s team has designed a paper-based DNA diagnostic tests for a range of infectious diseases in humans and animals, which when combined with mobile phone-based imaging technology, provides rapid, very low cost point-of-care testing in remote locations – that enable informed decisions to be made around treatment. “Microbial detection has often depended upon having infrastructure in place - whether to support the growth of bacteria in a lab for its subsequent detection or for genetic analysis. Recent efforts, however, have focused on enabling DNA analysis to happen at point of need settings, so patients can be treated quickly. “Our project is taking DNA testing into communities – even where there is very little infrastructure, with no power or running water. Using the principles of paper-folding, we’ve developed very low-cost DNAbased tests that analyse the species of the microorganism infecting patients. From just a finger-prick sample of blood, deposited on a piece of paper, we can inform the appropriate treatments for these infectious diseases.
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| BIOSCIENCE TODAY |
| combat and control of parasitic diseases |
“The tests are low-cost and user-friendly - enabling health workers to test entire communities that are at risk and live in remote areas, and the tests are easily and safely disposed of by burning. Perhaps most importantly, we have employed very accessible production techniques; using commercially available printing technologies to develop devices that would be easy to produce in countries where the disease elimination initiatives are taking place. “After initial development in the UK, we tested our devices in the Mayuge District, on the banks of Lake Victoria, working with healthcare workers from Uganda’s Ministry of Health. The design of the device means that testing can be performed by a non-expert - using folding of the paper in a manner similar to origami to bring the sample and the reagents together and provide an answer. “Importantly, we integrated the sample preparation into a easily-read device - akin to a conventional pregnancy test - so that untrained staff could easily read the result - with the appearance of coloured lines indicating the outcome.” It is at this point that we ask Jonathan about schistosomiasis, a parasitic disease of which there is far less awareness than malaria. “It is one of the neglected diseases,” explains Jonathan, “as it is not widely recognised in terms of mortality, yet its impact is far-reaching in communities. New evidence is showing it may be involved in many co-morbitidies. For example, it most recently has been implicated in deaths associated with liver failure, especially in patients with hepatitis.
“The aim of which,” explains Jonathan, “is to support projects that change outcomes in low and middle income countries in producing healthcare and economic benefits. In our particular project, we aim to reduce the impact of these parasitic diseases on those affected: diseases which prevent children from going to school and adults from going to work, and hence have a huge impact on the community.” The GCRF harnesses the strengths of the UK’s research base to support excellent, multidisciplinary research that addresses complex global development challenges. Funding for the project is part of the GCRF’s focus on the development of affordable, robust, reliable and portable imaging and diagnostics tools that can be used to diagnose and monitor both infectious and noncommunicable diseases. The project brings together the expertise of the University’s School of Engineering, Institute of Health and Wellbeing, and Institute of Biodiversity, Animal Health and Comparative Medicine, with Epigem Ltd, FIND, Omega Diagnostics (UK), the Gloag Foundation, The Ministry of Health in Uganda and the University of California Los Angeles. The Royal Academy of Engineering has also had a large role to play in the project, as Jonathan is quick to acknowledge.
“Schistosomiasis is caused by a parasitic worm that lives in water, which infects humans and then lives in the vein surrounding the liver. The worms produce eggs continuously, which return to the lake, either through urine or faeces, where the offspring hatch and infect snails – going on to infect more humans.
Health Technology Assessment (HTA) methods are being used to identify, measure, and value the health and broader environmental and societal impacts resulting from the improved diagnosis and targeted treatment for both diseases. The team in Glasgow has demonstrated that the “origami” sensors can not only detect infectious diseases with the same sensitivities as the goldstandard laboratory methods, such as those using PCR amplification, but that the tests can be performed in under-served communities, where there are no powersupplies or infrastructure.
“Many hundreds of millions of people are infected worldwide and the disease affects many hundreds of millions more, as it is physically debilitating, eroding the livelihoods of families and disrupting children’s education in schools. It also kills many, especially if patients have complicating diseases.”
The tests have also been used to detect multiple infections simultaneously, providing healthcare teams with a new tool to carry out disease surveillance. It is now possible to visit a rural village and test and treat for two or more diseases that are co-endemic, or to monitor the decline in rates of infections as part of an elimination programme
The projects all began in a small way. “We were working in a laboratory with colleagues in Africa on a project with little funding,” explains Jonathan, “but all of that changed earlier this year when the project received £1.5m in funding.”
What began as a small project in the Mayuge District of Uganda, is also starting to be used across more of SubSaharan countries including Tanzania as well as in parts of Asia, including China and India. The diagnostic devices are now also being adapted to diagnose other veterinary diseases, including those which infect livestock and which transfer disease from cattle to humans.
The Glasgow-led project was one of 15 projects to be awarded a share of £16m in funding from the Engineering and Physical Sciences Research Council (EPSRC) and the National Institute of Health Research (NIHR), all of which aim to tackle international health challenges. The funding is part of the Global Challenges Research Fund (GCRF), a £1.5 billion government fund to support cutting-edge technology and methods that address challenges faced by low and middle income countries.
Moving forward, the hope is that at least some of those many hundreds of millions of people infected by parasitic diseases will benefit from informed, appropriate and rapid treatment, when they need it most - even where healthcare facilities are few and far between – in fact, especially when that is the case.
“We were working in a laboratory with colleagues in Africa on a project with little funding, but all of that changed earlier this year when the project received £1.5m in funding.” 47
| combat and control of parasitic diseases |
| BIOSCIENCE TODAY |
New type of bed net could help fight against malaria
Professor Steve Lindsay
Professor in the Department of Biosciences at Durham University
A new type of bed net could prevent millions of cases of malaria, according to new research published in The Lancet. The two-year clinical trial in Burkina Faso, West Africa involving 2,000 children showed that the number of cases of clinical malaria was reduced by 12 per cent with the new type of mosquito net compared to the conventional one used normally. The study resulted from a collaboration of scientists from Durham University (UK), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Liverpool School of Tropical Medicine (UK) and the Swiss Tropical and Public Health Institute (Switzerland).
TACKLING MALARIA The research found that: The number of cases of clinical malaria reduced by 12 per cent with the new type of mosquito net compared to conventional nets. Children sleeping under the new bed nets were 52 per cent less likely to be moderately anaemic than those with a conventional net. Malaria anaemia is a major cause of mortality in children under two years old. In areas with the new combination bed nets, there was a 51 per cent reduction in risk of a malaria-infective mosquito bite compared to areas with conventional nets. Blood-seeking malaria mosquitoes (female Anopheles mosquitoes) are increasingly becoming resistant to the most common insecticides, called pyrethroids, used to treat traditional bed nets.
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MOSQUITO RESISTANCE Latest figures from the World Health Organisation (WHO) show that after a dramatic decrease in malaria since the start of the millennium, progress has stalled and the number of people infected with malaria is now going up in some areas, with insecticide-resistant vectors as one of the possible causes of this. The researchers suggest the use of bed nets with a combination of chemicals should be explored for areas where mosquito resistance is a problem.
NEW TYPE OF BED NETS The new combination nets used in the study contain a pyrethroid insecticide which repels and kills the mosquitoes as well as an insect growth regulator, pyriproxyfen, which shortens the lives of mosquitoes and reduces their ability to reproduce. In combination, the ingredients on the nets kill more mosquitoes and reduce the number of infective bites than conventional nets treated only with a pyrethroid. As it is less likely that mosquitoes become resistant to both chemicals in the combination bed nets, they are considered a better alternative to tackling malaria in areas where mosquitoes have become resistant to the single chemical used in traditional bed nets.
MALARIA CONTROL
THE LATEST FIGURES FROM THE WORLD HEALTH ORGANISATION SHOW THAT IN 2016 MALARIA INFECTED ABOUT 216 MILLION PEOPLE ACROSS 91 COUNTRIES, UP FIVE MILLION FROM THE PREVIOUS YEAR.
Professor Steve Lindsay, from the Department of Biosciences at Durham University in the UK, said: “This study is important because malaria control in subSaharan Africa has stalled, partly because the mosquitoes are adapting and becoming resistant to the pyrethroid insecticides used for treating the old bed nets. “In our trial in Burkina Faso we tested a new type of net that had a pyrethroid plus an insect growth hormone, which was significantly more protective than the old net type. If we had scaled up our trial to the whole of Burkina Faso we would have reduced the number of malaria cases by 1.2 million. “Malaria still kills a child every two minutes so we need to keep working to find the best ways to stop this from happening. It is clear that conventional methods used for controlling malaria mosquitoes need to be improved and new additional tools developed.”
INFECTION RATES The latest figures from the World Health Organisation show that in 2016 malaria infected about 216 million people across 91 countries, up five million from the previous year. The disease killed 445,000 which was about the same number as in 2015. The majority of deaths were in children under the age of five in the poorest parts of sub-Saharan Africa. Burkina Faso, with more than 10 million cases of malaria annually, is one of 20 sub-Saharan countries where malaria increased between 2015 and 2016. Mosquitoes in this area are highly resistant to the traditional insecticide with a dose which is designed to kill 100 per cent of susceptible mosquitoes killing only up to 20 per cent in 2015.
CLINICAL TRIAL This study is the first clinical trial that has compared a bed net with two active ingredients, a pyrethroid plus an insect growth hormone, against the traditional widely-used nets treated with the pyrethroid insecticide alone. In this study, conventional bed nets were replaced over time with the new combination nets in 40 rural clusters in Burkina Faso covering 91 villages and involving 1,980 children in 2014 and 2,157 in 2015. The children were aged between six months and five years. The number of mosquito bites and incidence of clinical malaria in the children in the study were recorded by health clinics and the number of mosquitoes in the houses was tracked through monthly light traps. A number of randomly selected children were visited at home four times and examined clinically for signs of illness. Their blood levels were also tested for possible anaemia.
NEW HOPE Principal investigator in the field trial, Dr Alfred B. Tiono, from the Centre National de Recherche et de Formation sur le Paludisme in Burkina Faso, commented: “We have seen our gains in the battle against malaria progressively lost with the emergence and spread of resistant mosquitoes. The results from this trial gave us a new hope. “This new invaluable tool would enable us to tackle more efficiently this terrible and deadly disease that affects many children. If deployed correctly, we could certainly prevent millions of cases and deaths of malaria. On behalf of our team, we would like to thank our health authorities and the trial participants for helping us towards reaching this major milestone.” Bed nets are crucial to protect people from malaria and the researchers stress that people in affected areas should always sleep under a bed net, whether that is a conventional or a combination type. The research was funded by the European Union Seventh Framework Programme and the bed nets used were Olyset® nets donated by Sumitomo Chemical Company in Japan.
“Malaria still kills a child every two minutes so we need to keep working to find the best ways to stop this from happening. It is clear that conventional methods used for controlling malaria mosquitoes need to be improved and new additional tools developed.” 49
| combat and control of parasitic diseases |
| BIOSCIENCE TODAY |
Discovery aids disease elimination efforts David Horn
Professor of Parasite Molecular Biology, University of Dundee
Researchers at the University of Dundee have identified a new drug target in parasites that cause major neglected tropical diseases, a discovery that contributes towards a global drive to eliminate these diseases by 2030. African trypanosomes, transmitted by tsetse flies, cause lethal diseases in humans and livestock, known as sleeping sickness and nagana respectively. Around 70 million people in sub-Saharan Africa are thought to be at risk of contracting sleeping sickness, which kills thousands of people each year. Nagana causes vast economic harm to these countries and can exacerbate food shortages. New drugs in development have been shown to effectively kill the parasites, but until now it has remained unclear how these drugs actually work, hindering further development of the therapies and an understanding of potential resistance mechanisms. Taking on this challenge, a team from Dundee’s Wellcome Centre for Anti-Infectives Research examined the modeof-action of acoziborole, a cheap, safe and effective, orally administered drug, currently progressing well in advanced clinical trials against sleeping sickness. Using cutting-edge genetic technologies, they were able to show that acoziborole targets a protein called CPSF3.
Structure modelling then revealed key differences between human and parasite CPSF3, at the site where the drug binds, explaining why the drug is safe and non-toxic to humans. These findings will facilitate development of improved therapies and prediction and monitoring of drug resistance. David Horn, Professor of Parasite Molecular Biology at the University, said, “Our starting point here was a group of potentially excellent drugs but with parasite killing mechanisms that remained a mystery. To investigate how they acted against trypanosomes, we developed and optimised a new advanced high-throughput genetic screening approach and used it to pinpoint the target of acoziborole. “It is possible to use drugs against disease without knowing exactly how they work, but a problem arises when resistance develops because you don’t know how to tackle it and can’t set up surveillance for resistant parasites because you don’t know which genetic mutations are involved. Knowing the mode of action helps you to adapt, update and improve drugs, reduce toxicity, increase efficacy and put rational combinations together as well as understand resistance. “This study is a great example of how new high-throughput and precision genetic technologies can rapidly fill that knowledge-gap. In this case, even pinpointing a key interaction with a specific site in a single enzyme. CPSF3 is now among the most comprehensively validated drugtargets in this important group of parasites.” CPSF3 is also the target of a related compound (AN11736) in veterinary trials against nagana. Notably, CPSF3 may also be targeted by similar drugs that are effective in killing related parasites that cause other major neglected tropical diseases such as Chagas’ disease and leishmaniasis. Acoziborole and AN11736 form part of a broader class of boron-containing compounds with many potential applications. The antitrypanosomal compounds have been progressed through pre-clinical and clinical development by Anacor, Scynexis and the Drugs for Neglected Diseases initiative (DNDi). The new study is the result of a push to identify the targets of this increasingly important class of antitrypanosomal drugs, which offer hope of achieving a World Health Organisation target of disease control by 2030. There is currently no effective vaccine against African trypanosomes and the drugs used to treat sleeping sickness are limited in their use and efficacy due to toxicity, resistance or complexity of administration. The paper has been published in the journal PNAS USA and the research was funded by the Wellcome Trust and the UK Medical Research Council.
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“Our starting point here was a group of potentially excellent drugs but with parasite killing mechanisms that remained a mystery. To investigate how they acted against trypanosomes, we developed and optimised a new advanced high-throughput genetic screening approach and used it to pinpoint the target of acoziborole.� 51
| combat and control of parasitic diseases |
| BIOSCIENCE TODAY |
Regulator protein key to malaria parasite’s lifecycle Malaria remains a significant threat to human health with approximately 216 million cases annually and over 400,000 deaths worldwide. It is caused by the Plasmodium parasite, which has a complex lifecycle involving transmission to humans via the Anopheles mosquito. New experimental research by the University of Glasgow and the Wellcome Sanger Institute published in Nature Microbiology, demonstrates that a regulator protein, AP2-G, may hold the key to finding new approaches to prevent this potentially devastating disease. The study, designed a new experimental system to investigate, in detail, the role of AP2-G in the parasite’s life. Scientists found that AP2-G is the master switch in the parasite that controls a pattern of gene expression essential for the parasite to successfully infect mosquitoes. The authors believe these findings highlight a potential new target for approaches that, with further research and investigation, may unlock a new potential way to prevent the spread of this devastating disease. Professor Andy Waters, Director of the Wellcome Centre for Molecular Parasitology at the University of Glasgow, said: “This new experimental approach enabled us to confirm that AP2-G controls vitally important developmental pathways in gametocytes, and that it controls further gene expression and development. “We also showed that both male and female specific genes are expressed and that blocking the expression of one of
these genes resulted in parasites that could not make male gametocytes, thus ending the parasite lifecycle. Foremost, our work has the potential to uncover further novel biology as well as strategies that will prevent the spread of this devastating disease.” The Plasmodium parasite has a complex lifecycle, which relies on a cycle of transmission between humans and mosquitoes. The disease-causing forms grow asexually inside red blood cells of an infected human host. These forms are not infectious to mosquitoes. At a key stage in the lifecycle, specialised forms of the parasites called gametocytes are produced in the blood. These gametocytes exist as male and female forms and they can initiate the mosquito
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| combat and control of parasitic diseases |
“We also showed that both male and female specific genes are expressed and that blocking the expression of one of these genes resulted in parasites that could not make male gametocytes, thus ending the parasite lifecycle. Foremost, our work has the potential to uncover further novel biology as well as strategies that will prevent the spread of this devastating disease.”
phase of the parasite life cycle when they get taken up by a female mosquito biting an infected human. Dr Oliver Billker, from the Wellcome Sanger Institute, said: “What led us to the breakthrough was that we designed a new experimental parasite line in which we could dial the amount of AP2-G up and down. By dialing AP2-G up, we managed to turn all blood stage parasites into parasites that were able to infect mosquitoes. This is how we know AP2-G is the master regulator. That we can now make transmission forms in larger quantity and perfect synchrony will help future research to find out how transmission works and how it can be blocked by drugs and vaccines.” Dr Katarzyna Modrzynska, from the Wellcome Centre for Molecular Parasitology at the University of Glasgow, said: “This study revealed how flexible the parasite
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development cycle is. By switching on this one gene, we could convert almost all parasites into gametocytes – something never seen in nature. Even the parasites that have already invaded the red blood cells and were just hours away from asexual division could change into fully functional sexual forms – an act that was previously thought to require at least one cycle of further multiplication in preparation. It shows how many mysteries the parasites are still hiding from us.” The paper, ‘Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei’ is published in Nature Microbiology. The work was funded by Wellcome, The BBSRC and the Royal Society.
| training |
| BIOSCIENCE TODAY SEPTEMBER•OCTOBER 2018 |
Using apprenticeships to build skills for innovation in life sciences the future success of the science-based sector. 1. informatics and big data 2. synthetic biology and biotechnology 3. advanced manufacturing 4. formulation technology 5. materials science Through consultation and analysis we have identified a number of shortage occupations, which require immediate action to increase availability in the labour market. These include informaticians, computational scientists and formulation scientists as well as some engineering roles critical to the adoption of such technologies.
Dr. Gillian Burgess, Site Head of UK Research and Vice President at Vertex Pharmaceuticals and Board Member of the Science Industry Partnership (SIP) of employers, sets out the business case for greater use of apprenticeships across the life science industries. Gillian chairs the SIP’s Education Working Group.
In order to meet this challenge, science employers have been turning to apprenticeships, including Degree Level apprenticeships, to build a scientific and technical skills pipeline. As employers, we recognise that skills for innovation are a combination of both the academic and the practical. We increasingly want individuals who can manage and analyse data and use it to make decisions. We also want team members with leadership and management skills, to be able to solve problems, work through challenges, and manage projects.
Over the last few years, the life science sector’s approach to recruiting new talent has been undergoing a period of positive transformation. Advances in digital technologies will create enormous possibilities and opportunities across the life science sector and we need people with the necessary skills to optimise these exciting new advances.
Apprenticeships, particularly Degree Apprenticeships, can deliver all of this. Degree Apprenticeships combine work, on-the-job learning and funded part-time university education. Thus they provide a mixture of workplace learning, practical experience and academic study, and lead to a university degree.
Until recently, life science companies seeking manufacturing or research and development professionals focussed their new talent recruitment on a regular intake of graduates straight from University. Of course, such graduate talent has long supported our sector’s ability to innovate, but there is more to do as we face replacement demand, introduction of new technologies and growing skills shortages in key vocational areas.
The employer-led Science Industry Partnership (SIP), of which Vertex is a member, is working to drive the development of specialist apprenticeships for the sector by identifying the key job roles where an apprenticeship represents the ideal solution to closing a skills gap or shortage.
The above drivers and the changing shape of the sector have seen a revision in approach to skills and talent. There has been an increase in the use of highly specialised, demanding apprenticeships across the science-based industries. We know that the skills needs of the future will be driven by the adoption of a range of scientifically focused, digital technologies combined with core science skills. The Science Industry Partnership*, through its Skills Strategy 2025, identified five enabling technologies which will underpin
The SIP is developing high-level apprenticeship standards, which are the foundation upon which all apprenticeships are built. One example of this is the Laboratory Scientist Degree Apprenticeship Standard, the first one at Degree level to be developed by the employer-led Life Sciences and Industrial Science Trailblazer Group. This approach allows young people to gain a full University honours degree while earning a salary, and working on practical tasks in a laboratory environment. Another innovative approach to specialised education that the SIP has supported is the Apprenticeship Levy, which was
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| training |
developed by the Government, and is designed to encourage apprenticeships. Companies with a payroll of over £3 million must pay into the pot, but companies of any size or payroll can take from the levy pot and utilise the funding for training of an apprentice at any level. All types of life science employers can utilise the levy ‘pot’ to take on new talent and future-proof their organisation. Information on Apprentice Training Providers and Apprentice Training Agencies, which can take on parts of the apprentice training and management process can be found on the Education and Skills Funding Agency website www.gov.uk/government/organisations/ education-and-skills-funding-agency The SIP is working to tackle the significant skills challenge the sector faces. Forecasts suggest that the science industries cumulative demand for staff between 2015 and 2025 will be in the range of 180,000 to 260,000 professional and technical staff. Which is one reason why our members worked closely with Government to provide input to a comprehensive skills component to the Life Science Sector Deal. The Deal sets out commitments we have developed with the Government to support and deliver the skills we need for jobs now and in the future.
There is a significant skills challenge ahead and the SIP is working collaboratively with our skills partners, nationally and regionally. Our roles range from technical to specialist, all delivering long term and rewarding careers in a growth industry, and many of which can be accessed through apprenticeships. For all of us in life sciences, innovation is the critical success factor for a sustainable science industry future. This means that we need to equip our incoming new talent with the practical skills to be able to step into a range of key science occupations, which support us in delivering the products and technologies that, as we say at Vertex, help us create transformative medicines for people with serious and lifethreatening diseases. *The Science Industry Partnership (SIP) is a network of employers influencing and developing the skills needed for the life science sector. https://www.scienceindustrypartnership.com/
The Life Sciences & Industrial Science Trailblazer group has delivered and received ministerial approval for a range of apprenticeship standards:
• Technician Scientist
• Laboratory Technician
• Science Industry Plant/Process Engineer
• Science Manufacturing Technician
• Bioinformatics Standard
• Laboratory Scientist
• Clinical Trials Specialist
• Science Industry Maintenance Technician
• Science Manufacturing Process Operative
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| antimicrobial solutions |
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Discovery helps fight against drug-resistant
Tuberculosis “Our findings are very exciting and the first step towards developing a new, effective drug treatment for patients with rifampicin resistant TB to prevent fatalities in the future.� Professor Nikolay Zenkin
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| antimicrobial solutions |
A team of scientists have identified a naturally occurring antibiotic that may help in the fight against drug-resistant Tuberculosis. Each year, approximately 10 million people fall ill with Tuberculosis (TB) and around 1.7 million die from the devastating disease worldwide. One of the main antibiotics for TB is rifampicin, however, many strains of the Tuberculosis-causing bacteria Mycobacterium tuberculosis - have developed resistance to it. Approximately 600,000 people every year are diagnosed with rifampicin-resistant tuberculosis. Now researchers from Newcastle University and Demuris Ltd have identified that a naturally occurring antibiotic, called kanglemycin A – related to the antibiotic rifampicin – is active against rifampicin-resistant Mycobacterium tuberculosis. The findings of their study have been published in the journal, Molecular Cell, and it is hoped that this compound and the enhanced understanding gained from these studies may lead to effective new drug treatments in the future.
EXCITING FINDINGS The team used chemical, biophysical, molecular biology and microbiological methods, as well as X-ray crystallography, to show how kanglemycin A binds to its target RNA polymerase and how it manages to overcome resistance. It was known that rifampicin binds to a groove in the RNA polymerase molecule and that mutations that change the amino-acid sequence of the RNA polymerase can prevent this binding, while maintaining the ability to produce RNA. Kanglemycin A binds to the same groove, but its structure revealed extensions that also bind just outside the groove allowing it to maintain its affinity to the rifampicin-resistant RNA polymerase and antibiotic activity in rifampicinresistant bacteria. Professor Nikolay Zenkin, from Newcastle University’s Institute for Cell and Molecular Biosciences, led the international study. He said: “Treatment of TB involves a cocktail of antibiotics administered over many months, and resistance to several key antibiotics is becoming a major public health problem around the world. “Our findings are very exciting and the first step towards developing a new, effective drug treatment for patients with rifampicin resistant TB to prevent fatalities in the future.” Dr Michael Hall, from Newcastle University, who led chemical characterization of kanglemycin A, added: “This is an exciting development for the future treatment of rifampicin resistant TB and shows what can be achieved when local businesses and universities work together.”
SEARCHING FOR NEW ANTIBIOTICS Binding of kanglemycin A in rifampicin-binding pocket of RNA polymerase Researchers screened more than 2,000 extracts from filamentous soil bacteria using a collection from Newcastle University spin-out company, Demuris Ltd, to assess their ability to inhibit cell growth or prevent the production of RNA— an essential process in all living organisms — in bacteria.
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Professor Zenkin said: “The main finding of our study is that kanglemycin A is effective against rifampicin resistant RNA polymerases and can also kill rifampicin resistant Mycobacterium tuberculosis. “We describe the details of the inhibition mechanism and how kanglemycin A manages to stay active against the drugresistant bacteria. “The results will help to accelerate approval of kanglemycin A for use in patients with Tuberculosis, and provide a rationale for the further development of new drug treatments.” Katsuhiko Murakami, professor of biochemistry and molecular biology department at Pennsylvania State University, who led crystallographic characterization of interactions of kanglemycin A with RNA polymerase, believes the discovery is essential for public safety. He said: “Recent development of drug-resistant Mycobacterium tuberculosis has made treatment of this disease even more challenging. “Identifying new compounds that are effective against the rifampicin-resistant RNA polymerase is incredibly important for public health.”
ANTIBIOTICS NEEDED The research project involved a large multidisciplinary team involving Newcastle and Penn State university scientists, Public Health England, Newcastle upon Tyne Hospitals NHS Foundation Trust and Demuris Ltd. Dr Nick Allenby, Principal Scientist at Demuris Ltd, which own and will be taking on the commercialization of the compound, said: “There is an urgent need for new antibiotics to combat drug resistant Mycobacterium tuberculosis. “We have shown that our compound discovered through a collaboration between Newcastle University and Demuris is effective against these drug resistant strains. “However, before we can start to think about using the compound much more work and development is needed. The next step for our compound is to prove that it is safe and effective for use in the clinic.”
| antimicrobial solutions |
| BIOSCIENCE TODAY |
Researchers discover how fatal biofilms form By severely curtailing the effects of antibiotics, the formation of organized communities of bacterial cells known as biofilms can be deadly during surgeries and in urinary tract infections. Yale researchers have just come a lot closer to understanding how these biofilms develop, and potentially how to stop them. Biofilms form when bacterial cells gather and develop structures that bond them in a gooey substance. This glue can protect the cells from the outside world and allow them to form complex quasi-organisms. Biofilms can be found almost everywhere, including unwashed shower stalls or the surfaces of lakes. Because the protective shell can keep out potential treatments, biofilms are at their most dangerous when they invade human cells or form on sutures and catheters used in surgeries. In American hospitals alone, thousands of deaths are attributed to biofilm-related surgical site infections and urinary tract infections. “Biofilms are a huge medical problem because they are something that makes bacterial infections very difficult to deal with,” said Andre Levchenko, senior author of the study, which was published Oct. 5 in Nature Communications. Fighting biofilms has been particularly difficult because it hasn’t been well understood how bacteria cells make the transition from behaving individually to existing in collective structures. However, the researchers in the Levchenko lab, working with colleagues at the University of California-San Diego, recently found a key mechanism for biofilm formation that also provides a way to study this process in a controlled and reproducible way.
The investigators designed and built microfluidic devices and novel gels that housed uropathogenic E. coli cells, which are often the cause of urinary tract infections. These devices mimicked the environment inside human cells that host the invading bacteria during infections. The scientists found that the bacterial colonies would grow to the point where they would be squeezed by either the walls of the chamber, the fibers, or the gel. This self-generated stress was itself a trigger of the biofilm formation. “This was very surprising, but we saw all the things you would expect from a biofilm,” said Levchenko, the John C. Malone Professor of Biomedical Engineering and director of the Yale Systems Biology Institute. “The cells produced the biofilm components and suddenly became very antibioticresistant. And all of that was accompanied by an indication that the cells were under biological stress and the stress was coming from this mechanical interaction with the environment.” With this discovery, Levchenko said, researchers can use various devices that mimic other cellular environments and explore biofilm formation under countless environments and circumstances. They can also use the devices introduced in this study to produce biofilms rapidly, precisely, and in high numbers in a simple, inexpensive, and reproducible way. This would allow screening drugs that could potentially breach the protective layer of the biofilms and break it down. “Having a disease model like this is a must when you want to do these kinds of drug-screening experiments,” he said. “We can now grow biofilms in specific shapes and specific locations in a completely predictable way.”
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| antimicrobial solutions |
New ‘trap’ to analyse, in real time, how cells communicate Using multiple laser beams and Raman spectroscopy, experts at the Universities of Nottingham and Glasgow have designed and built a new instrument which could help scientists learn more about how infections take hold and the formation of antibiotic-resistant bacterial biofilms. Ioan Notingher, Professor of Physics in the School of Physics and Astronomy, at the University of Nottingham, said: “Many techniques in biology measure a large number of cells at once or require added labels or invasive techniques to look at the single cell level. Our technique is non-invasive and requires no labelling – so it doesn’t disturb or destroy the biological sample.” Their research – Holographic optical trapping Raman microspectroscopy for non-invasive measurement and manipulation of live cells – has been published in The Optical Society journal Optics Express. They have demonstrated how their instrument uses optical traps - which use light to hold and move small objects – to form a connection between multiple human immune cells and then measure the changes in the cell interactions over time with Raman spectroscopy. This, they say, could be the starting point for investigating how these immune cells communicate in the body. Professor Notingher said: “The instrument we have created is quite robust and sensitive and can be used in many types of experiments on cells. In addition to biological investigation the instrument could also be used to study polymers, nanomaterials and various chemical processes. It would also be combined with other microscopy techniques to obtain even more information.”
COMBINING TRAPPING AND SPECTROSCOPY Raman spectroscopy uses the interaction between laser light and a sample such as DNA or protein to obtain information about the sample’s chemical composition. Traditionally, Raman spectroscopy uses one focused laser beam to obtain measurements from a point on a sample. Using a setup where the emitted light passes through a small pinhole, or aperture, can help increase the quality of these measurements by removing unwanted stray light. To use optical trapping and Raman spectroscopy simultaneously at many sample points requires many focused laser spots. Although this has been previously achieved with an optical component known as a liquidcrystal spatial light modulator (LCSLM), that approach
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requires the use of pinholes matched to each sampling point. The research team built a more flexible instrument by combining an LCSLM with a digital micro-mirror device (DMD) to create reflective virtual pinholes that were customized for each sampling point and could be rapidly controlled with a computer. DMDs are used in many modern digital projectors and are made of hundreds of thousands of tilting microscopic mirrors. Dr Faris Sinjab, who led the study at Nottingham, said: “The multipoint optical trapping and Raman spectroscopy can be controlled interactively and in real-time using the software developed by Miles Padgett’s group at the University of Glasgow. This software allows completely automated experiments, which could be useful for carrying out complex or large systematically repeated experiments.”
FAST ACQUISITION After demonstrating that the performance of the Raman instrument is comparable to a single-beam Raman microscope, the researchers used it to move multiple polystyrene particles around with the optical traps while simultaneously acquiring Raman spectra at 40 spectra per second. Dr Sinjab said: “This type of experiment would not previously have been possible because spectra could not be acquired from such rapidly changing locations.” Next, the researchers showed they could control the power in each laser beam and avoid damaging trapped cells with the laser. Finally, to demonstrate the capability of the instrument for cell biology applications, they brought multiple live T cells into contact with a dendritic cell to initiate the formation of immunological synapse junctions where these immune cells met. Measuring Raman spectra at multiple points over time revealed molecular differences among the junctions formed. The researchers are now working to further automate portions of the Raman spectroscopy so that non-expert users could carry out experiments. They are also exploring how to miniaturise the instrument by incorporating a custom microscope and spectrometer with a more compact high-power laser.
“Many techniques in biology measure a large number of cells at once or require added labels or invasive techniques to look at the single cell level. Our technique is non-invasive and requires no labelling – so it doesn’t disturb or destroy the biological sample.”
| antimicrobial solutions |
| BIOSCIENCE TODAY |
UK-led study marks shift towards genetic era in tackling TB In a landmark study that may herald a quicker, more tailored treatment for the millions of people around the world living with tuberculosis (TB), UK researchers have shown how our understanding of TB’s genetic code is now so detailed that we can now predict which commonly used anti-TB drugs are best for treating a patient’s infection and which are not. This study, led by the international CRyPTIC consortium based at the University of Oxford and facilitated by the United Kingdom government’s 100,000 Genomes Project in partnership with Public Health England, is by far the largest of its kind, covering over 10,000 TB genomes from 16 equal partner countries around the globe. The paper, ‘Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing’, was published on Wednesday 26 September by the New England Journal of Medicine, and its findings announced at the United Nations General Assembly high-level meeting on tuberculosis. The study revealed a much greater accuracy in predicting the susceptibility of the bacterium to anti-TB drugs than had been expected.
PARADIGM SHIFT The lead investigator, Dr Tim Walker, Academic Clinical Lecturer in Microbiology and Infectious Diseases at the University of Oxford’s Nuffield Department of Medicine, said: “This study represents a paradigm shift away from a dependence on testing drugs against bacteria in culture and towards the genetic era. “With ever-faster and more portable DNA sequencing technologies being developed, this advance means that we are now much closer to delivering tailored therapy to TB patients around the world whose treatments have so far been largely based on a ‘best guess’. Giving the correct drugs to more patients will improve cure rates and help stop the spread of drug-resistant strains,” said Dr Walker, who, like a number of partners in the research, is supported by the National Institute for Health Research (NIHR).
Professor Derrick Crook, Director of National Infection Service at Public Health England and Antimicrobial Resistance Theme Lead at the NIHR Oxford Biomedical Research Centre, said: “We are delighted by the results of this study which suggest that we will be able to treat patients with the right treatments more quickly. “This is particularly important in an infection like TB where we know that many people who have the infection may be homeless or not have good access to the health system. Being able to choose the most effective drugs when starting treatment should lead to a quicker reduction in the infection being passed on to others.” Professor Chris Whitty, Chief Scientific Adviser for the Department of Health and Social Care (DHSC), said: “Developing more effective approaches to treating multidrug-resistant TB is crucial for the thousands of people affected in the UK and millions worldwide. This study is just one example of how the government is supporting research into how new technologies can help us tackle drug-resistant infections and thus preserve the effectiveness of current antibiotic treatments.”
PRECISION CARE Professor Mark Caulfield, Chief Scientist at Genomics England, Co-Director of the Queen Mary University William Harvey Research Institute (WHRI) and Director of the NIHR Barts Biomedical Research Centre, said: “The 100,000 Genomes Project has amassed the largest collection of whole human genomes linked to direct healthcare. Here researchers working with Genomics England and with other agencies have demonstrated that DNA sequencing can be used to guide first-line treatment of tuberculosis. This shows that genomic medicine can enable precision care of millions of people, in the UK and around the world.” Dr Jonathan Pearce, Head of Infections and Immunity at the MRC, said: “The results of this study represent an important step forward for rapid clinical decision-making and antibiotic stewardship for TB treatment, and also provide a potential precedent for a sequencing approach for other pathogens.” Tuberculosis remains the world’s biggest infectious disease killer, claiming 1.7 million lives in 2016. The number of
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TUBERCULOSIS REMAINS THE WORLD’S BIGGEST INFECTIOUS DISEASE KILLER, CLAIMING 1.7 MILLION LIVES IN 2016.
| BIOSCIENCE TODAY |
| antimicrobial solutions |
“Developing more effective approaches to treating multi-drugresistant TB is crucial for the thousands of people affected in the UK and millions worldwide. This study is just one example of how the government is supporting research into how new technologies can help us tackle drugresistant infections and thus preserve the effectiveness of current antibiotic treatments.” drug-resistant cases is rising, meaning new strategies and interventions are urgently needed if the World Health Organisation’s (WHO) target to end the global TB epidemic by 2035 is to be met. One of the key interventions for achieving this target – and saving millions of lives – is getting the correct drugs to patients in a timely manner. Since TB-antibiotics were first introduced 70 years ago, tests to determine which antibiotics will best treat an individual patient have depended on growing the bacteria in a laboratory, a process that takes weeks or even months. These difficult and slow tests remain out of reach for most of the world’s TB patients, leaving many on the wrong combination of drugs and with a reduced chance of cure and survival.
ACCURACY It is estimated that only 22 per cent of an estimated 600,000 patients requiring treatment for multi-drug-resistant tuberculosis received diagnoses and were treated in 2016, which has facilitated the spread of multidrug-resistant strains. The analysis conducted by the researchers, who looked at all major strains of TB, “suggests that whole-genome sequencing can now characterise profiles of susceptibility to first-line anti-tuberculosis drugs with a degree of accuracy sufficient for clinical use.”
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“The importance of this is twofold: first, it shows that the genomic approach could be used to guide the choice of which drugs to prescribe and not just which drugs to avoid, in a way similar to phenotyping; second, the data can be used to support plans to reduce the workload associated with culture and sensitivity analysis in places where routine whole-genome sequencing is performed.” The improved knowledge of the genomic variations of TB should lead to more accurate PCR tests for the disease. The results of this study have already led to decisions in England, the Netherlands and by the Wadsworth Centre for Public Health, New York State, to reduce reliance on bacterial culture and deliver treatment according to DNA sequencing results alone. This international research was supported in the UK by the Department of Health and Social Care through the National Institute for Health Research, Public Health England and the 100,000 Genomes Project. The research also received support from the EMBL’s European Bioinformatics Institute (EMBL-EBI), the Medical Research Council, the Wellcome Trust, and the Bill and Melinda Gates Foundation. As well as the University of Oxford, the University of Leeds, Imperial College London, and the London School of Hygiene & Tropical Medicine were involved in the research.
| antimicrobial solutions |
| BIOSCIENCE TODAY |
Biological engineers discover new antibiotic candidates Screen of human proteins reveals some with antimicrobial power The human body produces many antimicrobial peptides that help the immune system fend off infection. Scientists hoping to harness these peptides as potential antibiotics have now discovered that other peptides in the human body can also have potent antimicrobial effects, expanding the pool of new antibiotic candidates. In the new study, researchers from MIT and the University of Naples Federico II found that fragments of the protein pepsinogen, an enzyme used to digest food in the stomach, can kill bacteria such as Salmonella and E. coli. The researchers believe that by modifying these peptides to enhance their antimicrobial activity, they may be able to develop synthetic peptides that could be used as antibiotics against drug-resistant bacteria. “These peptides really constitute a great template for engineering. The idea now is to use synthetic biology to modify them further and make them more potent,” says Cesar de la Fuente-Nunez, an MIT postdoc and Areces Foundation Fellow, and one of the senior authors of the paper. Other MIT authors of the paper, which appears in the Jan. 20 issue of the journal ACS Synthetic Biology, are Timothy Lu, an associate professor of electrical engineering and computer science and of biological engineering, and Marcelo Der Torossian Torres, a former visiting student.
DISCOVERING NEW FUNCTIONS Antimicrobial peptides, which are found in nearly all living organisms, can kill many microbes, but they are typically not powerful enough to act as antibiotic drugs on their own. Many scientists, including de la Fuente-Nunez and Lu, have been exploring ways to create more potent versions of these peptides, in hopes of finding new weapons to combat the growing problem posed by antibiotic-resistant bacteria. In this study, the researchers wanted to explore whether other proteins found in the human body, outside of the previously known antimicrobial peptides, might also be able to kill bacteria. To that end, they developed a search algorithm that analyzes databases of human protein sequences in search of similarities to known antimicrobial peptides. “It’s a data-mining approach to very easily find peptides that were previously unexplored,” de la Fuente-Nunez says. “We have patterns that we know are associated with classical antimicrobial peptides, and the search engine goes through the database and finds patterns that look similar to what we know makes up a peptide that kills bacteria.” In a screen of nearly 2,000 human proteins, the algorithm identified about 800 with possible antimicrobial activity. In
the ACS Synthetic Biology paper, the research team focused on the peptide pepsinogen, whose role is to break down proteins in food. After pepsinogen is secreted by cells that line the stomach, hydrochloric acid in the stomach mixes with pepsinogen, converting it into pepsin A, which digests proteins, and into several other small fragments. Those fragments, which previously had no known functions, showed up as candidates in the antimicrobial screen. Once the researchers identified those candidates, they tested them against bacteria grown in lab dishes and found that they could kill a variety of microbes, including foodborne pathogens, such as Salmonella and E. coli, as well as others, including Pseudomonas aeruginosa, which often infects the lungs of cystic fibrosis patients. This effect was seen at both acidic pH, similar to that of the stomach, and neutral pH. “The human stomach is attacked by many pathogenic bacteria, so it makes sense that we would have a host defense mechanism to defend ourselves from such attacks,” de la Fuente-Nunez says.
MORE POTENT DRUGS The researchers also tested the three pepsinogen fragments against a Pseudomonas aeruginosa skin infection in mice, and found that the peptides significantly reduced the infections. The exact mechanism by which the peptides kill bacteria is unknown, but the researchers’ hypothesis is that their positive charges allow the peptides to bind to the negatively charged bacterial membranes and poke holes in them, a mechanism similar to that of other antimicrobial peptides. The researchers now hope to modify these peptides to make them more effective, so that they could be potentially used as antibiotics. They are also seeking new peptides from organisms other than humans, and they plan to further investigate some of the other human peptides identified by the algorithm. “We have an atlas of all these molecules, and the next step is to demonstrate whether each of them actually has antimicrobial properties and whether each of them could be developed as a new antimicrobial,” de la Fuente-Nunez says.
The researchers believe that by modifying these peptides to enhance their antimicrobial activity, they may be able to develop synthetic peptides that could be used as antibiotics against drug-resistant bacteria. 62
IN A SCREEN OF NEARLY 2,000 HUMAN PROTEINS, THE ALGORITHM IDENTIFIED ABOUT 800 WITH POSSIBLE ANTIMICROBIAL ACTIVITY.
| BIOSCIENCE TODAY |
| antimicrobial solutions |
Scientists in New Zealand have used genomic mining to discover a new protein that could have antimicrobial properties Antimicrobial resistance is one of the biggest threats to global health and the race is on to find new molecules with antibiotic properties. One way scientists try to find these molecules is to study proteins produced by microorganisms themselves, as the bacteria often uses these to fight off other competing bugs. Scientists analyse the microorganism’s genetic make-up – its genome – looking for sequences of code that correspond to types of proteins known to have antibiotic properties. One group of such proteins are called lanthipeptides that have a particular structure known to be effective at fighting off bacteria. Researchers in New Zealand recently applied this process, known as ‘genome mining’, to a strain of Thermogemmatispora – a type of bacteria that lives in extreme conditions in the heated soil of New Zealand’s Taupo geothermal zone. They discovered a new type of lanthipeptide, called tikitericin, which they believe is part of the microorganism’s host defence system. “The global issue of antimicrobial resistance will affect everyone, so we need to find new solutions,” says Professor Margaret Brimble from the University of Auckland, whose research group are behind the discovery. “Naturally occurring antimicrobial peptides, produced by
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microorganisms to fend off other microorganisms, are a rich source of lead compounds to develop new antibiotics.” Other lanthipeptides have already shown evidence of antimicrobial properties, and one has even been approved as food preservation agent, so Margaret’s team knew the protein they had isolated had potential. However, extracting proteins from microorganisms is time-consuming and often the yields are small. The team knew that to be able to study tikitericin in detail, they would need to develop a way to make it in the lab. Using a number of different techniques to analyse the protein isolated from the Thermogemmatispora strain, the team were able to identify the structure of tikitericin, enabling them to build the peptide in the lab. Now that they can produce larger quantities of the molecule, the team can investigate its antimicrobial properties and hope that it will one day play a role in fighting bacterial infections. “I am passionate about trying to understand the intricate chemistry that links organisms together,” says Dr Robert Keyzers, senior lecturer at the Victoria University of Wellington and co-author of the paper. “If we are lucky enough, one of our compounds may spearhead a greater understanding of biochemistry, metabolism or molecular biology that in the future, could lead to advances in medicine. One day a molecule we discover may help some sick people somewhere and that is a legacy we would all be amazingly proud of.”
| biopharmaceutical manufacturing |
| BIOSCIENCE TODAY |
Making pharmaceuticals person specific Dr Mohammed Maniruzzaman
Lecturer in Pharmaceutics and Drug Delivery at the University of Sussex
In this issue of BioScience Today, we speak to Dr Mohammed Maniruzzaman, Lecturer in Pharmaceutics and Drug Delivery at the University of Sussex, about his work developing biopharmaceutical manufacturing systems. Biopharmaceuticals now account for over 30% of drugs in the drug pipeline, with more than hundreds of approved
products on the market and 7,000 products in development stage derived from biological sources, with year on year growth of around 15%. Biologics, Dr Maniruzzaman believes, will provide advances in therapies to help meet more of our unmet healthcare challenges and ultimately provide solutions to treat complex medical problems which are otherwise currently impossible. Indeed, they are already doing so, for just as we are preparing this issue, we hear that James P. Allison and Tasuku Honjo have been awarded the Nobel Prize for Physiology or Medicine 2018 – which illustrates the potential of biologics i.e. proteins that function as a brake on the immune system.
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| BIOSCIENCE TODAY |
| biopharmaceutical manufacturing |
“Their work is perhaps the best example of how antibodies have been harnessed to treat a disease, representing a major breakthrough in cancer treatment and leading to new drugs being made available,” explains Dr Maniruzzaman. Hand in hand with the discovery and development of biopharmaceuticals, come advances in the manufacturing systems producing them, which make these treatments available, when and where people need them. It is this aspect of research which most interests Dr Maniruzzaman. “I’ve always been interested in creating innovations which help human beings,” he explains. “I am motivated every day by filling the gap between what people need and what is available.” It is a commitment which saw him travel from Bangladesh to the UK at just 17 to undertake his undergraduate degree at the University of Greenwich, before completing his PhD - becoming the youngest overseas student in the UK ever to obtain this accolade. Since joining the University of Sussex, Dr Maniruzzaman’s research has focused on the manufacture of medicine and specifically on making that process more affordable. Developing a continuous manufacturing platform for pharmaceuticals has been a key part of his work, with the hope of enabling drugs to be produced in a more seamless, cost-effective and timely manner. Whilst another aspect of his research focuses on developing person specific biopharmaceutical manufacturing systems capable of providing treatments tailored to the needs of individual patients. “Many medical solutions are based on the assumption that one size fits all,” explains Dr Maniruzzaman, “but in treating disease, a huge variation can be found from one patient to another, and in a single patient from one day to another. The needs of some patients, like those with diabetes, for example, can change on a daily basis. “A person specific biopharmaceutical manufacturing system, however, has the potential to provide a solution that meets the changing needs of a patient, making the treatment delivered more effective and efficient.” “When we started this work, there was a very limited provision for personalised medicine and what was available was prohibitively expensive, we hoped to provide a solution that would meet demand whilst proving more cost-effective and accessible, so we looked to 3D printing.” Utilising 3D printing for biopharmaceutical manufacturing is something that’s been explored for some time, but what is innovative about Dr Maniruzzaman’s work is the small scale on which he and his team are developing this technology, as he explains: “We are developing a small, handheld 3D printer, much like a smartphone, which has the ability to create medication of precisely the right dosage - meaning patients would benefit from tailor-made medication.” 3D printers have the potential to provide on-demand medications, with doctors using the cloud to prescribe medications and send them to a patient’s or pharmacy’s printer to be created.
Dr Mohammed Maniruzzaman The dose of medication could be modified as required, meaning patients would receive suitable medication when needed, whilst controls built into the system would prevent them being misused. Individual manufacturing units would enable a dose to be created of exactly the right amount, even if it varied from the standard tablet, negating the need to cut a tablet in half for example and mitigating waste. Each year, it has been estimated that around £300million is wasted on medication that is unused or partially used. Having the capacity to print and provide medicine of exactly the right quantity at the point of need, may help address this problem to some degree. Whilst the problem of pharmaceuticals degrading over time may also be mitigated, ensuring the medicine issued is working at its optimum capacity. 3D printing is also being harnessed for diagnostics, with a ‘lab in a pill’ helping to diagnose conditions such as bowel cancer, by detecting traces of blood in the body. Given the devices are swallowable, the whole procedure is more patient-friendly and speedier than other methods – precluding the need to collect stool samples, post them and wait for the lab results. Whilst these smart oral systems, once swallowed, could collect information from within the body, then transmit their findings to an external receiver, so that the most appropriate treatment could be provided. Both of these applications of 3D printing have the capacity to transform the patient experience, being less invasive, more targeted and allowing for faster, more effective treatment. Moving forward, 4D printing, where a medication is produced using 3D printing techniques but transforms/ deforms inside the body in response to specific stimuli, like temperature or water, is also being explored. As are smart intelligent systems that could be fitted inside the body sending information to an external receiver, potentially allowing a patient to be monitored remotely 24/7, preventing the need for a hospital stay. These are just a few of the projects on which Dr Maniruzzaman and his team are working. “Whatever we do is highly transformative,” he explains. “We are interested in taking research from the lab to the bedside, finding the practical application of that research so that it will benefit patients.”
“When we started this work, there was a very limited provision for personalised medicine and what was available was prohibitively expensive, we hoped to provide a solution that would meet demand whilst proving more cost-effective and accessible, so we looked to 3D printing.” 65
| biopharmaceutical manufacturing |
| BIOSCIENCE TODAY |
A new way to manufacture small batches of biopharmaceuticals
on demand
Biopharmaceuticals, a class of drugs comprising proteins such as antibodies and hormones, represent a fast-growing sector of the pharmaceutical industry. They’re increasingly important for “precision medicine” — drugs tailored toward the genetic or molecular profiles of particular groups of patients.
Such drugs are normally manufactured at large facilities dedicated to a single product, using processes that are difficult to reconfigure. This rigidity means that manufacturers tend to focus on drugs needed by many patients, while drugs that could help smaller populations of patients may not be made. To help make more of these drugs available, MIT researchers have developed a new way to rapidly manufacture biopharmaceuticals on demand. Their system can be easily reconfigured to produce different drugs, enabling flexible switching between products as they are needed. “Traditional biomanufacturing relies on unique processes for each new molecule that is produced,” says J. Christopher Love, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research. “We’ve demonstrated a single hardware configuration that can produce different recombinant proteins in a fully automated, hands-free manner.” The researchers have used this manufacturing system, which can fit on a lab benchtop, to produce three different biopharmaceuticals, and showed that they are of comparable quality to commercially available versions. Love is the senior author of the study, which appears in the October 1 issue of the journal Nature Biotechnology. The paper’s lead authors are graduate students Laura Crowell and Amos Lu, and research scientist Kerry Routenberg Love.
A STREAMLINED PROCESS
Biopharmaceuticals, which usually have to be injected, are often used to treat cancer, as well as other diseases including cardiovascular disease and autoimmune disorders. Most of these drugs are produced in “bioreactors” where bacteria, yeast, or mammalian cells churn out large quantities of a single drug. These drugs must be purified before use, so the entire production process can include dozens of steps, many of which require human intervention. As a result, it can take weeks to months to produce a single batch of a drug. The MIT team wanted to come up with a more agile system that could be easily reprogrammed to rapidly produce a variety of different drugs on demand. They also wanted to create a system that would require very little human oversight while maintaining the high quality of protein required for use in patients. “Our goal was to make the entire process automated, so once you set up our system, you press ‘go’ and then you come back a few days later and there’s purified, formulated drug waiting for you,” Crowell says. One key element of the new system is that the researchers used a different type of cell in their bioreactors — a strain of yeast called Pichia pastoris. Yeast can begin producing proteins much faster than mammalian cells, and they can grow to higher population densities. Additionally, Pichia pastoris secretes only about 150 to 200 proteins of its own, compared to about 2,000 for Chinese hamster ovary (CHO) cells, which are often used for biopharmaceutical production. This makes the purification process for drugs produced by Pichia pastoris much simpler. The researchers also greatly reduced the size of the manufacturing system, with the ultimate goal of making it portable. Their system consists of three connected modules: the bioreactor, where yeast produce the desired protein; a purification module, where the drug molecule is separated
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| BIOSCIENCE TODAY |
| biopharmaceutical manufacturing |
“Traditional biomanufacturing relies on unique processes for each new molecule that is produced. We’ve demonstrated a single hardware configuration that can produce different recombinant proteins in a fully automated, hands-free manner.” from other proteins using chromatography; and a module in which the protein drug is suspended in a buffer that preserves it until it reaches the patient. In this study, the researchers used their new technology to produce three different drugs: human growth hormone; interferon alpha 2b, which is used to treat cancer; and granulocyte colony-stimulating factor (GCSF), which is used to boost the immune systems of patients receiving chemotherapy. They found that for all three molecules, the drugs produced with the new process had the same biochemical and biophysical traits as the commercially manufactured versions. The GCSF product behaved comparably to a licensed product from Amgen when tested in animals. Reconfiguring the system to produce a different drug requires simply giving the yeast the genetic sequence for the new protein and replacing certain modules for purification. With colleagues at Rensselaer Polytechnic Institute, the researchers also designed software that helps to come up with a new purification process for each drug they want to produce. Using this approach, they can come up with a new procedure and begin manufacturing a new drug within about three months. In contrast, developing a new industrial manufacturing process can take 18 to 24 months.
DECENTRALIZED MANUFACTURING The ease with which the system switches between production of different drugs could enable many different applications. For one, it could be useful for producing drugs to treat rare diseases. Currently, such diseases have few treatments available, because it’s not worthwhile for drug companies to devote an entire factory to producing a drug that is not widely needed. With the new MIT technology, small-scale production of such drugs could be easily achieved, and the same machine could be used to produce a wide variety of such drugs.
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Another potential use is producing small quantities of drugs needed for “precision medicine,” which involves giving patients with cancer or other diseases drugs that are specific to a genetic mutation or other feature of their particular disease. Many of these drugs are also needed in only small quantities. These machines could also be deployed to regions of the world that do not have large-scale drug manufacturing facilities. “Instead of centralized manufacturing, you can move to decentralized manufacturing, so you can have a couple of systems in Africa, and then it’s easier to get those drugs to those patients rather than making everything in North America, shipping it there, and trying to keep it cold,” Crowell says. This type of system could also be used to rapidly produce drugs needed to respond to an outbreak such as Ebola. The researchers are now working on making their device more modular and portable, as well as experimenting with producing other therapies, including vaccines. The system could also be deployed to speed up the process of developing and testing new drugs, the researchers say. “You could be prototyping many different molecules because you can really build processes that are simple and fast to deploy. We could be looking in the clinic at a lot of different assets and making decisions about which ones perform the best clinically at an early stage, since we could potentially achieve the quality and quantity necessary for those studies,” Routenberg Love says. The research was funded by the Defense Advanced Research Projects Agency, SPAWAR Systems Center Pacific, and the Koch Institute Support (core) Grant from the National Cancer Institute.
| biopharmaceutical manufacturing |
| BIOSCIENCE TODAY |
New research predicts a positive future for biosimilars The prospect of reducing treatment costs for payors supports a positive future for biosimilars Biosimilar approvals in the US market still significantly lag behind Europe despite an evolving regulatory landscape and three new biosimilar approvals to date in 2018 The biosimilars market is predicted to grow from USD 4.4 billion annual sales to USD 25 billion by 2023 at a Compound Annual Growth Rate (CAGR) of 34%
Results Healthcare, the leading corporate advisory firm focused on public and private healthcare and life sciences companies, today publishes its report looking at the clinical and commercial potential of biosimilars. The whitepaper, Biosimilars: Prospects and challenges, argues that we have reached an important watershed moment in the clinical and commercial acceptance of biosimilars, creating opportunities for investors to acquire interests and partners in the growing sector. The analysis predicts that the size of the biosimilars market will grow from USD 4.4 billion annual sales to USD 25 billion by 2023 at a Compound Annual Growth Rate (CAGR) of 34%. Commenting on the findings, Kevin Bottomley, Partner at Results Healthcare, said: “The market impact of biosimilars has been predicted for many years, but it is only recently that they have started to realise their potential for patients, and have a positive commercial impact. As the process and business case for developing and commercialising biosimilars is becoming better defined, investors have become more certain about the risks and rewards associated with these products. Biosimilars present a number of opportunities, including the potential to offer more affordable and accessible healthcare. This growth is supported by a number of positive tailwinds including a continued growing demand for healthcare as the population grows and ages while at the same time payors increasingly emphasise cost reduction. For investors in the sector there are significant growth opportunities and potential high returns where blockbuster biologics products face patent expiration. In addition, complexities in manufacturing and regulatory approval create barriers to entry and economic moats.
BIOSIMILARS FINALLY IN VOGUE Recently biosimilars manufacturers have recorded increases in revenue, which are an indication of the biosimilar market being on a strong growth trajectory. The biosimilars
market reached USD 4.4 billion in annual sales in 2017,with predicted double digit growth to reach between USD14 billion and USD 31 billion by 2023. Growth is spurred by a number of factors including increasing biosimilar approvals in the US market and payor drive towards reducing healthcare spending. Achim Newrzella, Associate at Results Healthcare, and author of the paper, commented: “As the fundamentals remain supportive and approval processes, in particular in the US market, become better defined, the prospect for the growth of the biosimilars market should make it increasingly attractive for investment. Depending on the nature of the investor, this can be captured through investing in listed companies, private companies or partnerships.� The report points out that each biosimilar has its own characteristics, and each market has its own dynamics. Pricing forms an important part of the launch strategy. Expectations in the US market are that biosimilars will need to provide discounts of 15-30% compared to the reference product while in Europe there have been examples of 3040% cuts. At the same time, originators have established defence mechanisms to incoming biosimilars through intellectual property portfolios, marketing strategies and the benefits of being the existing brand. However, since the creation of BPCIA in 2010 to establish a pathway for biosimilars, the process has become much smoother. Despite evident challenges, the prospect of reducing treatment costs for payors support a positive future for biosimilars. The challenges involved in producing biosimilars provide opportunities for companies with the relevant know-how, capacity and financial resources to make products that meet regulatory requirements and can take market share from originator products.
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| cell culture |
CELL HANDLING Cell Collection
Cell Transfer
Cell Incubation
Cell Staining
Culture media and cells are combined and transferred to a centrifuge tube. The tubes can vary in size depending on the sample’s volume and how it’s being processed.
Cells are centrifuged and separated from the supernatant, then placed in a new tube with fresh culture media. The OHAUS Frontier™ Series centrifuges can spin samples up to 23,000 × g with high volume and aerosol-safe rotor options.
Cells are transferred to a culture flask and incubated long enough to attach and grow. The OHAUS Incubating Shakers can replicate a cell’s natural environment through precise temperature control of ± .5 °C at 37 °C, and an orbital motion that promotes oxygen transfer.
After placing cells in a cell culture dish, the culture medium is removed and replaced with staining solution. The OHAUS Incubating Rocking and Waving Shakers provide more efficient staining and washing results, because they have tilt angles and speeds that are adjustable while in process.
Fluorescence Study
Prior to fluorescence studies of a sample, the staining solution is substituted by a buffer to wash off the excess dye. Afterwards microscopy can be performed and cells can be viewed using a fluorescence microscope.
Cell culture applications for cell biology In every successful relationship, communication is key. This can be among friends in a social setting, at home with family or in the workplace with colleagues. Depending on our different personalities and behaviors, we give off signals to each other that are then interpreted. It is from these signals as well as our surrounding environment that we adapt and learn how to interact with each other. Interestingly enough, a similar type of interaction also occurs within organisms at the cellular level. Cells can communicate by transmitting and receiving chemical signals. Many researchers spend their careers studying cells and cell-to-cell interactions to understand how healthy and diseased cells respond to each other and their changing environment. In research, once interest in a specific cell type is determined, cells are removed from an animal or plant and cultured or grown in an artificial environment to expand the cell type of interest. Depending on the experiment, researchers will select from mammalian or non-mammalian cells and determine the best growth method, either adherent – attached to an artificial substrate, or suspension – grown free-floating in media. To ensure good cell growth during scale up work, a researcher uses laboratory equipment to replicate the natural environment for optimized cell growth. For example, when culturing mammalian cells, a CO2 incubator running at 37° C is required as opposed to non-mammalian cells that can be grown in a non-CO2 or dry incubator. Suspension cells need to be kept in motion to promote gas transfer. This can be done by growing cells in a flask and using an orbital shaker to precisely control the speed at which the cells are shaking. Not every orbital shaker that is placed inside a CO2 incubator can tolerate that type of harsh
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environment. However, the OHAUS Extreme Environment Shaker fits the application since the shaker can withstand conditions up to 100% humidity. Replicating a natural CO2 environment can be tedious work and CO2 incubators are costly. As an alternative, insect cell culture has become popular since insect cells do not require a CO2 environment. More importantly, insect cells serve as a model for studying cellular processes that can be applied to higher eukaryotes. For ideal insect cell culture conditions, it is important to maintain stable temperature and shaking speeds. The OHAUS Incubating Cooling Orbital Shaker fits well in an insect cell culture workflow since it combines features of precise temperature control down to 10° C below ambient along with consistent uniform shaking. All of these various methods of cell culture can be considered a process that enables cell biologists to study cell-to-cell interaction. Understanding the interaction between and within healthy or diseased cells impacts all of us because it allows researchers to develop more effective medicines, new vaccines and generally provides a better understanding of how all living things live. So the next time you are out with friends or in a meeting room, take a look at the people around you and observe how they are communicating – communication is key.
| excipients |
| BIOSCIENCE TODAY SEPTEMBER•OCTOBER 2018 |
The challenges inherent in
Excipients By Professor Donyai Have you ever wondered how a cough lozenge dissolves just at the right speed or how some medicines smell and taste so good? We have ‘excipients’ to thank for these useful properties in our medicines. So, what exactly are excipients? In fact, the total excipient content of a medicine is likely to be much higher than the amount of active drug itself. Excipients are ingredients added to the formula to, say, help dissolve the drug, or make the medication taste sweet, smell nice, or keep its goodness. And so, while some excipients are added to secure the quality of the product, others are added to help make the medicine more acceptable to users or to help the medicine get to the right part of the body. But rather than thinking of excipients as harmless components, some excipients come with their own warnings and cautions. For example, excipients can break down within the final drug formulation, losing their potency and use, and some even have their own effects on the body, causing allergies and other unwanted effects. An added issue is when someone’s beliefs prevents them from taking a medicine with a forbidden excipient. What do we know about problematic excipients? Actually, scientists now know quite a lot about pharmaceutical excipients and their various properties. 2017 saw the publication of the 8th edition of the Handbook of Pharmaceutical Excipients. This 1000+ page publication brings together detailed information about more than 400 excipients, their different chemical features, as well as their stability and safety. In addition to that, in 2017 the European Medicines Agency published updated guidance to drug manufacturers about which excipients to display on the label of medicines and how to draw attention to their adverse effects on the package leaflets. For example, excipients such as glucose, invert sugar, sucrose are harmful to teeth. The same excipients also need to be used with caution in people with diabetes. And some excipients have a laxative effect and can cause diarrhoea, such as glycerol, mannitol, sorbitol, xylitol.
Another potential problem is when people are allergic to an excipient. For example, a range of colouring agents (e.g. tartrazine, amaranth, cochineal red) when swallowed in a medicine could cause an allergic reaction. Ingredients commonly added to creams and ointments too can be problematic (e.g. chlorocresol, fragrances, lanolin) causing skin irritation or allergic reactions. And because some excipients come from foods these could be problematic for those with foods allergies. For example, some medicines contain peanut oil also known as arachis oil. Others could contain extracts of egg, fish, gelatine, milk, sesame or soy. These are all potential triggers for allergy sufferers. Manufacturers are obliged to highlight the presence of these ingredients and their features clearly in writing to users, on the package labelling or in the information leaflet inserted within the medicine pack. In this way, manufacturers warn users about the potential for problems, at least within the written material that accompanies the medicine. As well as that, guidelines are given to health professionals who administer medicines such as vaccines in cases of allergy. For example, the influenza vaccine (which contains an egg component) should only be given to an individual with a history of egg allergy in a specialist hospital setting, unless an egg free vaccine can be sourced. But despite scientific advances in discovering the harmful effects of excipients and steps taken to highlight these, people using medicines can still experience problems and confusion when it comes to excipients. Why would that be the case? Well, for one, it is widely accepted that not every patient will read the text that accompanies their medication. This is a problem if the main mode of communicating with patients is assumed to be through written material. And even if patients do read the material, there are some who will not fully understand the information and what to do with it. For example, if a cream for eczema warns about skin irritation, then what does this irritation look and feel like, how many patients are actually likely to experience this, and what should someone do if they do experience it or are unsure? Added to this, not everyone will know beforehand if they are, for example, allergic to an excipient in their medicine. These patients could end up experiencing an allergy quite by accident. And when people do experience symptoms, not everyone will automatically recognise this as an allergic reaction. This is easy to understand. Although some allergic reactions are almost immediate and extreme (e.g. anaphylaxis, severe asthma), some skin reactions don’t happen until 3-10 days or even up to 6 weeks after first contact.
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| BIOSCIENCE TODAY SEPTEMBER•OCTOBER 2018 |
| excipients |
Now consider a different problem where some people’s beliefs prevent them from using a medicine with a prohibited excipient. This is the case with gelatine, which poses a problem for vegans/vegetarians, because they do not consume anything derived from meat: gelatine is made from collagen obtained from the connective tissue of animals. Pork gelatine is also problematic for muslins whose religion prohibits the use of products derived from pigs. Pork gelatine is an excipient in a number of vaccines including the nasal influenza vaccine, vaccines against chickenpox and shingles as well as one brand of the measles, mumps, Rubella (MMR) vaccine. In these instances, therefore, patients need reliable information about safe alternatives. This long list of problems at the patient interface is where the pharmacist comes in. Pharmacists are trained professionals who bridge the information gap between medicines and patients. Pharmacy degrees in the UK typically take 4 years to complete with a further one year of workplace training before a specialised registration exam. Pharmacists therefore learn extensively about how new drugs are discovered, as well as their formulation into medicines such as tablets, creams and injections. They learn how the different medicines affect the body and how ill bodies handle different medicines. As well as that, pharmacists get to understand the patient perspective, and patient worries and concerns. A mainstay of pharmacist training is about communicating with patients and being able to interpret complex scientific information and to break this information down for patients to understand. This makes pharmacists not only experts in medicines but also people who are best placed to advise patients about the potential for an allergic reaction, what signs and symptoms to looks out for, what to do in case of an allergy, as well as the alternatives to potentially problematic medicines. And the scope of this work does not stop with medicines. Community pharmacists, for example, are often called upon to help consumers make sense of the excipients in products such as make-up, nutritional supplements and even liquids for vaping devices! The Reading School of Pharmacy runs a fully accredited 4-year pharmacy degree helping fully equip the next generation of scientists on the high street to answer questions about medicines and their excipients.
“Pharmacists are trained professionals who bridge the information gap between medicines and patients. Pharmacy degrees in the UK typically take 4 years to complete with a further one year of workplace training before a specialised registration exam.” 71
| excipients |
| BIOSCIENCE TODAY |
A pill for delivering biomedical micromotors American Chemical Society Using tiny micromotors to diagnose and treat disease in the human body could soon be a reality. But keeping these devices intact as they travel through the body remains a hurdle. Now in a study appearing in ACS Nano, scientists report that they have found a way to encapsulate micromotors into pills. The pill’s coating protects the devices as they traverse the digestive system prior to releasing their drug cargo. About the width of a human hair, micromotors are self-propelled microscopic robots designed to perform a host of biomedical tasks. In previous research, Joseph Wang, Liangfang Zhang and colleagues used micromotors coated with an antibiotic to treat ulcers in laboratory mice. They found that this approach produced better results than just taking the drugs by themselves. However, the researchers noted that body fluids, such as gastric acid and intestinal fluids, can compromise the effectiveness of micromotors and trigger early release of their payloads. In addition, when taken orally in fluid, some of the micromotors can get trapped in the esophagus. To overcome these issues, Wang and Zhang sought to develop a way to protect and carry these devices into the stomach without compromising their mobility or effectiveness.
The researchers created a pill composed of a pair of sugars — lactose and maltose — that encapsulated tens of thousands of micromotors made of a magnesium/ titanium dioxide core loaded with a fluorescent dye cargo. These sugars were chosen because they are easy to mold into tablet, can disintegrate when needed and are nontoxic. When given to laboratory mice, these pills improved the release and retention of the micromotors in the stomach compared to those encapsulated VEGF IS KNOWN TO in silica-based tablets or in a liquid solution. The STIMULATE DNA researchers concluded that encapsulating micromotors SYNTHESIS AND CELL in traditional pill form improves theirPROLIFERATION, ability to deliver medicines to specific targets without IS diminishing INVOLVED IN their mobility or performance. ANGIOGENESIS
ANDthe ATTRACTS The authors acknowledge funding from Defense ENDOTHELIAL Threat Reduction Agency Joint Science and Technology PROGENITOR Office for Chemical and Biological Defense, the CELLS ADDITIONNacional TO Charles Lee Powell Foundation, the IN Consejo BLOOD de Ciencia y Tecnología (CONACyT)STABILISING postdoctoral fellowship, Fulbright grants, the Comisión VESSELS.Nacional de Investigacion Cientifica y Tecnologica (CONICYT) and the China Scholarship Council.
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| BIOSCIENCE TODAY |
| contract manufacturing |
Industiral preparative chromatography platform
Servier launches InnoPreP™, its new preparative chromatography offer Servier, an independent international pharmaceutical company, has announced the launch of InnoPreP™ – a new preparative chromatography service offered under its contract development and manufacturing business. Servier has employed preparative chromatography for over 30 years and its team of experts based in Normandy, France has become a respected leading global authority on this accepted industry standard approach to purification. InnoPreP™ encompasses the capability for either continuous processing using SMB or 6-column batch chromatography at lab to industrial scale, and can reduce time-to-market by as much as three months. Dr. Gwenaël Servant, Senior Director of Business Development for Servier’s contract development and manufacturing business, said, “We can reduce time to market significantly by getting to the target molecule and into the clinic faster. To be able to do this at industrial volumes is appealing to companies seeking to scale up
existing processes or simply move quickly, as it delivers clear financial gains.” Servier has invested in expansion of its preparative chromatography infrastructure at its fully integrated Bolbec drug substance facility in Normandy, France. A new dedicated 500m2 space houses continuous processing using simulated moving bed (SMB) technology, which can achieve greater yields from fewer starting materials and is very efficient for racemic separation. There is green technology with Supercritical CO2 and a falling film evaporator recycles up to 90% of solvent. Lab to industrial scale chromatography is also available using Servier’s batch technology with six-column equipment. The InnoPreP™ area also has high containment to enable handling of highly potent compounds down to OEB 5, serving companies seeking to develop HPAPIs for oncology. Dr. Christophe Berini, Analytical Innovative Technologies Research Scientist at Servier, said, “The InnoPreP™ approach not only gets our client to their target molecule and into the clinic faster, it also helps to optimize the purity of their APIs and intermediates, and gains
“We can reduce time to market significantly by getting to the target molecule and into the clinic faster. To be able to do this at industrial volumes is appealing to companies seeking to scale up existing processes or simply move quickly, as it delivers clear financial gains.” Dr. Gwenaël Servant, Senior Director of Business Development for Servier’s contract development and manufacturing business
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| contract manufacturing |
| BIOSCIENCE TODAY |
Cobra Biologics, GE Healthcare and Centre for Process Innovation collaborate to advance gene therapy Innovate UK funded project supports development of scalable, cost effective production of regenerative medicines Cobra Biologics (Cobra), an international contract development and manufacturing organisation (CDMO) of biologics and pharmaceuticals, has announced a collaboration with the Centre for Process Innovation (CPI), a UK-based technology innovation centre and GE Healthcare Life Sciences. The three-way partnership, funded by a £570K Innovate UK grant, aims to increase the robustness and reduce costs for the manufacturing of adeno-associated virus (AAV) vectors, a delivery vehicle used for emerging gene therapy treatments. The gene therapy area has been developing rapidly and while only a small number of treatments are already approved for use, more than 200 clinical trials are underway. AAV vectors are effective and versatile, but their use in clinical trials is hampered by complicated production processes. Without improvements to manufacturing approaches and better process understanding, there is the risk of gene therapies being launched commercially at prices unaffordable to healthcare payers, such as the NHS. GE Healthcare’s Puridify fibre-based chromatography technology platform, can achieve high purification productivity of protein biopharmaceuticals, such as monoclonal antibodies. The collaboration with CPI and Cobra Biologics will help demonstrate the application of the purification platform to gene therapy, helping to provide more efficient and scalable gene therapy manufacturing and more affordable therapies. The project will extend the advantages of GE Healthcare’s technology and develop a multistep fibre-based chromatography purification process for AAV. These viral vectors will be produced in-house by Cobra Biologics and CPI using a system developed via an ongoing Innovate UK grant. The developed fibre-based
technology will then be transferred to CPI, where entire process flowsheets incorporating the technology will be run to demonstrate suitability for AAV manufacture. Prof. Daniel Smith, Chief Scientific Officer at Cobra Biologics, said: “The scalable chromatographic purification of recombinant AAV-based viral vectors for use in gene therapy applications remains an area of intense global development, essential to support the rapidly increasing market opportunity for these innovative medicines. As such, Cobra Biologics is pleased to be collaborating with both GE Healthcare Life Sciences and CPI as part of this Innovate UK funded project. The application and implementation of the fibre-based chromatography for the purification of AAV vectors could provide a step change in the technology available, allowing for the scalable, cost effective production of this emerging class of innovative medicines.” Dr. John Liddell, CPI Senior Scientific Advisor, said: “CPI is delighted to be working with GE Healthcare Life Sciences and Cobra Biologics on this exciting project working to help develop robust and efficient downstream processes for the rapidly developing area of gene therapy. Gene therapies have the potential to be transformative for areas of unmet clinical need and effective manufacturing processes which are the subject of this project, will be important enablers to achieving commercialisation. Additionally, the project builds on a successful relationship established with Cobra Biologics through an on-going AAV project.” Dr. Oliver Hardick, Business Leader, Puridify, GE Healthcare Life Sciences, said: “We are proud to establish this collaboration with Cobra and CPI that seeks to advance technologies for the manufacture of viral vectors that are necessary for emerging gene therapies. Collaboration and bringing together expertise from different fields is critical for improving access to these promising new treatments globally.”
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MEDICAL CARE WHERE IT’S NEEDED MOST INDEPENDENT. NEUTRAL. IMPARTIAL. Kenya, 2017. © Patrick Meinhardt
www.msf.org.uk
europium phospho
cerium sputtering target
dielectrics catalog:americanelements.com scandium powder
yttrium granules lanthanum rods
holmium disc 1
1
H
2 1
Li
Nd:YAG
4
6.941
11
Na
yttrium
Beryllium 12
22.98976928
19
K
Mg
erbium fluoride sputtering targets
Magnesium
medicine
2 8 8 1
20
39.0983
Ca
2 8 18 8 1
2 8 8 2
21
22
Ti
44.955912
Calcium 38
2 8 9 2
Sc
40.078
Potassium
37
2 8 2
24.305
Sodium
39
85.4678
2 8 18 9 2
87.62
40
nadium
55
Cs
2 8 18 18 8 1
56
132.9054
Ba
57
2 8 18 32 18 8 1
88
Francium
(226)
2 8 18 18 9 2
La
72
Hf
89
thin film
Ac (227)
Radium
41
Nb
73
Ta
2 8 18 32 18 9 2
104
Rf (267)
Mo
74
W
105
Db (268)
Rutherfordium
2 8 18 13 1
43
2 8 18 32 12 2
Sg (271)
Dubnium
2 8 18 13 2
Tc
75
Ce
59
Pr
2 8 18 21 8 2
60
140.116
140.90765
Cerium
Th
Praseodymium
2 8 18 32 18 10 2
91
Pa
2 8 18 32 20 9 2
Bh (272)
144.242
92
Thorium
ten carbide
231.03588
U
(145)
238.02891
Protactinium
93
Np (237)
Uranium
Neptunium
2 8 18 32 22 9 2
Os
108
Hs (270)
2 8 18 24 8 2
63
150.36
(244)
2 8 18 32 14 2
Plutonium
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77
Ir
46
Pd
109
Mt (276)
47
106.42
Ag
2 8 18 32 15 2
78
Pt
79
195.084
Meitnerium
110
Ds (281)
30
Zn
Au
2 8 18 18 1
48
Cd
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Rg (280)
31
Ga
14
Si 28.0855
49
In
112.411
2 8 18 32 18 1
80
Hg
Roentgenium
Cn (285)
72.64
2 8 18 18 3
50
114.818
2 8 18 32 18 2
81
Tl
200.59
112
Ge Sn
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2 8 18 32 18 3
82
Pb
Eu
64
95
Gd
65
157.25
2 8 18 32 25 8 2
96
Americium
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2 8 18 27 8 2
158.92535
Gadolinium
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2 8 18 25 9 2
97
Bk (247)
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2 8 18 28 8 2
67
162.5
Terbium
2 8 18 32 25 9 2
66
98
Cf (251)
68
2 8 18 32 28 8 2
Californium
99
Es (252)
Er 167.259
Holmium
Erbium 2 8 18 32 29 8 2
Einsteinium
100
Fm (257)
Fermium
51
2 8 18 32 32 18 3
114
Fl (289)
69
Tm
34
Se
52
Te
121.76
2 8 18 32 18 4
83
Bi
84
2 8 18 32 32 18 5
116
208.9804
115
Uup (288)
70
alternative energy
Yb
2 8 18 18 6
53
2 8 18 18 7
54
I
Kr
2 8 18 32 32 18 6
117
crystal
83.798
Xe
2 8 18 18 8
131.293
Iodine
85
2 8 18 8
Krypton
126.90447
2 8 18 32 18 6
europiu
39.948
Argon
79.904
Xenon
2 8 18 32 18 7
86
cone sit
2 8 18 32 18 8
Po At Rn electrochemistry (210)
Lv (293)
(222)
Astatine
Uus (294)
Livermorium
71
36
Bromine
(209)
2 8 18 32 8 2
2 8 18 7
niobium
Radon
titanium
2 8 18 32 32 18 7
Ununseptium
118
Uuo (294)
2 8 18 32 32 18 8
Ununoctium
terbium ingot Lu
2 8 18 32 9 2
cerium polishing powder 168.93421
173.054
Thulium
2 8 18 32 30 8 2
101
Md (258)
174.9668
Ytterbium
2 8 18 32 31 8 2
Mendelevium
102
No (259)
Lutetium
2 8 18 32 32 8 2
Nobelium
103
Lr (262)
2 8 18 32 32 8 3
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Br
Polonium
Ununpentium
2 8 18 31 8 2
35
127.6
Bismuth 2 8 18 32 32 18 4
2 8 18 6
2 8 8
Ar
35.453
Tellurium 2 8 18 32 18 5
Neon
18
Chlorine
78.96
2 8 18 18 5
20.1797
2 8 7
Cl
32.065
Antimony
Flerovium
2 8 18 30 8 2
S
17
2 8
Ne
Fluorine
Selenium
Sb
207.2
Ununtrium
164.93032
Dysprosium 2 8 18 32 27 8 2
Ho
2 8 18 29 8 2
2 8 18 18 4
Lead
aluminum nanoparticles
2 8 18 25 8 2
As
2 8 18 5
10
18.9984032
2 8 6
Sulfur
74.9216
Tin
204.3833
113
P
16
2 7
F
15.9994
Arsenic
118.71
Thallium 2 8 18 32 32 18 2
33
9
Oxygen
30.973762
2 8 18 4
2 6
O
Phosphorus
Germanium
Indium
Mercury 2 8 18 32 32 18 1
32
15
rod
Helium
14.0067
2 8 5
2
He 4.002602
8
Nitrogen 2 8 4
Silicon 2 8 18 3
2 5
N
12.0107
69.723
2 8 18 18 2
7
Carbon 2 8 3
Gallium
Cadmium
Gold
111
Al
Zinc
196.966569
2 8 18 32 32 17 1
2 8 18 2
65.38
Silver
Platinum 2 8 18 32 32 15 2
2 8 18 1
107.8682
2 8 18 32 17 1
10.811
Boron 13
2 4
C
26.9815386
63.546
2 8 18 18
6
Aluminum
Copper
Palladium
192.217
2 8 18 32 32 14 2
Cu
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2 3
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2 8 18 16 1
Iridium
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29
Nickel
102.9055
Europium 2 8 18 32 24 8 2
Pu
Ni
2 8 16 2
58.6934
Rhodium
151.964
Samarium 94
45
Hassium
62
Promethium 2 8 18 32 21 9 2
2 8 18 32 32 13 2
Bohrium
2 8 18 23 8 2
2 8 18 15 1
190.23
Nd Pm Sm
Neodymium
refractory metals 232.03806
61
76
28
Cobalt
Osmium
107
Seaborgium
2 8 18 22 8 2
Ru
2 8 15 2
58.933195
101.07
186.207
quantum dots 2 8 18 19 9 2
44
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Re
27
Iron
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183.84
106
Fe
2 8 14 2
55.845
Technetium
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26
54.938045
95.96
2 8 18 32 11 2
Mn
2 8 13 2
Manganese
Molybdenum
180.9488
diamond micropowder 90
42
2 8 18 12 1
Tantalum 2 8 18 32 32 10 2
25
51.9961
92.90638
2 8 18 32 10 2
Cr
2 8 13 1
Chromium
Niobium
Hafnium
Actinium
58
2 8 18 10 2
178.48
Lanthanum 2 8 18 32 18 8 2
50.9415
Zirconium
138.90547
Barium
Fr Ra tantalum (223)
2 8 18 18 8 2
V
24
2 8 11 2
Vanadium
91.224
Yttrium
137.327
Cesium 87
88.90585
Strontium
23
Titanium
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47.867
Scandium 2 8 18 8 2
5
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