SCIENCETODAY
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JULYAUGUST2018
UK AND world News • cardiovascular • Intellectual Property • cell lines • artificial intelligence • growth of the bio industry
cover story:
discovering a new future
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| BIOSCIENCE TODAY SUMMER 2018 |
www.biosciencetoday.co.uk
| welcome |
Welcome
In which Saturday night and Sunday morning play a part Ellen Rossiter Editor in chief
Editor Ellen Rossiter ellen.rossiter@distinctivepublishing.co.uk
Design Distinctive Publishing, 3rd Floor, Tru Knit House, 9-11 Carliol Square, Newcastle, NE1 6UF Tel: 0191 580 5990 www.distinctivepublishing.co.uk
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Valentine’s Day may be long gone, but matters of the heart figure significantly in this issue of Bioscience Today. We take a look at the work of two researchers for whom it is clear, combatting cardiovascular disease is the driving force that propels their work. Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation (BHF) provides us with an overview of the progress that’s been made in cardiovascular research and explains the work that is ongoing to find the next breakthrough treatment. We also speak to Dr Vijay Kunadian, Senior Lecturer and Honorary Consultant Interventional Cardiologist, about her life, work and inspiration. We learn too, how the treatment offered to patients with heart disease has been transformed in recent years and the challenge that remains. In this issue, we also turn our sights on Alzheimer’s disease, which accounts for twothirds of all dementia cases, meaning around 500,000 people are living with the disease in the UK alone. Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, takes us through a century of progress and the hope that is on the horizon. Advances in drug delivery and drug delivery devices are also top priorities and in this issue of Bioscience Today, we discover how researchers are harnessing wireless systems to power devices in the body, with the prospect of enabling the remote control of drug delivery and for other medical applications too.
Distinctive Publishing or BioScience Today cannot be held responsible for any inaccuracies that may occur, individual products or services advertised or late entries. No part of this publication may be reproduced or scanned without prior written permission of the publishers and BioScience Today.
Since our last issue, the government has held the inaugural meeting of their newly-established UK Life Sciences Council, which brings together government ministers and industry experts with the aim of ensuring the UK continues to be a global leader in life sciences. The formation of this council is a significant step. We know, you know of the considerable
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contribution bioscience makes to the economy. Research just released shows that the UK life sciences sector is soaring, with a record turnover of over £70 billion, providing jobs for almost 241,000 people across the country. Look a little closer and you’ll find that SMEs account for 82% of these businesses and 24% of all UK life sciences employment. So it is pertinent that in this issue, we discover how a bioscience incubator is supporting just such SME’s and in turn, contributing to a new model for regional development. As a company based in Newcastle, where many of our region’s traditional industries have declined, we were intrigued to find out how one city is forging a new path. Yes, yes, we hear you shout ‘new technology’, the ‘digital sector’ and ‘Jony Ive’, plus a few other choice things too, but read on to discover how Nottingham is turning its historic strengths to new purposes. You may associate Nottingham with the manufacturing economy portrayed in Alan Sillitoe’s ‘Saturday Night and Sunday Morning’, but in this issue, we learn how it is giving the biotechnology golden triangle of London, Oxford and Cambridge a run for its money. Look to Dundee and find another city making a significant contribution to the UK’s life science sector. Learn how the University’s Drug Discovery Unit is operating as a standalone ‘biotech style’ small molecule drug discovery organisation, collaborating with partners worldwide. Finally, for anyone involved in biotechnology, protecting your Intellectual Property (IP) is a key concern. In this issue, we learn why filing a comprehensive and good-quality patent application is crucial and why forming a strong IP strategy is an important stepping stone to building a firm foundation for your business. We also look at the impact that Brexit may have on your IP rights. Turn the page to find out more.
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| BIOSCIENCE TODAY SUMMER 2018 |
features
The importance of Intellectual Property strategy; creating a foundation on which to build value in your company
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13 Discovery of novel Malaria parasite behaviour offers new target for treatmentÂ
Combatting cardiovascular disease today
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| BIOSCIENCE TODAY SUMMER 2018 |
| contents |
contents
www.biosciencetoday.co.uk / issue 13 /summer 2018
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Introduction/Foreword
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Contents
6-7
Contributors
8-9 Biodigestables 10 News
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Ebola virus disease – Democratic Republic of the Congo: Update on Ring Vaccination
12-17 News New class of drugs could help tackle treatment-resistant cancers 18-29
Cardiovascular Disease
30-31
Big Interview
32-33
Alzheimer’s News
36-37
News
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Intellectual Property The importance of Intellectual Property strategy
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Artificial Intelligence Discovering a new future through Artificial Intelligence
46-51 52-57
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Breaking through cardiovascular disease
Focus on Alzheimer’s disease – Hope on the horizon
Genes linked to Alzheimer’s contribute to damage in different ways
Wireless system can power devices inside the body
Cell Lines
Body in Miniture
Growth of the Bio Industry
The rise of biotechnology: How biotechnology is contributing to regional development
Discovering a new future through Artificial Intelligence and Machine Learning
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| BIOSCIENCE TODAY SUMMER 2018 |
Dr Catrin Rutland BSc PGCHE MSc MMedSci PhD SFHEA FAS Associate Professor in Anatomy and Developmental Genetics Catrin undertakes research and teaching at the School of Veterinary Medicine and Science, University of Nottingham. Her research concentrates on anatomy and cardiovascular health in both animals and humans. Her goal is to improve heart health by identifying cardiac problems, understanding the genetics behind them and developing prognostic and treatment techniques.
Andrea Gruber, IATA Head, Special Cargo at International Air Transport Association (IATA) Andrea is Head of Special Cargo at IATA. In this capacity she is responsible for leading IATA’s Cargo governing bodies, comprised of airlines and air cargo supply chain stakeholders in the development of regulations for the air transportation of Live Animals, Perishables and Healthcare Products.
Malcolm Skingle Director, Academic Liaison GlaxoSmithKline (GSK) and Science Industry Partnership Chair Malcolm Skingle CBE has a BSc in Pharmacology/Biochemistry and a PhD in Neuropharmacology. He has managed Academic Liaison at GSK for over a decade. He now chairs several groups including the SIP.
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| BIOSCIENCE TODAY SUMMER 2018 |
Professor Metin Avkiran, BSc PhD DSc FAHA FESC FISHR, Associate Medical Director, British Heart Foundation (BHF) Metin Avkiran was appointed as Associate Medical Director for Research at the British Heart Foundation, on secondment from King’s College London, from September 2016. At King’s, he is Professor of Molecular Cardiology and Deputy Head of the Cardiovascular Division within the British Heart Foundation Centre of Research Excellence, where his laboratory’s research focuses on investigating the molecular signalling mechanisms that regulate cardiac function in health and disease.
Jim Robertson Partner Jim is a patent attorney and partner at Wynne-Jones IP, where he leads the life sciences team, helping clients create value by protecting their businesses, technology and innovations through obtaining granted patents, due diligence on transactions, and handling contentious and litigious matters.
Dr Emma Longland Senior Patent Attorney Emma is a UK and European Patent Attorney in the Life Sciences Group at HGF Limited. She works with Universities, spin-outs and growing companies on a wide range of medical and biotech inventions, including inventions related to humanised antibodies, CRISPR technologies and therapeutic nucleic acids.
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Craig Thomson Partner Craig Is a qualified European, UK and Irish Patent Attorney and has considerable experience in providing pragmatic, commercially focused advice to a wide-range of clients and in relation to biotechnological, pharmaceutical and chemical inventions. As well as patent drafting and prosecution, Craig advises on the development of companywide IP strategies, preparing for or carrying out funding/acquisition due diligence, and advising on aggressive/defensive strategies in relation to third party IP.
Professor David Smith
Daniel Mcdonald-Junor Senior Lecturer, Nottingham Business School, Nottingham Trent University Daniel is a lecturer at Nottingham Trent University, he teaches both undergraduate and postgraduate students, is actively involved in academic research and is based in the Management Division of the Business school. Daniel runs a company that aims to identify the different approaches biotechnology incubators take to support start-ups, spin-offs and very early stage life science companies in the UK.
Professor of Innovation Management, Nottingham Business School, Nottingham Trent University
William Rossiter Associate Professor, Nottingham Business School, Nottingham Trent University
David is an economist by background, he undertakes teaching and research in a variety of aspects of innovation. He is the author of ‘Exploring Innovation’, the bestselling textbook published by McGraw-Hill, now in its third edition and his work has been published in many journals in the Innovation field.
Will manages the Economic Strategy Research Bureau at Nottingham Business School. The team offers a range of economic research, evaluation and strategic consultancy services to public, private and third sector clients. Will’s research interests relate to local and regional economic development, the policy process, economic and institutional path dependence.
Dr Beth Mortimer 1851 Research fellow, Department of Zoology & St Anne’s College, University of Oxford
Dr David Reynolds Chief Scientific Officer, Alzheimer’s Research UK
Beth investigates how animals are able to use vibrations through materials and along surfaces for information. Studying this form of informationtransferrequiresaninterdisciplinary understanding of the generation, propagation and detection of vibrations.
Before joining Alzheimer’s Research UK, David worked in the pharmaceutical industry for 18 years at Merck Sharp & Dohme, Lundbeck and latterly Pfizer, where he was the Cambridge Neuroscience & Pain research site head.
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| biodigestables |
| BIOSCIENCE TODAY SUMMER 2018 |
BIODIGESTABLES
Calcium may play a role in the development of Parkinson’s disease
Rare Scottish dinosaur prints give key insight into era lost in time
PhoreMost completes $15M (£11M) Series-A round to enter drug discovery
The international team, led by the University of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alphasynuclein, the protein associated with Parkinson’s disease. Excess levels of either calcium or alphasynuclein may be what starts the chain reaction that leads to the death of brain cells.
Dozens of giant footprints discovered on a Scottish island are helping shed light on an important period in dinosaur evolution. The tracks were made some 170 million years ago, in a muddy, shallow lagoon in what is now the north-east coast of the Isle of Skye.
PhoreMost, the UK-based biopharmaceutical company dedicated to drugging ‘undruggable’ disease targets, has announced it has completed an £11m Series-A investment round. The investment will be used to expand operations on the Babraham Research Campus and progress several novel drug targets from its next-generation “SITESEEKER®” phenotypic screening platform into first-in-class drug discovery programmes.
Dementia friendly swimming sessions
Applied Photophysics to Major funding could get to expand distribution in Europe the root of crop diseases
Specially organised ‘dementia friendly’ swimming sessions can be beneficial to people with dementia and their carers, according to a new study by researchers at the University of Nottingham and the Institute of Mental Health. The research, published in Dementia, was carried out with the help of the Amateur Swimming Association (ASA) and Swim England who run a national project to improve access to swimming for people with dementia.
Applied Photophysics, a leading provider of systems for biophysical characterization of biomolecules, has announced that it has signed distribution agreements with scientific equipment distributors, Paralab and Alfatest. The distributors will supply both academic and biopharmaceutical labs in Southern Europe with Applied Photophysics’ Chirascan™ circular dichroism (CD) systems and SX-range of stopped-flow spectrometers.
Big funding for big data Dundee and NUS partner follows Prime Minister’s for new joint degree programme AI speech Funding of £1million has been announced to help University of Dundee scientists tackle the challenges of dealing with big data, just 24 hours after Theresa May heralded the potential of artificial intelligence to transform healthcare.
The University of Dundee and the National University of Singapore (NUS) have established a new partnership which will see students share their study time between Scotland and Singapore and earn a degree from both institutions.
Professor Geoff Barton, Head of Computational Biology in the University’s School of Life Sciences, has received the funding by the Biotechnology and Biological Sciences Research Council (BBSRC). The award will enable the development of advanced computational methods that allow researchers to organise, compare, understand and exploit the vast amounts of data produced in modern scientific experiments.
NUS and Dundee are both globally prominent in the field of life sciences and offer top-quality teaching and excellent student experience. The new Bachelor of Science degree programme jointly offered by the two universities combines these qualities in a package which allows students to experience life and study in both the UK and Asia.
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A world-leading plant disease researcher at the University of Dundee has been awarded major funding for a study which may explain the mechanisms of crop killing diseases across the globe. Plant diseases currently account for 40 per cent of crop losses each year world-wide, representing a serious threat to food security.
Research identifies novel unconventional type of immune cell capable of fighting viral infections Research led by the University of Birmingham has identified a novel unconventional type of immune cell capable of fighting viral infections. The study, published today in Nature Communications and carried out in collaboration with the Academic Medical Center, Netherlands, and Skolkovo Institute of Science and Technology, Russia, focussed on T cells that control our immune system.
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| biodigestables |
BIODIGESTABLES
Human anti-cancer drugs could Existing cancer treatment Scientists enhance help treat transmissible cancers could be used for common understanding of cancer ‘untreatable’ form of lung cancer development mechanisms in Tasmanian devils A cancer treatment already approved for use in certain types of cancer has been found to block cell growth in a common form of lung cancer for which there is currently no specific treatment available. The new findings, just published in Science Translational Medicine and led by the University of Glasgow, suggest that a large number of patients could benefit from this treatment – a second generation EGFR inhibitor (a drug that slows down or stops cell growth) – if used in combination with additional therapies.
Major UK trial to test benefits of exercise in early dementia
Encouraging people to drink more?
A large clinical study to test a specially-designed programme of exercise for people who are in the early stages of dementia is to go ahead after a feasibility trial showed positive results.
Wines and beers labelled as lower in alcohol strength may increase the total amount of alcoholic drink consumed, according to a study published in the journal Health Psychology. The study was carried out by the Behaviour and Health Research Unit at the University of Cambridge in collaboration with the Centre for Addictive Behaviours Research at London South Bank University.
The PrAISED (Promoting Activity Independence and Stability in Early Dementia) study is being led by a team of Nottingham-based experts thanks to a £2.8million grant from the National Institute for Health Research (NIHR).
University of Birmingham wins accolade
£6 million state-of-the-art dairy centre launched
A research paper showing the results of a study led by researchers at the University of Birmingham has been crowned ‘UK Research Paper of the Year’ in The BMJ Awards 2018.
A new £6 million centre that will position the University of Nottingham at the forefront of research into the health, nutrition and welfare of dairy cows has been officially unveiled at its Sutton Bonington campus.
The paper, published in The BMJ last October, described the results of the BUMPES trial which aimed to investigate the most ideal position a first-time mother with a low dose epidural should adopt to increase the chance of a birth without interventions such as forceps or a Caesarean.
The new Centre for Dairy Science Innovation is a state-of-the-art extension to the University’s longstanding dairy facilities and will offer the latest research technologies for studying a range of dairy-related topics including mastitis control, antimicrobial resistance, feed efficiency, environmental emissions and new so-called wearable technologies for the herd.
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An interdisciplinary research collaboration has taken a significant step towards understanding the mutational causes of cancers, a finding which may one day lead to personalised cancer treatment. The team from the University of Dundee, European Bioinformatics Institute (EMBL-EBI) and the Wellcome Sanger Institute used a type of worm called C. elegans as a model to study how cancercausing genetic mutations arise when DNA is inaccurately replicated or when damaged DNA is not repaired.
Eurovision Song Contest associated with increase in life satisfaction Participating in the Eurovision Song Contest may be linked to an increase in a nation’s life satisfaction, according to new research. The study, by scientists at Imperial College London, found that people were four per cent more likely to be satisfied with their life for every increase of ten places on the final score board.
Short story or article to share? Send them to our Editor, Ellen Rossiter, at ellen.rossiter@distinctivepublishing.co.uk
BIO
SCIENCETODAY
Transmissible cancers are incredibly rare in nature, yet have arisen in Tasmanian devils on at least two separate occasions. New research from the University of Cambridge identifies key anti-cancer drugs which could be trialled as a treatment for these diseases, which are threatening Tasmanian devils with extinction.
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| BIOSCIENCE TODAY SUMMER 2018 |
Ebola virus disease – Democratic Republic of the Congo: Update on Ring Vaccination In response to the ongoing outbreak of Ebola in Equateur Province, Democratic Republic of the Congo, the World Health Organization (WHO) is working with the Ministry of Health, Médecins Sans Frontières (MSF), UNICEF and other partners including the Ministry of Health of Guinea, to conduct vaccination against Ebola for people at high risk of infection in affected health zones. On 21 May 2018, ring vaccination started along with vaccination of health workers in Mbandaka (WHO) and Bikoro (MSF). As of 21 May, Merck has provided WHO with 8640 doses of the rVSVΔG-ZEBOV vaccine of which 7540 doses are available in the Democratic Republic of the Congo (approximately enough for 50 rings of 150 people). An additional 8000 doses will be available in the coming days. In 2017, the Strategic Advisory Group of Experts on Immunization (SAGE) recommended, that for outbreaks of Zaire ebolavirus, the rVSVΔG-ZEBOV vaccine should be used under the Expanded Access framework, with informed consent and in compliance with Good Clinical Practice. The rVSVΔG-ZEBOV vaccine is highly protective against Zaire ebolavirus and is the first with demonstrated efficacy. Several study trials that included more than 16 000 volunteers in Europe, Africa and America show that the vaccine has a good safety profile among persons six years of age and above. In Guinea and Sierra Leone, the vaccine was used in an efficacy trial of 7500 adults in 2015 and found safe and protective against Zaire ebolavirus infection. The evidence from all 117 rings in Guinea and Sierra Leone showed that no cases of Ebola virus disease occurred 10 days or more after vaccination among all immediately vaccinated contacts and contacts of contacts versus 23 cases among eligible contacts and contacts of contacts who were not vaccinated or for whom vaccination was delayed. The estimated vaccine efficacy was 100% (95% CI 79·3–100·0, p=0·0033). This trial was conducted by WHO, with the Guinean Ministry of Health, MSF, and the Norwegian Institute of Public Health, in collaboration with other international partners. The vaccine works by replacing a gene from a harmless virus known as vesicular stomatitis virus (VSV) with a gene encoding an Ebola virus surface protein. The vaccine does not contain any live Ebola virus. In March 2016, following a newly identify chain of Ebola virus transmission in Guinee Forestiere, 1510 individuals were vaccinated in four rings, including 303 individuals aged between 6–17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among persons who received the vaccine.
Given the remote location and limited road access to the populations affected in the current outbreak, implementing ring vaccination and maintaining the required -80⁰C cold chain presents major logistical challenges for the Ministry of Health, MSF, WHO and other partners on the ground. Vaccination will be implemented using a ring approach, similar to that used in Guinea in 2015, whereby the vaccine will be offered to people at risk, including but not limited to: (i) contacts and contacts of contacts; (ii) local and international health-care and front-line workers in the affected areas and (iii) health-care and front-line workers in areas at risk of expansion of the outbreak. With their agreement and consent, the individuals in the ring will be considered for the vaccination. After receiving the vaccine, individuals will be followed up for a period of time. Each vaccination team is trained and knowledgeable of Good Clinical Practices. The team includes Guinean researchers that conducted the Ring Trial in Guinea and Sierra Leone and the intervention under Compassionate use/Expanded Access in Guinea. Any adverse effects will be treated by qualified physicians and all serious adverse effects will be reported to authorities in the Democratic Republic of the Congo, Merck and Data and Safety Monitoring Board (DSMB). They are supported by experienced logisticians. The steps for the ring vaccination are clearly defined and include: n 1–2 social mobilizers in the vaccination team will visit the community and explain the process to people potentially eligible for the vaccine. n The definition of the ring is made by two members of the vaccination team who are trained and will list all the contacts and contacts of contacts of a patient confirmed with Ebola virus (including absent residents). n Eligibility of participants is assessed. n Informed consent of each individual eligible person is sought. n Vaccination of eligible persons who have given their consent. n Persons vaccinated will be monitored by a doctor for 30 minutes following vaccination and then followed up by home visits on days 3 and 14 after vaccination. The use of the investigational rVSVΔG-ZEBOV vaccine in the Democratic Republic of the Congo marks a milestone for the control of Ebola virus outbreaks. Nonetheless, the vaccine is just one of several outbreak control measures, including case finding, contact tracing, isolation of suspected cases, prompt laboratory diagnosis, infection control in routine healthcare facilities, safe and dignified burials, community mobilization, and effective response coordination.
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1–2 SOCIAL MOBILIZERS IN THE VACCINATION TEAM WILL VISIT THE COMMUNITY AND EXPLAIN THE PROCESS TO PEOPLE POTENTIALLY ELIGIBLE FOR THE VACCINE.
| BIOSCIENCE TODAY SUMMER 2018 |
| Your Guide to R&D Tax Relief |
Is R&D Tax Relief part of your budgeting process? Whether you are a Biotech, a Pharmaceutical, a Medical Device company or a Clinical Research Organisation, you really should be budgeting for your Research and Development Tax Relief claims.
These are generally very well defined in the industry, as a guideline Drug Discovery, PreClinical Development and Clinical Development (including feasibility trials) are all within the spectrum for claiming R&D Tax Relief, it is only in very rare cases within these trials that there is no attempt to overcome scientific uncertainty.
There were originally two R&D Tax Relief schemes, the SME scheme and the Large Company Scheme. As a former European Finance leader for a growing CRO, even when we were a small company, we were only ever eligible to claim under the Large Company Scheme because the R&D was subcontracted to the company, and only then if the contractor was a large or overseas company.
Post Launch Phase IV trials are generally excluded from eligibility because normally by this point the scientific uncertainty has been resolved, the product licensed and any work being performed is more associated with identifying unknown side effects as a result of interactions with other medicines, looking into patient subgroups or longer-term markers. The results of such studies might kick start a new project, where R&D is once again at the forefront of the activities.
The major downfall of the large company scheme was that a loss-making company could only ever enhance losses and therefore delay the payment of tax, however on 1 April 2013, the Research and Development Expenditure Credit was born, and so was the ability to convert some R&D spend in to cash regardless of whether or not the company was profitable in that financial year. The large company scheme expired on 31 March 2016 and since then large companies and CROs have had to claim under RDEC. Now, I have to admit, if you’ve never claimed before, budgeting for your first claim is a bit like sticking your finger in the air to see which way the wind is blowing, but once you’ve claimed, budgeting for future years should become a lot easier and may even influence some of your riskier decisions.
HOW? YOU MAY ASK Well, regardless of which side of the industry your business sits, there are a number of rules of thumb that can be applied: 1. you have to have a project, it has a defined start point and a defined end point; 2. your project has to advance science or technology, it doesn’t have to be new, it can be a significant enhancement of something existing, or a repurposing of an existing solution for a completely new use; 3. you have to overcome scientific or technological uncertainty whilst attempting to achieve the advance, you also don’t have to succeed, a failed project is normally enough to demonstrate that an advance could not be achieved because the uncertainties were too great; and 4. a competent professional operating in the field cannot readily deduce the solution, either on his own or through normal discussion with peers.
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The research and development associated with the naming and the branding of the drug, is not arrived at through a process of scientific or technological evaluation and likewise the market research associated with identifying whether or not there is a viable market and ultimately financial payback for the end product doesn’t resolve any scientific uncertainties and is in effect the commercialization of the R&D. That being said the development of a complex piece of software to forecast the financial returns from a particular drug, might be eligible for a claim! Having established that you have some eligible projects, we’ll have a look at the costs that you can be claiming for in the next article, which will enhance your budgeting capability. If in the meantime you’d like to discuss whether R&D Tax Relief could be beneficial for your business, please give Simon Bulteel a call on 01424 225345, or visit our website www.coodentaxconsulting.co.uk. After 10 years in practice as an accountant and 6 years in Clinical Research, Simon spent 14 months at a World Championship winning Motorsport team before leaving to work full time in Cooden Tax Consulting in September 2013.
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| BIOSCIENCE TODAY SUMMER 2018 |
New class of drugs could help tackle treatment-resistant cancers Researchers have discovered a new class of drug that has the potential to help cancer patients who no longer respond to existing therapies. The drug may not become available to patients for a number of years yet, but researchers believe that if clinical trials are successful, it could be used to tackle a variety of treatment-resistant cancers. Patients with breast cancer for example frequently become resistant to existing hormone-based treatments, leading to the disease becoming fatal. In a bid to come up with new forms of treatment that work in a distinct way from established ones, chemists, biologists and clinicians at Imperial College London collaborated on creating a new drug, the properties of which are reported in the journal Molecular Cancer Therapeutics. The team of scientists at Imperial was funded by Cancer Research UK. The drug was then developed by Imperial, in collaboration with Emory University in the USA. Early lab-based tests of ICEC0942 were successful in targeting resistant breast cancers and indicated minimal side effects. ICEC0942 was then licenced to Carrick Therapeutics, who developed it into a molecule named CT7001, which they have taken to early-stage clinical trials in less than two years. The first patient was given the drug in November 2017 as part of Carrick’s a Phase I clinical trial to assess its safety and how well it can be tolerated. The trial is still ongoing, so results are not available yet. Professor Charles Coombes, from the Department of Surgery & Cancer, said: “Treatment-resistant tumours represent a significant threat for patients, as once a cancer stops responding to treatments there is increasingly little clinicians can do. “Drugs such as these could help to shift the balance back in favour of the patients, potentially providing a new option to patients for who existing treatments no longer work.” Professor Tony Barrett, from the Department of Chemistry, said: “This work is the result of extensive collaboration between chemists, biologists and clinicians, which has helped to bring a new treatment from discovery to clinical testing in record time, streamlining the process.” The drug targets an enzyme called CDK7, involved in directing cells through their lifecycle, which consists of growth, DNA replication and cell division. CDK7 is also involved in the process of transcription, a vital step in gene expression - the creation of proteins to carry out cell functions. Particular cancers, such as treatment-resistant breast cancers, have a unique dependence on transcription, meaning targeting CDK7 may be particularly effective.
of the cancer to spread. As well as breast cancers, cancers such as acute myeloid leukaemia and small-cell lung cancer are particularly transcription-dependent, so ICEC0942 may work well for these too, especially where they have become resistant to other treatments. The discovery of the drug was spurred by an initial meeting between Professor Anthony Barrett, from the Department of Chemistry, and oncologist Professor Charles Coombes from the Department of Surgery & Cancer. Professor Simak Ali, also from the Department of Surgery & Cancer, was working on understanding the action of CDK7 in treatment-resistant breast cancer. Professors Coombes and Ali suggested CDK7 as a drug target, leading the collaboration to attempt to design a molecule that would inhibit its action. From early attempts, a large collaborative team was eventually founded for drug discovery from ‘bench to bedside’, directed by Dr Matthew Fuchter in the Department of Chemistry. Possible compounds for CDK7 inhibition were modelled using computational drug design, aided by collaboration with Emory University. Ultimately, a candidate molecule called ICEC0942 supressed tumour growth in a wide range of cancer types in lab tests. In addition, laboratory studies showed ICEC0942 worked better in combination with traditional hormone therapies for estrogen receptor positive breast cancer cells, which have not yet become resistant. It is this molecule, in oral pill form, that was taken forward by Carrick as CT7001 and is currently in Phase I clinical trials. If the Phase I trial proves successful, the compound must pass further stages of trial over the next few years before it becomes available to patients. Early funding for the study came from the Engineering and Physical Sciences Research Council (EPSRC), and a major contribution of whole-project funding was from Cancer Research UK. Licensing of the technology to Carrick Therapeutics was led by Cancer Research UK’s Commercial Partnerships Team and Imperial Innovations, the Technology Transfer Office of Imperial, with support from Emory University. Dr Iain Foulkes, Cancer Research UK’s executive director of research and innovation, said: “It’s exciting to see how Cancer Research UK’s partnerships with both academia and industry are bringing urgently needed new tests and treatments to patients. “Drug resistance continues to be a major challenge across many cancer types so it’s vital that we explore new ways to tackle tumours that have stopped responding to standard therapies. We hope that this promising new class of drug will offer more options to patients who have few left available to them, and help more people survive their cancer.”
By inhibiting transcription, ICEC0942 shuts down the ability
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| BIOSCIENCE TODAY SUMMER 2018 |
| news |
Discovery of novel Malaria parasite behaviour offers new target for treatment
Researchers have demonstrated novel parasite behaviour which offers a potential new target for malaria diagnosis and intervention. Malaria, a blood borne disease caused by single cell parasites, remains a major global public health issue with millions of cases, and nearly half a million deaths every year. The new discovery in the parasite’s biology is revealed across a set of three studies led by the University of Glasgow’s Wellcome Centre for Molecular Parasitology. The studies are published in Nature Communications, Science Advances and MBio. The researchers have discovered that malaria parasites can occupy sites outside the bloodstream, specifically in the bone marrow and spleen where red blood cells are formed. The studies show in animal models and human infection that this is the major niche for the development of malaria transmission stages and a significant reservoir for the parasite’s replicative stages.
THE RESEARCHERS DEMONSTRATE, FOR THE FIRST TIME, THE MOVEMENT OF BLOOD STAGE PARASITE FORMS AND THEIR MIGRATION ACROSS THE VASCULAR BARRIER TO OTHER PARTS OF THE BODY.
The researchers demonstrate, for the first time, the movement of blood stage parasite forms and their migration across the vascular barrier to other parts of the body. Further, the work demonstrates that localization in the bone marrow and spleen allows the parasite not only to build a ‘reservoir of infection’, but also to gain additional protection from certain antimalarial drugs including the current frontline drug artemisinin. The findings from these new studies show why malaria parasites invading the bone marrow and spleen, where red blood cells are formed, could be crucial to targeting the disease. Professor Andy Waters, Director of the Wellcome Centre for Molecular Parasitology, said: “These papers together represent a step forward in our understanding of the behaviour of the malaria parasite. It is possible that bone marrow serves as the reservoir of infection avoiding the immune system and preferentially producing and releasing gametocytes so that when mosquitoes appear the disease can be retransmitted.” Professor James Brewer, Chair in Basic Immunology at the Institute of Infection, Immunity and Inflammation, added: “These findings will also allow us to potentially find new drug targets for the disease, redefine what drugs have to achieve in terms of parasite killing and find new ways to fight back against the malaria parasite.”
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Malaria is a blood borne disease caused by single cell parasites that invade, grow and then replicate in red blood cells, which then burst releasing new parasites that initiate a new blood stage cycle of invasion – a process which makes malaria such a deadly disease. Malaria is transmitted by female mosquitoes which themselves become infected when they take up parasites from an infected person as they take their blood meal. However, this human to mosquito transmission is only achieved if a small subset of blood borne parasites have escaped the cycle described above and instead have developed into a specialised form (a gametocyte) for transmission. Matthias Marti, Professor of Parasitology, said: “Malaria has a complex lifecycle which involves stages within the Anopheles mosquito, and within the human host, and past research to develop effective therapeutics targeting transmission has specifically focused on the mosquito stage. “In close collaboration with the lab of Prof. Volker Heussler (University of Berne, Switzerland) we have unravelled novel biological features of the parasite in its natural bone marrow and spleen environment, and we anticipate that these exciting findings will open up a new area of research. At the same time, we will evaluate the potential of our study for a new target for malaria diagnosis and intervention.” ‘A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy’ is published in Nature Communications; ‘Bone marrow is a major parasite reservoir in Plasmodium vivax infection’ is published in mBio; and ‘Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow’ is published in Science. Two of the three studies were performed in an international collaborative effort including groups led by Prof. Volker Heussler (University of Berne, Switzerland), Prof. Terrie Taylor (College of Medicine, Blantyre, Malawi), Profs. Dyann Wirth, Manoj Duraisingh and Curtis Huttenhower (Harvard University, Boston, USA), Prof. Tom Wellems (National Institute of Health, Bethesda, USA) and Dr. Nicanor Obaldia (Gorgas Institute, Panama). The Glasgow work was funded by the Wellcome Trust, the MRC and BoneMalar. The work of Prof Marti is funded through an European Research Council grant worth around EUR 2.3 million.
| news |
| BIOSCIENCE TODAY SUMMER 2018 |
Picking up good vibrations: Feeling the beat through the elephants feet Dr Beth Mortimer Iconic and intelligent creatures, elephants continue to fascinate curious onlookers and scientists alike. Now a new Oxford University collaboration with Save The Elephants has shown that elephant behaviour can be determined in a new way: through the vibrations they create. The findings of the study, published in the journal Current Biology, offer a new way to detect elephants and discern their behaviour without having them in sight. It also has the potential to provide real-time information on elephant distress and poaching threats in remote locations. Researchers from the University’s Department of Zoology and Earth Sciences worked together with Save The Elephants to develop an innovative way of classifying elephant behaviours by monitoring the tremors that their movements send through the ground. To capture the information, the two lead scientists, Dr Beth Mortimer and Professor Tarje Nissen-Meyer, along with Masters student Mr William Rees and Dr Paula Koelemeijer, used small sensors called ‘geo-phones’ to measure the
ground-based vibrations generated by elephants in Kenya’s Samburu National Reserve. The study relied on the application of cutting-edge seismological techniques, commonly used to study earthquakes and dynamic processes inside Earth. The team also performed an active but complementary experiment wielding a sledge hammer against the ground, which allowed them to generate and measure a controlled vibration, and recorded the sound of cars, people hopping up and down, planes flying overhead and a variety of other noises that contributed to the signals scientists might pick up when recording elephants. Due to their large size, it is perhaps unsurprising that elephants generate vibrations through their normal movements. But, they also produce detectable seismic vibrations through low frequency vocalisations – known as ‘rumbles’, which were studied in the research, as well as trumpets. These movements were then compared with the airborne and ground-based vibrations that they produced. By distilling the vibrations caused by elephant behaviour from background noise, and by quantifying how far and wide these sounds travel through the ground, this study demonstrates that seismological techniques are well suited to solving problems within conservation monitoring. ‘Vibration detection is a forgotten sense in the study of many animals, but is particularly important for elephants,’ says Dr Mortimer. Prof. Tarje Nissen-Meyer adds, ’Our findings bore out of multi-disciplinary research across traditional domain boundaries, relying on novel seismological methods.’ Computer models developed in this research indicate that these vibrations are detectable beyond what is audible, suggesting that elephants can use ground-transmitted information to know the whereabouts of the rest of the herd, even over several kilometres, depending on terrain type. Scientists and conservationists are increasingly worried about the effects of noise caused by humans. By preserving wild landscapes, elephants can continue to detect the signal above the noise. ‘The impact of other noise on this mode of communication mode is particularly worrying given the increased levels of human-generated seismic vibrations in remote locations,’ says Dr Beth Mortimer. Save The Elephants’ CEO, Frank Pope comments: ‘Legends and folklore have long spoken about the way elephants can not only communicate across long distances, but also detect other events that shake the ground like far-off thunder. This study marks a new phase in trying to understand the nature of the vibrations elephants produce and how they might be used by elephants themselves. Along the way it is opening our eyes to the challenges posed by human-generated noise in an increasingly crowded landscape.’ ‘We hope to build on these initial findings to develop a comprehensive approach for monitoring and understanding the behaviour of large mammals in these pristine, changing and fragile environments, and examine whether elephants can localise not only their peers or other species, but also environmental factors such as water’ adds Nissen-Meyer.
Photo credit: Robbie Labanowski
By preserving wild landscapes, elephants can continue to detect the signal above the noise.
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| BIOSCIENCE TODAY SUMMER 2018 |
| news |
Vital research into incurable lung condition affecting millions to take place in Kensington 1,000 people are needed for ground-breaking research into an incurable lung condition at Imperial College London. Supported by the British Lung Foundation, a research team led by Professor Wisia Wedzicha, will conduct a nationwide project looking into the very early stages of the development of chronic obstructive pulmonary disease (COPD), which affects three million people. For the first time, through this research they will be able to identify people at risk of developing the condition which is a major cause of illness and death. The research team will establish the “BLF Early COPD Cohort�, a group of young adult smokers between the ages of 30-45, to track changes in their lung function over time. This will identify and study the people whose lung function is beginning to decline and are at risk of developing COPD. COPD is a life-long condition that makes breathing difficult because the airways have been narrowed. People living with COPD will feel out of breath doing everyday tasks such as hoovering or walking to the shops. Though 20% of people with COPD have never smoked and not all smokers
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develop COPD - it is mainly caused by smoking from early adulthood. The study, led by Professor Wisia Wedzicha at Imperial College London expects to recruit approximately 1000 participants from eight centres across the UK. People locally looking to get involved with this significant study can do so by contacting SmokingStudy@imperial.ac.uk. Participants could benefit by having a CT scan of the chest free of charge, access to stop smoking support, a research team specialising in COPD, and follow-ups with the NHS is abnormalities are found. Volunteers can be male or female, must be aged 30-45 years old and current smokers, but have no current lung disease diagnosis.
| news |
| BIOSCIENCE TODAY SUMMER 2018 |
£4 million immune system grant means 50 years of research for Sir Philip Cohen Professor Sir Philip Cohen, one of the UK’s most respected scientists, has been awarded new research grants that will mean his work at the University of Dundee has been funded continuously for 50 years.
Sir Philip Cohen
The research will build on new findings that have been made in the laboratories of Sir Philip and Professor Simon Arthur, also of the University of Dundee and a co-applicant on the grant from the Medical Research Council. Sir Philip said, “Just over ten years ago I realised that the technology and know-how I had developed to work out how insulin controls the body’s metabolism would also enable me to understand how the immune system works at the molecular level. “I therefore took the somewhat risky decision to abandon all my other research projects and focus on this entirely new, but very exciting, project about which I had little knowledge at the time. It has been a huge learning experience for me, and indeed I am continuing to learn something new about immunity every day, but all the effort has paid off with a number of novel and exciting findings that we will be building on with these new awards. “I believe that there is a good chance that our research, together with our research collaborations with other academic laboratories and the pharmaceutical industry will lead to the development of improved drugs to treat diseases immune diseases and cancers.” Sir Philip joined the University of Dundee in late 1971 and the first research grant he wrote was turned down the following year by what was then called the Science Research Council (now the Biotechnology and Biological Sciences Research Council). He said, “My first successful grant application was funded in 1973 by the British Diabetic Association, which is now called Diabetes UK. This means that in 2023, when these new grants will enter their final year, I will have received continuous funding for my research for 50 years. “I am therefore most grateful to all the funding agencies that have provided these grants over the years, most notably the Medical Research Council but also the Wellcome Trust and medical charities who supported my research when it was just getting underway and have continued to do so.
Sir Philip is a biochemist who has made major contributions to our understanding of protein phosphorylation and its role in cell regulation and human disease. Phosphorylation processes are very important because they control almost all aspects of cellular functions. Abnormal phosphorylation is a factor in many diseases, including cancer, high blood pressure and Parkinson’s. Among his major findings was the discovery of how insulin works. Over the past decade Sir Philip has switched the focus of his research to how the human immune system works at the molecular level. He has now been given a Senior Investigator Award of £2.3million from the Wellcome Trust and a new Programme Grant of £1.6million from the Medical Research Council to support his research on the immune system for the next five years. Both research programmes are aimed at understanding how to control the power of the body’s immune system to prevent autoimmune diseases such as arthritis, asthma, fibrosis and lupus, as well as enhance the power of the immune system to destroy cancers.
“Finally, I hope that these new awards will stop people asking me how I am enjoying my retirement! Although I stepped down from managing the School of Life Sciences at Dundee some years ago, my research lab continues to be as active as it ever was and, with these new awards, I am afraid that the University of Dundee will have to put up with me until I am nearly 78!” Sir Philip has received an extensive list of awards and honours from around the world, ranging from the Colworth Medal (1977), membership of EMBO (1982), Fellowship of the Royal Society of Edinburgh and the Royal Society (1984), Knight Bachelor in the Queen’s Birthday Honours list (1998), Foreign Associate of the National Academy of Science (2008), the Royal Medal of the Royal Society (2008), the MRC Millennium Medal (2013) and the Albert Einstein World Award of Science (2014). He has published over 500 research papers and according to Thomson Scientific, Philadelphia, he was the world’s second most cited scientist in the field of biology and biochemistry from 1992-2003, and the world’s most cited biochemist from 1999-2009.
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THE RESEARCH WILL BUILD ON NEW FINDINGS THAT HAVE BEEN MADE IN THE LABORATORIES OF SIR PHILIP AND PROFESSOR SIMON ARTHUR, ALSO OF THE UNIVERSITY OF DUNDEE AND A COAPPLICANT ON THE GRANT FROM THE MEDICAL RESEARCH COUNCIL.
| BIOSCIENCE TODAY SUMMER 2018 |
| news |
Sumatra’s tigers defy expectations on genetic diversity A joint study led by scientists from international conservation charity ZSL (Zoological Society of London) in collaboration with Imperial College London and Panthera, the global wild cat conservation organization, has revealed that despite low numbers and a fragmented population, Sumatran tigers (Panthera tigris sumatrae) have retained reasonable levels of genetic diversity. SEVERE HABITAT LOSS AND OTHER THREATS SUCH AS POACHING HAVE REDUCED SUMATRA’S TIGER POPULATION TO AN ESTIMATED 400 INDIVIDUALS AND HAVE LEFT FEWER SAFE CORRIDORS THROUGH WHICH THEY CAN MOVE.
Severe habitat loss and other threats such as poaching have reduced Sumatra’s tiger population to an estimated 400 individuals and have left fewer safe corridors through which they can move, forcing them to live in scattered pockets of forest habitat across the island. Such low numbers living largely in isolation from one another would usually be expected to result in reduced genetic diversity. However, this study shows Sumatran tigers have confounded this expectation. By analysing genetic data obtained from tiger faeces (or ‘scats’) the ZSL researchers concluded that despite the increasing fragmentation of tiger habitat and the low population numbers, there is little evidence that individual habitat patches are genetically differentiated from each other, except in the most secluded southern population. These findings suggest that the loss and fragmentation of lowland habitat has occurred only recently in the Sumatran tiger’s history, and thus has not had time to substantially impact the remaining population. Therefore, conservationists still have a unique opportunity to implement land management strategies to protect what few tigers remain before the continued isolation of forested lands degrades the population further.
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| cardiovascular |
| BIOSCIENCE TODAY SUMMER 2018 |
Breaking through cardiovascular disease Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation (BHF) explains the work they are doing to find the next breakthrough treatment for cardiovascular disease. Since the BHF was formed over 50 years ago, the number of people in the UK dying of cardiovascular disease each year has halved. This impressive reduction is largely down to an improvement in our understanding of heart disease, and the lifestyle changes and treatments that this new knowledge has led to. Take statins, for example. Entering clinical use in the 1980s, statins tackle the most common type of cardiovascular illness – coronary heart disease. They are the most commonly prescribed medicine in the UK, and save lives by reducing a person’s risk of heart attack and stroke by stopping fatty deposits from building up inside their arteries. However, even after the development of statins, around 150,000 people in the UK still die each year from cardiovascular disease. And over 7 million people across the UK are living with various heart and circulatory conditions. It’s important that we don’t become complacent, as it is clear there is still plenty of work to be done. That’s why the BHF is investing £100million every year into research towards improved prevention, diagnosis and treatment of cardiovascular disease. With such a vast programme of funding comes hope and the promise of new breakthroughs to help save more lives.
PREVENTION OF COMMON CONDITIONS Coronary heart disease affects 2.3 million people in the UK, but present diagnostic techniques do not allow identification of people whose coronary arteries are not significantly narrowed but are inflamed and therefore still at high risk of triggering a heart attack. These tests only detect changes in the shape and structure of the coronary arteries once damage has already taken place. Professor Charalambos Antoniades and colleagues at the University of Oxford are trying to develop a new test that could transform how we prevent and treat these diseases. The test analyses heart scan images to identify changes in the fat surrounding the coronary arteries and uses this to look for atherosclerotic plaques that are unstable. If a plaque is unstable or vulnerable it is at a higher risk of rupturing and causing a blood clot to form and block the artery. Professor Antoniades has discovered that these plaques release chemicals that prevent small immature fat cells turning in to bigger mature ones. As part of his BHF-funded research Professor Antoniades is examining whether the test can be used to predict plaque rupture and therefore risk of heart attack, thus allowing preventive treatments to be given before the attack occurs. He is also investigating whether this technique can identify people
who are more prone to developing new plaques, or those whose plaques are likely to worsen, again helping doctors prescribe preventive treatments.
NEW TREATMENTS FOR RARE CONDITIONS Research into rare conditions is incredibly important, as these conditions can be devastating but have limited treatment options. Pulmonary arterial hypertension (PAH) is one such example – at present this life changing condition, which affects around 6,500 people in the UK, has no cure. Yet PAH is serious, and causes high blood pressure in the blood vessels between the heart and the lungs. It leaves sufferers weak and short of breath and can lead to heart failure. Recently, scientists the BHF funds at the University of Edinburgh have made exciting new progress, which could lead to the development of new treatments for people with PAH. By studying muscle cells from pulmonary arteries in mice, and clones of human cells, the team were able to show that they can use the existing treatments for PAH to regulate a new calcium channel, called TPC2. How these drugs work against the condition has been hotly debated as they were initially designed for other targets. Using them as a template to develop new drugs could speed up the road to new specific treatments for PAH. Although this research is in early stages, it is really encouraging to see new targets emerge that could help develop treatments for conditions that blight the lives of thousands of people and their families.
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| BIOSCIENCE TODAY SUMMER 2018 |
| cardiovascular |
LEARNING FROM TICKS Sometimes a viral or bacterial infection can spread, leading to severe inflammation of the heart muscle, known as myocarditis. In extreme cases this can cause lasting damage to the heart, or even death. Occasionally, a viral or bacterial infection can lead to severe and potentially fatal inflammation of the heart muscle, known as autoimmune myocarditis. Around 20% of people who suffer from this develop heart failure, which in severe cases can result in the person needing a transplant. Myocarditis has, so far, proven difficult to diagnose and treat. This is because although the dangerous inflammation of the heart muscle seen in the disease is known to be caused by a certain type of white blood cells, called T-cells, researchers do not yet know exactly how this process occurs. Researchers funded by the BHF at the University of Oxford think that we may be able to learn to design drugs targeted at this problem from an unlikely source, parasitic ticks. During autoimmune myocarditis, chemicals called chemokines are released in the
heart and attract cells that cause inflammation. If you’ve ever been bitten by a tick you will know that, unlike a mosquito bite, you do not feel it. Ticks need to feed for a long time, so they inject proteins that block your body’s chemokines and prevent painful inflammation. BHF Professor Shoumo Bhattacharya and his team have identified 31 of these tick proteins, called evasins, and are now studying which chemokines they block, and are planning to trial them in autoimmune myocarditis in mouse models. The aim is to take inspiration from the tick’s anti-inflammatory strategy and design a life-saving medicine for this dangerous heart condition.
GENE-EDITING – PROVIDING HOPE FOR THOUSANDS If left undetected and untreated, inherited heart conditions can sadly lead to heart failure or even sudden death from cardiac arrest. For many families, the first sign there’s a problem is when someone dies suddenly with no obvious cause or explanation. Hypertrophic cardiomyopathy (HCM) is a genetic condition caused by a change or mutation in one or more genes and is passed on through families. If you have HCM, the muscular wall of your heart – the myocardium – becomes thickened, making the heart muscle stiff. This thickening makes it harder for your heart to pump blood out of your heart and around your body and can also lead to life-threatening arrhythmias. Decades of BHF research has discovered many of the genes responsible for HCM so that genetic testing can be carried out for families at risk. However, there is no cure. Gene-editing is a relatively new and hugely exciting field which could see the cure for inherited heart disease by simply swapping a faulty, disease-causing gene for a ‘healthy’ gene. Of course, this type of genetic manipulation has unique ethical considerations and has not been tested in humans, but there are already examples of success in animal models. There are many diseases which fall under the cardiovascular disease ‘umbrella’ for which treatments are at best limited and at worst non-existent. A standout example is heart failure, where the only treatment for many is a heart transplant. Our great strides in cardiovascular research have resulted in a dramatically reduced death-rate from heart attack. Now we must strive to find treatments for those heart attack patients left with heart failure, and to enable advances that will end the heartbreak for the millions of people who suffer from the consequences of both common and rare forms of heart and circulatory disease.
Although this research is in early stages, it is really encouraging to see new targets emerge that could help develop treatments for conditions that blight the lives of thousands of people and their families. 19
| cardiovascular |
| BIOSCIENCE TODAY SUMMER 2018 |
Ulster University leads on €8.2M cross border collaborative research centre 20
| BIOSCIENCE TODAY SUMMER 2018 |
| cardiovascular |
The EU funded cross border centre of research excellence in cardiovascular medicine will transform cardiac care in the region by developing new models of care, smart wearable technologies and improved patient monitoring systems. The Eastern Corridor Medical Engineering Centre (ECME); a cross border centre of research excellence within the field of cardiovascular medicine with partners in Northern Ireland, Republic of Ireland and Scotland has just launched at Ulster University. Cardiovascular (heart and circulatory) disease causes more than a quarter (26 per cent) of all deaths in the UK; that’s nearly 160,000 deaths each year – an average of 435 people each day or one death every three minutes and in the Republic of Ireland this figure is slightly higher at around 30%. ECME will see researchers from academia and industry collaborate with partners in the health and social care system to create better models of heart disease care and develop new medical grade wearables and remote monitoring systems to improve clinical outcomes and patient experience. Innovative medical technology has the potential to alleviate some of the current pressures facing our healthcare system. As waiting lists grow and the demand for hospital beds increases, medical technologies such as smart wearables, user-ready sensor technology and patient monitoring systems can improve diagnostics and patient outcomes and enable patients to live independently.
David McEneaney MD, Consultant Cardiologist at the Southern Health & Social Care Trust said, “We are excited about the potential impact that the research generated by the ECME project could have on patient outcomes. There have been many innovations in recent years which have transformed how we treat patients and we believe this project will further enhance the well established research collaboration between Craigavon Cardiovascular Research Unit and the academic partners.” Gina McIntyre, CEO of the Special EU Programmes Body said: “This is a project which has the potential to positively transform the lives of thousands of people and their families across Northern Ireland, the border region of Ireland and Western Scotland. By increasing the levels of cross-border Research and Innovation within the Health & Life Sciences sector, there is the opportunity to create a strong economic impact, and this is one of the core objectives of the INTERREG VA Programme. This project has great potential and will have a highly significant impact upon how cardiovascular disease is treated on a cross-border basis.” The centre received €8.2M funding from the European Union’s INTERREG VA Programme, managed by the Special EU Programmes Body (SEUPB). ECME is a cross border partnership between Ulster University, Southern Health and Social Care Trust Cardiac Research Unit, Dundalk Institute of Technology, Dublin City University, University College Dublin and the University of Highlands and Islands.
As well as having a significant impact on health and social care, economic benefits will also follow from the partnership. Working closely with industry and health care professionals, ECME will bring new and innovative products to the market. Professor Jim McLaughlin, Director of NIBEC at Ulster University said, “Ulster University has established itself as a global leader in both data analytics, Artificial Intelligence and medical related research. An integral part of our Health Technology Hub, this partnership will create better models for cardiac care through research and the development of generic solutions within the growing patient monitoring market. Working with our project partners we will develop a cardiac data database to collate and analyse patient information from across the region and better inform decision making at both a clinical and policy level. Wearable technologies and remote monitoring systems have the potential to transform cardiac care. Smart technologies are helping to move care out of hospital and into the home, reducing pressure on the healthcare system. Our researchers will work to improve existing sensor technologies, point of care diagnostics and monitoring systems to improve clinical outcomes, free up hospital beds, predict patient needs and grow patient confidence and satisfaction. This partnership is an excellent example of industry, academia and healthcare joining forces to transform patient care and clinical outcomes.”
“This is a project which has the potential to positively transform the lives of thousands of people and their families across Northern Ireland, the border region of Ireland and Western Scotland.” 21
| cardiovascular |
| BIOSCIENCE TODAY SPRING 2018 |
Six Years of Exercise or Lack of It - May Be Enough to Change
Heart Failure Risk By analyzing reported physical activity levels over time in more than 11,000 American adults, Johns Hopkins Medicine researchers conclude that increasing physical activity to recommended levels over as few as six years in middle age is associated with a significantly decreased risk of heart failure, a condition that affects an estimated 5 million to 6 million Americans. The same analysis found that as little as six years without physical activity in middle age was linked to an increased risk of the disorder. Unlike heart attack, in which heart muscle dies, heart failure is marked by a long-term, chronic inability of the heart to pump enough blood, or pump it hard enough, to bring needed oxygen to the body. The leading cause of hospitalizations in those over 65, the disorder’s risk factors include high blood pressure, high cholesterol, diabetes, smoking and a family history. “In everyday terms our findings suggest that consistently
participating in the recommended 150 minutes of moderate to vigorous activity each week, such as brisk walking or biking, in middle age may be enough to reduce your heart failure risk by 31 percent,” says Chiadi Ndumele, M.D., M.H.S., the Robert E. Meyerhoff Assistant Professor of Medicine at the Johns Hopkins University School of Medicine, and the senior author of a report on the study. “Additionally, going from no exercise to recommended activity levels over six years in middle age may reduce heart failure risk by 23 percent.”
The researchers caution that their study, described in the May 15 edition of the journal Circulation, was observational, meaning the results can’t and don’t show a direct cause-andeffect link between exercise and heart failure. But they say the trends observed in data gathered on middle-aged adults suggest that it may never be too late to reduce the risk of heart failure with moderate exercise.
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| BIOSCIENCE TODAY SPRING 2018 |
| cardiovascular |
“The population of people with heart failure is growing because people are living longer and surviving heart attacks and other forms of heart disease,” says Roberta Florido, M.D., cardiology fellow at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. “Unlike other heart disease risk factors like high blood pressure or high cholesterol, we don’t have specifically effective drugs to prevent heart failure, so we need to identify and verify effective strategies for prevention and emphasize these to the public.” There are drugs used to treat heart failure, such as beta blockers and ACE inhibitors, but they are essentially “secondary” prevention drugs, working to reduce the heart’s workload after dysfunction is already there. Several studies, Florido says, suggest that in general people who are more physically active have lower risks of heart failure than those who are less active, but little was known about the impact of changes in exercise levels over time on heart failure risk. For example, if you are sedentary most of your life but then start exercising in middle age, does that decrease your risk of heart failure? Or, if you are active much of your life but then stop being active at middle age, will that increase your risk? To address those questions, the researchers used data already gathered from 11,351 participants in the federally funded, long term Atherosclerosis Risk in Communities (ARIC) study, recruited from 1987 to 1989 in Forsyth County, North Carolina; Jackson, Mississippi; greater Minneapolis, Minnesota; and Washington County, Maryland. The participants’ average age was 60, 57 percent were women and most were either white or African-American. Participants were monitored annually for an average of 19 years for cardiovascular disease events such as heart attack, stroke and heart failure using telephone interviews, hospital records and death certificates. Over the course of the study there were 1,693 hospitalizations and 57 deaths due to heart failure. In addition to those measures, at the first and third ARIC study visits (six years apart), each participant filled out a questionnaire, which asked them to evaluate their physical activity levels, which were then categorized as poor, intermediate or “recommended,” in alignment with guidelines issued by the American Heart Association.
FROM THE FIRST TO THE THIRD VISIT OVER ABOUT SIX YEARS, 24 PERCENT OF PARTICIPANTS INCREASED THEIR PHYSICAL ACTIVITY, 22 PERCENT DECREASED IT AND 54 PERCENT STAYED IN THE SAME CATEGORY.
The “recommended” amount is at least 75 minutes per week of vigorous intensity or at least 150 minutes per week of moderate intensity exercise. One to 74 minutes per week of vigorous intensity or one to 149 minutes per week of moderate exercise per week counted as intermediate level activity. And physical activity qualified as “poor” if there was no exercise at all. After the third visit, 42 percent of participants (4,733 people) said they performed recommended levels of exercise; 23
percent (2,594 people) said they performed intermediate levels; and 35 percent (4,024 people) said they had poor levels of activity. From the first to the third visit over about six years, 24 percent of participants increased their physical activity, 22 percent decreased it and 54 percent stayed in the same category. Those with recommended activity levels at both the first and third visits showed the highest associated heart failure risk decrease, at 31 percent compared with those with consistently poor activity levels. Heart failure risk decreased by about 12 percent in the 2,702 participants who increased their physical activity category from poor to intermediate or recommended, or from intermediate to recommended, compared with those with consistently poor or intermediate activity ratings. Conversely, heart failure risk increased by 18 percent in the 2,530 participants who reported decreased physical activity from visit one to visit three, compared with those with consistently recommended or intermediate activity levels. Next, the researchers determined how much of an increase in exercise, among those initially doing no exercise, was needed to reduce the risk of future heart failure. Exercise was calculated as METs (metabolic equivalents), where one MET is 1 kilocalorie per kilogram per hour. Essentially, sitting watching television is 1 MET, fast walking is 3 METs, jogging is 7 METs and jumping rope is 10 METs. The researchers calculated outcomes in METs times the number of minutes of exercise. The researchers found that each 750 MET minutes per week increase in exercise over six years reduced heart failure risk by 16 percent. And each 1,000 MET minutes per week increase in exercise was linked to a reduction in heart failure risk by 21 percent. According to the American Heart Association, fewer than 50 percent of Americans get recommended activity levels. Other authors on the study include Lucia Kwak, Mariana Lazo, Gary Gerstenblith, Roger Blumenthal, Elizabeth Selvin and Josef Coresh of Johns Hopkins; Vijay Nambi and Christie Ballantyne of Baylor College of Medicine; Haitham Ahmed of Cleveland Clinic; Sheila Hegde of Brigham and Women’s Hospital and Aaron Folsom of University of Minnesota. The research was funded by a Robert E. Meyerhoff Professorship, a Robert Wood Johnson Amos Medical Faculty Development Award, a JHU Catalyst Award and grants from the National Heart, Lung, and Blood Institute (K23HL12247) and the National Institute of Diabetes and Digestive and Kidney Diseases (K24DK106414).
“Heart failure risk decreased by about 12 percent in the 2,702 participants who increased their physical activity category from poor to intermediate or recommended, or from intermediate to recommended, compared with those with consistently poor or intermediate activity ratings.” 23
| cardiovascular polio | |
| BIOSCIENCE TODAY SUMMER 2018 |
Combatting cardiovascular disease today
Cardiovascular disease remains the most common cause of death in the UK and across the world, so in this issue of BioScience Today, Ellen Rossiter speaks to Dr Vijay Kunadian, Senior Lecturer and Honorary Consultant Interventional Cardiologist at Newcastle University and Freeman Hospital Newcastle upon Tyne, about the progress that’s been made and the challenge that remains. “The way we treat people with heart disease has been transformed in recent years. We used to treat patients with drugs, but now for anyone in our region experiencing chest pain, that’s a population of over 2 million, they are given an ECG in the ambulance, then transferred directly to the Freeman Hospital for treatment when they experience a full blown heart attack. “In fact today, we often capture patients before they even experience damages to the heart following heart attack, identifying and treating the emerging problem quickly, often within 15 minutes. Just 10 years ago patients who’d had heart procedures would stay in hospital for about a week, now within about 10 minutes of a procedure, it is as if a miracle has happened and people are wanting to go home straight away. Sometimes we have to remind them that they’ve experienced a life-threatening event and keep them in for a night or two. “So much progress has been made, and cardiovascular deaths have been reduced, but cardiovascular disease remains the leading cause of death and we want to know why that is, especially given we’ve made so much progress.” Newcastle University and neighbouring Freeman Hospital
are together paving the way in the realm of cardiovascular research, you might have seen the latter’s cardiothoracic surgeons at work in a recent BBC documentary, Vijay’s research interests, however, lie in a different area of cardiac care. “I’m more of a plumbing cardiologist” explains Vijay, “I fix blocked heart arteries. Few women do my job, but I did it because my supervisors/mentors were very supportive. I didn’t realise I had this potential, but I made the most of the opportunities that came my way and I was surprised to find that I was able to do this.” “Science always fascinated me, even when I was in school, especially the human body and in particular the heart. At the same time, I started scoring high marks in science and that stimulated my interest. I was encouraged to be a doctor by my parents, and from day one when you are studying medicine you learn about anatomy and you dissect organs – and the heart really caught my attention. “My very first job was at the Freeman Hospital here in Newcastle in the cardiothoracic section, where I was preparing for my surgical exams. I was working in the lung area, rather than the cardio section and it just didn’t feel
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right, even though I had wanted to be a heart surgeon since Medical School. “I went on to work in Gateshead and Darlington as a junior doctor training in general medicine, at the time, however, the biggest interventional heart centre in the region was in Middlesbrough, so one of the defining points of my career was being invited to take up a research position at the James Cook Hospital in the cardiology department. “Another crucial moment came a few years later when I was studying for my doctorate of medicine at Newcastle University and I took it upon myself to email a Harvardbased researcher, whose work I almost always quoted in my papers, saying I’d love to work with your team for a year and to my surprise, I had a reply within a couple of minutes saying ‘yes, we’d love to have you, but you’ll have to find your own grant’. “I successfully applied to the training programme and I was awarded a grant by the South Cleveland Heart Fund, which made joining the research team in Boston MA USA possible, with some support also forthcoming from the Brigham and Women’s Hospital at Harvard Medical School. “Going to Boston to work with the most prestigious cardiovascular researchers in the world, including Braunwald, the father of cardiology who actually defined heart attacks, and Professor Mike Gibson who was my mentor, was an inspiration. “I was asked to stay in Boston where there are a lot of opportunities, but I wanted to come back to here to finish my clinical interventional cardiology training and to give something back to the region which provided me with such excellent training. Once back in Newcastle, however, I was torn between my clinical work and research interests, I applied for a clinical post but was disappointed not to get it and I was encouraged to take up academic posts. I was invited to take up a clinical Consultant post in Edinburgh but followed my instinct to take up the academic post in Newcastle University instead.
THE UNIVERSITY HAS BEEN HIGHLY SUPPORTIVE, WITH ME NOW HOLDING A TENURED POST, WHICH IS 50% CLINICAL AND 50% RESEARCH BASED – WHICH IS IDEAL FOR MY RESEARCH INTERESTS WHICH ARE PATIENT CENTRED
“In the end, you have to go with what you feel comfortable with, deep down you know your abilities, it was a risk as the academic posts were usually short term (2 year) contracts, whilst clinical posts were permanent, but looking back it was the right decision for me. I worked hard to generate grants and publish in journals, working from a building in which there was no other academic cardiologist. “The University has been highly supportive, with me now holding a tenured post, which is 50% clinical and 50% research based – which is ideal for my research interests which are patient centred. “The Freeman Hospital, where I am based on my clinical days, is rated outstanding by the care quality commission, I am so happy to work in an organisation that is so patient centred, the hospital is one of the main reasons I stay in the North East, being patient centred is what we do, it is not just a logo. “There are very few centres in the country that offer cardiac care as advanced as you’ll find here at the Freeman, from babies right through to patients of 100 years plus. The team here that perform heart transplants are so inspiring. “In terms specifically of the clinical provision for treating patients with coronary heart disease, we are also one of the largest centres in the country, with regards to the volume, complexity and diversity of the cases that we treat. We see everything here and I never know who is coming through the door next, as my entire list is an urgent or emergency list. “One thing I noticed during my first day back in Newcastle working as a Consultant, having been in Boston, was that the demographics of my patients had changed dramatically in just 12 months.
“Almost all of my patients were now in their 80’s or 90’s, where previously older patients had not been referred by doctors for advanced care and were sent home, this was no longer the case and we had the opportunity to treat them. “As it was a recent phenomenon, there was so little supporting evidence to show how best to treat our older patients with heart disease - should they be treated the same as a 50-year-old for example or not? “Everything we do is evidence based, typically based on research involving 20,000 patients, yet here there was little evidence on how best to treat the clinical problem. We’ve made great progress in the treatment of many diseases, and people are surviving things that they would not have done previously, but ultimately their heart catches up with them.” Newcastle University, is a world leader in research into ageing, its causes, and consequences, having been awarded funding from the National Institute for Health Research (NIHR) to form a Biomedical Research Centre (BRC) in partnership with the Newcastle upon Tyne Hospitals NHS Foundation Trust, one of only 20 BRCs in the country and the sole one researching aging. So Vijay’s interest in how best to treat her older patients with heart disease fit in perfectly, her work in this area has been supported by both the BRC and the British Heart Foundation (BHF). Vijay is quick to highlight how supportive the BHF has been of her research and her career – even helping her to find a new mentor. “I wouldn’t be here without the BHF – I wasn’t too sure that I could survive academia back then, but they did and they supported me all the way.” The biggest trial in which Vijay is involved, has been facilitated by an incredible £1.7m grant from the BHF, the biggest research grant in clinical cardiology research ever brought into Newcastle University, involving over 40 hospitals and 2,000 patients – which is examining the benefit and risk of coronary revascularisation versus conservative management in high-risk older patients who have had minor heart attacks. In addition, Vijay is working on a project to see if medications such as Aspirin and Ticagrelor, which are used to prevent clots forming, might also prevent heart attacks
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in COPD patients. Patients with COPD are at a higher risk of suffering heart disease and heart attacks - yet she found only 2% of COPD patients were on heart medication. Now with a $1.2m grant awarded by Astra Zeneca, work is afoot to see if existing drugs could help tackle the problem and reduce the risk. Vijay also hopes to examine the link between heart attacks and brain function, as an estimated 50% of patients who suffer a heart attack also experience a decline in brain function, so one of her priorities is to see if there is anything that can be done to prevent that decline. One can’t help wondering how Vijay does it all, in a role which she describes as “300% everything: 100% clinical, 100% research, 100% teaching.” Co-Chair of the European Society of Cardiology ESC/European Association of Percutaneous Cardiovascular Interventions EAPCI Scientific Documents and Initiatives Committee; with editorial responsibilities for a number of journals and sitting on several steering committees, it is no wonder Vijay’s is the Winner of the Sunday Times ‘We Are The City Rising Star Award 2018’. “Balancing my clinical and research work can be a challenge, but the team here are very supportive, flexible and understanding - an absolutely brilliant team with whom to work.” NHS burnout is a hot topic of conversation, and her advice on how best to avoid it is “look after yourself, have early nights and there are certain things you have to say no to. I always make sure I have plenty of rest before I am on call,” explains Vijay. “For me, time management, self-discipline and prioritisation are key. On Sunday afternoon I plan the week ahead and that helps me to keep on top of things. When people entrust you with so much, you want to give your all. “I looked up to my mentors and watched how they handled their responsibilities and learnt a lot from them, they taught me to stop sitting there worrying and to just get on with things. Challenges make you stronger, make you better, they are opportunities. My mentors played a major role in my career and now, in turn, I’m teaching students and nurturing the next generation. Being a doctor is an amazing thing. Importantly my entire family have always been very supportive and encouraging in everything I do.
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“Newcastle itself inspires me, the people in the North East are amazing, and I take great inspiration from my patients, they keep me motivated as I want to make a difference in their lives. I’ve received my training in the North East and I want to give something back. Sometimes the cases we deal with are horrendous, but we don’t give up on them, we keep going and we are able to make a difference. We give everything to save someone’s life. “You have to take the abilities you have and do the best that you can in the job that you do. Everything in life is about striving to go over and above with the abilities that you have, and doing that can lead on to so many things. You have to get your head down, do your everyday job and then everything else follows,” observes Vijay. As a publication based in Newcastle, the team at BioScience Today, were disappointed to learn that cardiovascular disease is still such a problem in the North East, in fact where people living in Kensington and Chelsea have an average life expectancy of 83.1 years, in some parts of the North East, like Teesside it is much lower. Statistics suggest that life expectancy is 16.6 years lower for men and 12.2 years lower for women in the most deprived areas of Stockton-on-Tees than in the least deprived areas. There are a number of factors involved, as Vijay explains, from deprivation to risk factors such as smoking, a poor diet, diabetes, hypertension, and family history. “It is the genetic aspect of heart that hasn’t yet been conquered, yes the gene that has been linked with heart disease has been identified, but there is still so much more to know.” Vijay’s best advice for us? “Life is precious, look after yourself, be physically active, walk wherever possible, pack in smoking and watch what you eat – particularly if you have a family history of cardiovascular disease; and keep an eye on your cholesterol. Even small changes can make a major difference.” What would be your dream we ask Vijay? “To see cardiovascular disease eradicated,” she says without a pause. “We have made huge progress in treating some diseases, some of which have been more or less eradicated, and although we have transformed our understanding and treatment of cardiovascular disease in recent years, we are a long way from eradication.” For Vijay, it is clear, combatting cardiovascular disease is the driving force that propels her work.
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New link between gut microbiome and artery hardening discovered
The gut microbiome is under increasing scrutiny in medical research as it is known to affect many different aspects of our health, including our metabolism and auto-immune system. A lack of diversity or range of healthy bacteria in the gut has previously been linked to various health problems, including diabetes, obesity and inflammatory stomach and bowel diseases. Now for the first time, researchers have found a link between gut bacteria and arterial stiffening which suggests that targeting the microbiome through diet, medication and probiotics may be a way to reduce the risk of cardiovascular disease. The British Heart Foundation and MRC-funded research has been published in the European Heart Journal 1. 1 “Gut microbial diversity is associated with lower arterial stiffness in women”, by Cristina Menni et al. European Heart Journal. doi:10.1093/eurheartj/ehy226
The gut microbiome has been implicated in a variety of potential disease mechanisms including inflammation which can predispose people to heart disease. The hardening of the arteries that happens at different rates in different people as we age, is known to be a factor in cardiovascular risk.
THE RESEARCH CONCLUDES THAT CARDIOVASCULAR RISK THAT IS NOT EXPLAINED BY THE USUAL RISK FACTORS COULD IN THE FUTURE BE ENHANCED BY ANALYSING THE HEALTH OF THE GUT MICROBIOME.
The researchers examined medical data from a group of 617 middle-aged female twins from the TwinsUK registry – a national registry of adult twins recruited as volunteers for data-based research. Measurements of arterial stiffening using a gold-standard measure called carotid-femoral pulse-wave velocity (PWV) were analysed alongside data on the composition of the gut microbiomes of the women. The results of the analysis revealed that there was a significant correlation in all the women between the diversity of the microbes in the gut and the health of the arteries. After adjusting for metabolic variations and blood pressure, the measure of arterial stiffness was higher in women with lower diversity of healthy bacteria in the gut. The research also identified specific microbes which were linked to a lower risk of arterial stiffening. These microbes have also previously been associated with a lower risk of obesity.
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Dr Ana Valdes, from the University of Nottingham’s School of Medicine and NIHR Nottingham Biomedical Research Centre, said: “We know that a substantial proportion of serious cardiovascular events like heart attacks are not explained by traditional risk factors such as obesity and smoking, particularly in younger people and in women and that arterial stiffness is related to risk in those groups. So our results reveal the first observation in humans linking the gut microbes and their products to lower arterial stiffness. It is possible that the gut bacteria can be used to detect risk of heart disease and may be altered by diet or drugs to reduce the risk.” Dr Cristina Menni, from the Department of Twin Research and Genetic Epidemiology at King’s College London, said: “There is considerable interest in finding ways to increase the diversity of gut microbes for other conditions such as obesity and diabetes. Our findings now suggest that finding dietary interventions to improve the healthy bacteria in the gut could also be used to reduce the risk of heart disease.” The research concludes that cardiovascular risk that is not explained by the usual risk factors could in the future be enhanced by analysing the health of the gut microbiome. This could be particularly useful in stratifying cardiovascular risk in younger people and in women. The gut microbiome could also be the target for nutrition-based health interventions – for example, a high-fibre diet is known to improve the quantity and diversity of useful microbes in the gut. In fact, the composition of the gut microbiome may contribute to the mechanism whereby dietary fibre intake influences cardiovascular risk, but more research into this mechanism is needed. The research was funded by the British Heart Foundation and Medical Research Council and is part of a programme grant, AIM-HY, to identify markers that may help taylor treatments to individuals (www.aimhy.org.uk).
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heart Patients who have had an irregular
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beat
can’t ever be considered ‘cured’, say researchers Patients with an abnormal heart rhythm that can leave them at a higher risk of suffering from stroke still need treatment even after their heart rhythm seems to have returned to normal, say researchers at the University of Birmingham.
“Therefore, we can conclude that people with resolved atrial fibrillation continue to be at high risk of stroke.”
Atrial fibrillation is the most common heart rhythm disturbance, affecting around 1.6 million people in the UK. Those with atrial fibrillation may be aware of noticeable heart palpitations, where their heart feels like it’s pounding, fluttering or beating irregularly. Sometimes atrial fibrillation does not cause any symptoms and a person who has it is completely unaware that their heart rate is irregular.
Dr Krish Nirantharakumar, of the University of Birmingham’s Institute of Applied Health Research, added: “Our research demonstrates that although people with resolved atrial fibrillation continue to be at high risk of stroke, they are not getting their prevention drugs.
People with atrial fibrillation are much more likely to develop blood clots and suffer from strokes. To avoid strokes it is important for them to take drugs to prevent blood clotting. Sometimes atrial fibrillation seems to go away and the heart goes back to its normal rhythm –the condition may then be deemed to have ‘resolved’. Up until now it has been unclear as to whether the clot-prevention drugs can be safely stopped when the condition is ‘resolved’.
WHAT WE FOUND WAS THAT STROKES WERE LEAST COMMON IN PEOPLE WHO NEVER HAD ATRIAL FIBRILLATION, AND MUCH MORE COMMON IN PEOPLE WHOSE RECORDS SAID THEIR ATRIAL FIBRILLATION HAD BEEN RESOLVED.
Now a study by researchers at the University of Birmingham, published today in the BMJ, has found that people whose heart rhythm returns to normal continue to be at high risk of stroke and should continue to be treated. Researchers looked at patient records from 640 general practices throughout the UK and compared the frequency of strokes in three groups of people: those with ongoing atrial fibrillation; those whose records said that atrial fibrillation had resolved; and those who never had atrial fibrillation. Dr Nicola Adderley, of the University of Birmingham’s Institute of Applied Health Research, said: “What we found was that strokes were least common in people who never had atrial fibrillation, and much more common in people whose records said their atrial fibrillation had been resolved. “Significantly, in recent years we found that strokes were nearly as common in people whose atrial fibrillation had resolved as in those with ongoing atrial fibrillation.
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The researchers also looked at patient treatment. What they found was that, while most people deemed to have atrial fibrillation as an ongoing condition continue to get the clot-prevention drugs they need, the vast majority of those whose atrial fibrillation had ‘resolved’ do not.
“Worryingly, we found that the problem seems to be becoming more common, with our research showing an increasing number of people are recorded as having atrial fibrillation as resolved and are highly unlikely to be given medication to prevent stroke.” The researchers said that in 2016 one in 10 people with atrial fibrillation – around 160,000 people in the UK – were classed to have had their condition resolved. Professor Tom Marshall, of the University of Birmingham’s Institute of Applied Health Research, added: “One possibility as to why people whose atrial fibrillation has resolved continue to be at high risk of stroke is that it had not really resolved in the first instance. “Atrial fibrillation can be present one day and absent the next, so giving someone the all-clear may be a mistake. Another possibility is that it can come back. Many people don’t know when they have this condition and it can come back without them or their doctor realising. “GPs keep a register of people with atrial fibrillation, this means they are reviewed regularly and are prescribed clotpreventing drugs. “But if the atrial fibrillation seems to have resolved they are taken off the register and rarely continue their treatment. It is as if they fall off the radar. “We have shown they are still at high risk of stroke and should still be treated. We cannot ever safely consider atrial fibrillation to have resolved.”
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Focus on Alzheimer’s disease – Hope on the horizon Dr David Reynolds Chief Scientific Officer at Alzheimer’s Research UK
Alzheimer’s Research UK is the UK’s leading dementia research charity and is dedicated to funding pioneering research to find ways to understand, diagnose, reduce risk and treat dementia. Since Alois Alzheimer first described amyloid plaques in the brain of Auguste Deter in 1906, Alzheimer’s disease has been known to the world. Over a century later, we are still waiting for the first diseasemodifying treatment. With drugs designed to target the disease processes driving Alzheimer’s having so far failed to show ultimate success in clinical trials, have we learnt anything about how to treat this cruel disease? In short, yes, we have. In fact, we’ve learnt an awful lot. It’s taken many years to do so, but research has shown that Alzheimer’s is a physical disease and not a natural part
of ageing. We now know more than ever about the genes, molecules and proteins involved in causing the disease and that is helping us zero in on the most promising areas of research to improve the lives of those affected. Alzheimer’s disease currently accounts for two-thirds of all dementia cases, that’s around 500,000 people in the UK alone living with the disease. So, how close are we to turning this understanding into new treatments? Research made a huge leap forward when scientists discovered the amyloid precursor protein gene. This gene is faulty in some rare families and goes on to cause early-onset Alzheimer’s disease. This genetic discovery pointed towards the build-up of a protein called amyloid as the key event that kick-starts damage to nerve cells in Alzheimer’s. This idea is known as the ‘amyloid cascade hypothesis’ – a theory that has been central to Alzheimer’s research for nearly three decades. The improperly processed amyloid protein clumps together to form sticky plaques in the spaces between nerve cells in the brain, ultimately causing these cells to die. This loss of nerve cells means the brain can’t function properly and people start to experience symptoms, like memory loss, confusion and changes in mood and behaviour.
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Anti-amyloid treatments are perhaps the most immediate drugs on the horizon and I am hopeful of success stories here, but there have been a number of high-profile setbacks in recent clinical trials that we must learn from. Alzheimer’s is a complex disease and to have the best chance of success, researchers must continue to tackle the problem from as many different angles as possible. Research is now also highlighting other key brain changes that occur in Alzheimer’s disease, opening the door to new targets for potential treatments. The build-up of the tau protein is a feature of a number of different degenerative brain diseases and is also characteristic of Alzheimer’s disease. The tau protein, which normally helps nerve cells maintain their proper shape as well as transporting cargo around cells, becomes modified during Alzheimer’s disease. One type of modification is the addition of a specific molecule, called phosphate, to particular parts of the tau protein. This changes the shape of the tau protein and can trigger an abnormal build-up into tau tangles. Drugs that could prevent tau from being modified or even clear away tangles of protein in the brain are a key goal for drug discovery scientists. The abnormal build-up of proteins is a key hallmark of many of the diseases that cause dementia, and processes that control protein synthesis and degradation are now an important area of research focus. Understanding how we could target these larger scale processes will help to identify drugs that could benefit several diseases rather than focusing specifically on a single protein associated with a single neurodegenerative disease. Another relatively recent, but key focus of work is the role of the immune system in the development of Alzheimer’s disease. We now appreciate that the brain has its own immune cells – microglia – which play a more important role in the disease processes than was once thought. We know from other areas of health research that the immune system provides the body with a beneficial defence mechanism, but in Alzheimer’s, research suggests that overactivity of the immune system could exacerbate the disease. Unpicking which parts of the immune system have an influence, at which points in the disease and in which patients, is a key area of research and offers a great opportunity in this space for potential treatments. When we understand the contribution of the immune system to Alzheimer’s more fully, we may be able to find shortcuts to new medicines for dementia by repurposing some of the many drugs that already target the immune system for disorders in other parts of the body.
THE BRAIN OF A PERSON AFFECTED BY LATE-STAGE ALZHEIMER’S IS ABOUT 140 GRAMS LIGHTER THAN AN UNAFFECTED BRAIN
Although Alzheimer’s disease can start in specific susceptible brain regions, this damage spreads as the condition progresses, causing more widespread and diverse symptoms. In fact, the brain of a person affected by late-stage Alzheimer’s is about 140 grams lighter than an unaffected brain – that’s about the weight of an orange. We also now know that this damage, and the build-up of proteins in the brain, can start ten to fifteen years before symptoms start to manifest. So, it may well be that we have already discovered a drug or drugs that could help slow or stop the progression of Alzheimer’s, but we just haven’t been able to test them early enough. Diagnosing people early with diseases like Alzheimer’s will be vital as we work to refine how we test emerging new treatments. A multifaceted approach is needed to do this as Alzheimer’s is a multifaceted disease. Focussing on one single detection technique is unlikely to provide all the information doctors will need to make a diagnosis. Combining genetic information, blood tests, brain scans, information we can glean from spinal fluid, as well as subtle changes in brain function using a battery of cognitive tests may give us the best chance of identifying those in the very
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earliest stages of Alzheimer’s who could benefit from future treatments. We’re also seeing some really innovative approaches being developed to address the challenge of early diagnosis in diseases like Alzheimer’s, including exploring how data can be collected from apps, wearables and smart devices to give a more holistic view of someone’s physical, cognitive and social activity and how it’s changing over time. All of this important research requires funding, and thankfully the research landscape is beginning to change for the positive. We’re seeing a more joined-up approach of industry, academia and charity and this is reflected in our funding strategy as a charity. At Alzheimer’s Research UK we have established some cutting-edge drug discovery initiatives like our Drug Discovery Alliance and Dementia Consortium that are fast-tracking the translation of promising lab discoveries towards new drug molecules. Drug discovery is not a quick and easy process but having a broad pipeline of approaches gives us the greatest chance of success for people affected by dementia. We are also now investing heavily in a world-leading research institute to revolutionise discovery science in dementia. This is the UK Dementia Research Institute (UK DRI), a £290million initiative founded with funding from the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The six centres of the UK DRI are now up and running more than 700 scientists expected to take up roles in the institute as its suite of research projects begin to get underway. This is a game-changing initiative. The UK DRI is not just bricks and mortar, it’s a network of experts across the country sharing knowledge, skill and ideas to change lives sooner. However, although the UK DRI is an important step forward and a strong foundation for further investment, we need to make sure dementia research doesn’t fall off the political radar. The job is by no means done and I hope the government sees this as a starting point for even more ambitious change for people with dementia and their families in future. It is through the dedication and hard work of researchers that we will continue to drive breakthroughs that pave the way for new treatments and provide hope to people with dementia and their families. I am hopeful for the future, new treatment approaches are coming through into clinical trials and at an increasing rate. The research landscape has changed considerably, but of course there is still much work to do.
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Genes linked to Alzheimer’s contribute to damage in different ways Understanding how specific genes trigger injury could lead to treatments. Multiple genes have been linked to Alzheimer’s disease, but not all genes linked to the disease contribute to damage in the same way. Researchers at Washington University School of Medicine in St. Louis have found that the types of brain cells damaged by the disease vary, depending on the genes involved. Multiple genes are implicated in Alzheimer’s disease. Some are linked to early-onset Alzheimer’s, a condition that develops in one’s 30s, 40s and 50s, while others are associated with the more common late-onset form of the disease. Eventually, all Alzheimer’s patients develop dementia, and their brain cells die. But not all genes linked to the disease contribute to damage in the same way, and understanding the various ways specific genes lead to damage is important to developing potential treatments to prevent or halt Alzheimer’s. To that end, scientists at Washington University School of Medicine in St. Louis have found that the types of brain cells damaged by the disease vary, depending on the genes involved. Their findings were published on June 8 in the journal Genome Medicine. “Different genes contribute to Alzheimer’s damage in different ways, and we are working to identify therapeutic targets to prevent that damage,” said senior investigator Carlos Cruchaga, PhD, an associate professor of psychiatry. “Alzheimer’s always leads to neuronal death, but we might identify better targets for therapy if we know how various genes lead to damage.” The researchers analyzed brain samples from deceased patients with rare and common forms of Alzheimer’s. The tissue banks also included samples from people who did not have the disorder. As expected, the brains of Alzheimer’s patients generally contained fewer neurons and larger numbers of brain cells called astrocytes. But a closer look showed that the cellular “signatures” in the brains sometimes differed, depending on
the genes contributing to the disease. “Our computer method determined the proportions of each cell type — neurons, astrocytes, oligodendrocytes, microglial cells — and found that specific gene variants were linked to different proportions of these cell types,” said co-investigator Oscar Harari, PhD, an assistant professor of psychiatry. Using a computerized method, the researchers attempted to differentiate the effects of the genes and identify pathways that might be therapeutic targets. Harari, Cruchaga and their colleagues analyzed postmortem samples from the Mayo Clinic Brain Bank, the Mount Sinai Brain Bank and from the Knight Alzheimer’s Disease Research Center at Washington University, as well as from deceased participants in the Dominantly Inherited Alzheimer Network (DIAN) Observational Study of people with genetic mutations that led to early-onset Alzheimer’s. Mutations in the genes APP, PSEN1 and PSEN2 are known to cause inherited Alzheimer’s. Samples from such patients showed lower numbers of neurons and higher numbers of astrocytes than samples from people who had Alzheimer’s but did not carry mutations in any of those genes. The researchers found similar patterns of more astrocytes and fewer neurons in patients with APOE4, a gene known to increase the risk of late-onset Alzheimer’s. But in carriers of a gene variant called TREM2, neuronal loss was not as pronounced. Instead, the TREM2 mutation damaged glial cells in the brain. “Many efforts are underway to identify novel Alzheimer’s disease genes,” Cruchaga said. “But once a gene is identified, we need to know what it does in the brain to understand how it can lead to disease. We also need to account for the proportions of various types of cells if we want to know what we should target with therapies.” Using computerized methods to identify what types of brain cells are present in tissue samples from deceased patients, the researchers found that populations of various brain cell types are different, depending on which genes led to the development of Alzheimer’s.
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MANY EFFORTS ARE UNDERWAY TO IDENTIFY NOVEL ALZHEIMER’S DISEASE GENES. BUT ONCE A GENE IS IDENTIFIED, WE NEED TO KNOW WHAT IT DOES IN THE BRAIN TO UNDERSTAND HOW IT CAN LEAD TO DISEASE.
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Research reveals how Tau aggregates can contribute to cell death in Alzheimer’s disease New evidence suggests a mechanism by which progressive accumulation of Tau protein in brain cells may lead to Alzheimer’s disease. Scientists studied more than 600 human brains and fruit fly models of Alzheimer’s disease and found the first evidence of a strong link between Tau protein within neurons and the activity of particular DNA sequences called transposable elements, which might trigger neurodegeneration. The study appears in the journal Cell Reports. “One of the key characteristics of Alzheimer’s disease is the accumulation of Tau protein within brain cells, in combination with progressive cell death,” said corresponding author Dr. Joshua Shulman, associate professor of neurology, neuroscience and molecular and human genetics at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “In this study we provide novel insights into how accumulation of Tau protein may contribute to the development of Alzheimer’s disease.” Although scientists have studied for years what happens when Tau forms aggregates inside neurons, it still is not clear why brain cells ultimately die. One thing that scientists have noticed is that neurons affected by Tau accumulation also appear to have genomic instability. “Genomic instability refers to an increased tendency to have alterations in the genetic material, DNA, such as mutations or other impairments. This means that the genome is not functioning correctly. Genomic instability is known to be a major driving force behind other diseases such as cancer,” Shulman said. “Our study focused on a new possible causal connection between Tau accumulation within neurons and the resulting genomic instability in Alzheimer’s disease.”
ENTER TRANSPOSABLE ELEMENTS Previous studies of brain tissues from patients with other neurologic diseases and of animal models have suggested that the neurons not only present with genomic instability, but also with activation of transposable elements. “Transposable elements are short pieces of DNA that do not seem to contribute to the production of proteins that make cells function. They behave in a way similar to viruses; they can make copies of themselves that are inserted within the genome and this can create mutations that lead to disease,” Shulman said. “Although most transposable elements are dormant or dysfunctional, some may become active in human brains late in life or in disease. That’s what led us to look specifically at Alzheimer’s disease and the possible association between Tau accumulation and activated transposable elements.” Shulman and his colleagues began their investigations by studying more than 600 human brains from a population study run by co-author Dr. David Bennett at Rush University Medical Center in Chicago. This population
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study follows participants throughout their lives and at death, allowing the researchers to examine their brains in detail postmortem. One of the evaluations is the amount of Tau accumulation across many brain regions. In addition, co-author Dr. Philip De Jager at the Broad Institute and Columbia University comprehensively profiled gene expression in the same brains. “With this large amount of data, we looked to identify signatures of active transposable elements, but this was not easy,” Shulman said. “We therefore reached out to Dr. Zhandong Liu, a co-author in this study, and together we developed a new software tool to detect signatures of active transposable elements from postmortem human brains. Then we conducted a statistical analysis in which we compared the amount of active transposable elements signatures with the amount of Tau accumulation, brain by brain.” Liu also is assistant professor of pediatrics – neurology at Baylor and a member of the Dan L Duncan Comprehensive Cancer Center. The researchers found a strong link between the amount of Tau accumulation in neurons and detectable activity of transposable elements. “We identified individual transposable elements that were active when Tau aggregates were present. Surprisingly, we also found evidence that the activation of transposable elements was quite broad across the genome,” Shulman said. Other research has shown that Tau may disrupt the tightly packed architecture of the genome. It is believed that tightly packed DNA limits gene activation, while opening up the DNA may promote it. Keeping the DNA tightly packed may be an important mechanism to suppress the activity of transposable elements that lead to disease. “The fact that Tau aggregates can affect that architecture of the genome may be one possible mechanism by which transposable elements are activated in Alzheimer’s disease,” Shulman said. “However, our studies in human brains only establish an association between Tau accumulation and activation of transposable elements. To determine whether Tau accumulation could in fact cause transposable element activation, we conducted studies with a fruit fly model of Alzheimer’s disease.” In this fruit fly model of the disease, the researchers found that triggering Tau changes similar to those observed in human brains resulted in the activation of fruit fly transposable elements, strongly suggesting that Tau aggregates that disrupt the architecture of the genome can potentially mediate the activation of transposable elements and ultimately cause neurodegeneration. “We think our experiments reveal new and potentially important insights relevant for understanding Alzheimer’s disease mechanisms,” Shulman said. “There is still a lot of work to be done, but by presenting our results we hope we can stimulate others in the research community to help work on this problem.”
| BIOSCIENCE TODAY SUMMER 2018 |
Heart Disease: A primary cause of death Dr Catrin Rutland BSc PGCHE MSc MMedSci PhD SFHEA FAS Heart disease is one of the primary causes of death throughout the world in both humans and animals. Research at The School of Veterinary Medicine and Science, University of Nottingham is dedicated to understanding differing types of cardiovascular disease in order to prevent, manage, treat and cure heart disorders. Cardiovascular disease is observed in many animals from dogs through to apes. We also translate our research into understanding related human disorders. Our approach combines the expertise from a number of medical and scientific professionals. We combine valuable work and expertise from veterinary clinicians such as cardiologists, pathologists, first opinion veterinarians, surgeons and anaesthetists with that from scientists in fields such as genetics, molecular and cellular biology, epidemiology, bioinformatics and protein biology.
CARDIOMYOPATHY RESEARCH PROGRAMME The Nottingham Canine Health Genomics team is directed by Dr Catrin Rutland, Professor Malcolm Cobb, Professor Nigel Mongan and Dr Mark Dunning. Their research brings together the expertise of cardiovascular and small animal clinicians with scientific disciplines including genetics, bioinformatics, histology and cell biology in order to comprehensively study heart disease. We have collected many thousands of canine samples, matched with clinical and owner reported data, which in turn enable us to gain valuable insights into the disorders. The group study a number of illnesses but their work into cardiomyopathy has advanced the field of veterinary genetics, whilst also having significant impact and highlighting areas of importance in humans and other animals. Cardiomyopathies affect up to
50% of animals in some breeds. It frequently significantly shortens lifespan and affects lifestyle and is therefore a very serious problem. Our genome analysis work has resulted in a predictive disease model and in the discovery of a multiple genetic associations for cardiomyopathy. We have also highlighted likely candidate genes, shown clinical similarities and differences between species and breeds and shown histopathological comparisons across differing species [1-3- 1.
Simpson, S., et al., PeerJ, 2015. 3: p. e842. / 2. Simpson, S., et al., Int J Genomics, 2015. 2015: p. 204823. / 3. Simpson, S., et al., Biomed Res Int, 2016. 2016: p. 6374082.]. We
have also published links between prognosis, age of onset, sex and associations with other cardiac disorders such as atrial fibrillation. The work on cardiomyopathy is not only being carried out in dogs, other mammals feature heavily too [4- 4. Simpson, S., et al., Vet Sci, 2017. 4(1).]. Work on this problem in cats has looked at congestive heart failure in relation to the safety and efficacy of present treatment options available lead by Professor Malcolm Cobb [5 - 5. James, R., et al., Journal of Veterinary Cardiology, 2018. 20(1): p. 1-12.].
APE HEART PROJECT Research within the school also looks into cardiovascular problems in more exotic animals. The Ape Heart Project is an excellent example of some of the work being undertaken. Professor Kate White and Dr Kerstin Baiker from the School of Veterinary Medicine and Science are working closely with other experts within the school and across Europe in the fields of zoological, comparative medicine and cardiology to form a European taskforce. Endorsed by the European Association of Zoos and Aquaria (EAZA) Great Ape Taxon Advisory Group (TAG), The Ape Heart Project; led by Twycross Zoo, is a pan-European collaborative initiative aimed at enhancing current understanding about all aspects (epidemiology, pathology and clinical) of great ape cardiovascular disease [6-8 - 6. Strong, V., et al., Journal of Zoo and Wildlife Medicine, 2017. 48(2): p. 277-286. / 7. Strong, V.J., et al., Journal of Zoo and Wildlife Medicine, 2016. 47(3): p. 697-710. / 8. Strong, V.J., et al., International Zoo Yearbook,
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RESEARCH WITHIN THE SCHOOL ALSO LOOKS INTO CARDIOVASCULAR PROBLEMS IN MORE EXOTIC ANIMALS.
| BIOSCIENCE TODAY SUMMER 2018 |
2018. 52: p. 1-11.].
Heart disease is often reported as a significant cause of death among captive great apes (chimpanzees, bonobos, gorillas and orangutans). However, our understanding about the condition and consequently our abilities to treat and prevent it are limited. In particular, very little work has been done looking at the European population of apes. Twycross Zoo and The University of Nottingham are leading the way in this exciting project which will help us to provide even better care for all captive great apes across Europe. https://twycrosszoo.org/conservation/researchat-twycross-zoo/ape-heart-project/ ductus venosus) [14, 15 - 14.White, R.N., et al.,Veterinary Record, 2000. 146(15):
CONGENITAL PORTOSYSTEMIC SHUNTS Another key area of research within the School of Veterinary Medicine and Science is based around congenital portosystemic shunts in cats and dogs lead by Professor Rob White. Congenital portosystemic shunts (CPSSs) are vascular anomalies that divert portal blood directly into the systemic circulation, bypassing the liver parenchyma. The absence of a normal hepatic portal circulation has two important consequences; 1) impaired hepatic development and function, and 2) direct systemic effects of toxins, nutrients, hormones and other factors that originate from the splanchnic area. CPSSs have been described with frequency in the dog and cats but are only occasionally reported in humans. CPSSs commonly occur as single vessels that may have either an intrahepatic (2033%) or extrahepatic (66-80%) localisation. Extrahepatic CPSSs mainly occur in small-sized dog breeds, whereas intrahepatic CPSSs often occur in larger dog breeds. Recently, the most common extrahepatic CPSSs which involve the azygos, left colic, left gastric, right gastric, left phrenic and splenic veins were independently described in detail using computed tomography angiography (CTA), intra-operative mesenteric portovenography and gross anatomical findings
[9-12 - 9. White, R.N., et al., J Small Anim Pract, 2013. 54(9): p. 459-67. / 10. White, R.N., et al., J Small Anim Pract, 2015. 56(7): p. 430-40. / 11. White, R.N., et al., J Small Anim Pract, 2016. 57(1): p. 28-32. / 12. White, R.N., et al., J Small Anim Pract, 2016. 57(5):
p. 425-429. / 15. White, R.N., et al., J Feline Med Surg, 2001. 3(4): p. 229-33. / ]. The
anatomical descriptions and classifications of both extrahepatic and intrahepatic CPSSs are important with regards to what is the recognised as the preferred therapeutic management of the condition; that is, the surgical closure of the anomalous shunting vessel [16 - 16.White, R.N., et al.,Vet Rec, 1996. 139(13): p. 314-7.].
PLATELET ACTIVITY DETERMINATION AND DEVELOPMENT OF ANTIPLATELET DRUGS. Dr Mark Dunning and a group of platelet biologists from the Queens Medical Centre have developed a test for dogs that is also used in humans which looks at how active platelets are in the circulation [17 - 17. Dunning, M., et al., Journal of Veterinary Internal Medicine, 2018. 32(1): p. 119-127.]. This is important as in certain types of heart disease in cats and dogs blood clots can occur. This test is unique in that it can be performed on blood taken from the patient and stored for up to 20 days. This is a major breakthrough as currently platelet activity testing must be conducted on fresh blood samples within just a few hours. Platelet activities can therefore be monitored from general veterinary practices, enabling them to predict which animals may form clots and whether their platelet activity is sufficiently suppressed by anti-platelet drugs, thus reducing their chances of forming clots. Further work is underway in cats and primates looking at whether the test can be applied to samples from these species in addition to dogs.
p. 247-54.]. These studies concluded that there was consistency
of morphology for these five most common shunt types and that with each type, the site of communication between the shunt and the systemic circulation was highly consistent and anatomically well-defined. In a further recent study it was concluded that in dogs four consistent shunt types (splenocaval, left gastro-phrenic, left gastro-azygos and those involving the right gastric vein) were responsible for 94% of shunts reported in the species, whereas, in cats three consistent shunt types (spleno-caval, left gastro-phrenic and left gastro-caval) were responsible for 92% of extrahepatic shunts reported [13 - 13. White, R.N., et al., J Small Anim Pract, 2017. 58(12): p. 669-677.].
Intrahepatic shunts are divided in left, central or right divisional shunts, depending on their localisation, draining in most instances into the intrahepatic or post hepatic vena cava. Previous studies have confirmed that in both dogs and cats the most common of the intrahepatic CPSSs results from failure of the ductus venosus to close after birth (persistent
HUMAN HEART DISEASE It may seem unusual for a Veterinary School to undertake research into human disorders, but the School has a very strong comparative medicine team. For example Dr Catrin Rutland has studied cardiomyopathies in several animals and this often informs the work in humans and vice versa. Her work includes searching for mutations in the human genome which cause not only cardiomyopathies but also septal and ventricular defects. This research helps us to understand not only the mechanisms behind heart disease but also to further the genetic tests available in order to establish whether a patient has cardiomyopathies/ heart defects prior to onset of clinical manifestations and to understand the complications observed during heart development. This work has used a number of complimentary techniques including genetic knockdown, cell culture, histology and protein analysis and includes collaborators from across the medical School but also with researchers throughout the world. Primarily the work has concentrated on the myosin and TBX5 genes and proteins and their involvement with cardiovascular morphology, contraction and electrical signalling pathways [18-21 - 18.
Rutland, C.S., et al., Development, 2011. 138(18): p. 3955-66. / 19. England, J., et al., J Mol Cell Cardiol, 2017. 106: p. 1-13. / 20. Ghosh, T.K., et al., J Mol Cell Cardiol, 2018. 114: p. 185-198. / 21. Rutland, C., et al., J Anat, 2009. 214(6): p. 905-15.].
The School of Veterinary Medicine and Science strives to support veterinary professionals throughout the world by undertaking research into cardiovascular disease. We work together with owners, veterinary professionals and scientists in order to further the knowledge known about each disorder. Using cutting edge technology in state-or-the-art laboratories, we are able to improve the well-being of animals and people through world-leading innovative research.
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| news |
| BIOSCIENCE TODAY SUMMER 2018 |
Algenuity appoints new Chief Scientific Officer
Algenuity, a leader in algal biology and industrial biotechnology, is delighted to welcome Dr Alex Pudney to the team as Chief Scientific Officer. Alex brings a wealth of experience to the role, having previously worked in both research and start-ups tackling issues of sustainability and renewable alternatives to petrochemicals. His skills in strain engineering, and expertise in directed evolution and design of experiments, are already proving invaluable to the Algenuity team. Alex said: “My background in microbial biotechnology has provided me with a broad and diverse overview of the
industry, and I feel very privileged to be joining Algenuity, as I have always held the company in high regard. In previous roles, I have benefitted from training in leadership, entrepreneurship and project management that took me beyond simply being technically proficient, and I’m very keen to pass on what I have learnt. I enjoy solving problems – from the small detailed intricacies of the lab, to the larger challenges facing the entire industry – and I’m looking forward to working with my new colleagues, who are highly competent and brimming with enthusiasm. It’s exciting to be working in an intellectually rigorous setting where you have the freedom and expectation to be creative, and where driving efforts forward will result in innovative tools for algal applications. As CSO, I feel it’s my role to manage the demands of the business and support the staff, helping them to be successful in an environment that brings out the best in people, which ultimately is what will help us achieve our goals in this fast-moving sector.” Dr Andrew Spicer, CEO of Algenuity, said: “We are delighted to bring Alex on board, and look forward to the knowledge and experience he will bring to the team. Algenuity has always prided itself on hiring high calibre scientists, and Alex is no exception to that rule.” For more information, visit www.algenuity.com
“We are delighted to bring Alex on board, and look forward to the knowledge and experience he will bring to the team. Algenuity has always prided itself on hiring high calibre scientists, and Alex is no exception to that rule.”
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| BIOSCIENCE TODAY SUMMER 2018 |
| news |
Wireless system can power devices inside the body New technology could enable remote control of drug delivery, sensing, and other medical applications.
HAVING THE CAPACITY TO COMMUNICATE WITH THESE SYSTEMS WITHOUT THE NEED FOR A BATTERY WOULD BE A SIGNIFICANT ADVANCE.
MIT researchers, working with scientists from Brigham and Women’s Hospital, have developed a new way to power and communicate with devices implanted deep within the human body. Such devices could be used to deliver drugs, monitor conditions inside the body, or treat disease by stimulating the brain with electricity or light. The implants are powered by radio frequency waves, which can safely pass through human tissues. In tests in animals, the researchers showed that the waves can power devices located 10 centimeters deep in tissue, from a distance of 1 meter. “Even though these tiny implantable devices have no batteries, we can now communicate with them from a distance outside the body. This opens up entirely new types of medical applications,” says Fadel Adib, an assistant professor in MIT’s Media Lab and a senior author of the paper, which will be presented at the Association for Computing Machinery Special Interest Group on Data Communication (SIGCOMM) conference in August. Because they do not require a battery, the devices can be tiny. In this study, the researchers tested a prototype about the size of a grain of rice, but they anticipate that it could be made even smaller. “Having the capacity to communicate with these systems without the need for a battery would be a significant advance. These devices could be compatible with sensing conditions as well as aiding in the delivery of a drug,” says Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital (BWH), Harvard Medical School, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, and an author of the paper. Other authors of the paper are Media Lab postdoc Yunfei Ma, Media Lab graduate student Zhihong Luo, and Koch Institute and BWH affiliate postdoc Christoph Steiger.
WIRELESS COMMUNICATION Medical devices that can be ingested or implanted in the body could offer doctors new ways to diagnose, monitor, and treat many diseases. Traverso’s lab is now working on a variety of ingestible systems that can be used to deliver drugs, monitor vital signs, and detect movement of the GI tract. In the brain, implantable electrodes that deliver an electrical current are used for a technique known as deep brain stimulation, which is often used to treat Parkinson’s disease or epilepsy. These electrodes are now controlled by a pacemaker-like device implanted under the skin, which could be eliminated if wireless power is used. Wireless brain implants could also help deliver light to stimulate or inhibit neuron activity through optogenetics, which so far has not been adapted for use in humans but could be
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useful for treating many neurological disorders. Currently, implantable medical devices, such as pacemakers, carry their own batteries, which occupy most of the space on the device and offer a limited lifespan. Adib, who envisions much smaller, battery-free devices, has been exploring the possibility of wirelessly powering implantable devices with radio waves emitted by antennas outside the body. Until now, this has been difficult to achieve because radio waves tend to dissipate as they pass through the body, so they end up being too weak to supply enough power. To overcome that, the researchers devised a system that they call “In Vivo Networking” (IVN). This system relies on an array of antennas that emit radio waves of slightly different frequencies. As the radio waves travel, they overlap and combine in different ways. At certain points, where the high points of the waves overlap, they can provide enough energy to power an implanted sensor. “We chose frequencies that are slightly different from each other, and in doing so, we know that at some point in time these are going to reach their highs at the same time. When they reach their highs at the same time, they are able to overcome the energy threshold needed to power the device,” Adib says. With the new system, the researchers don’t need to know the exact location of the sensors in the body, as the power is transmitted over a large area. This also means that they can power multiple devices at once. At the same time that the sensors receive a burst of power, they also receive a signal telling them to relay information back to the antenna. This signal could also be used to stimulate release of a drug, a burst of electricity, or a pulse of light, the researchers say.
LONG-DISTANCE POWER In tests in pigs, the researchers showed they could send power from up to a meter outside the body, to a sensor that was 10 centimeters deep in the body. If the sensors are located very close to the skin’s surface, they can be powered from up to 38 meters away. “There’s currently a tradeoff between how deep you can go and how far you can go outside the body,” Adib says. The researchers are now working on making the power delivery more efficient and transferring it over greater distances. This technology also has the potential to improve RFID applications in other areas such as inventory control, retail analytics, and “smart” environments, allowing for longer-distance object tracking and communication, the researchers say. The research was funded by the Media Lab Consortium and the National Institutes of Health.
| Intellectual Property |
| BIOSCIENCE TODAY SUMMER 2018 |
The importance of Intellectual Property strategy; creating a foundation on which to build value in your company Dr Emma Longland and Craig Thomson
patent application.
of HGF writing for the Chartered Institute of Patent Attorneys
With your help, a patent attorney can draft a patent application that should not only cover the product you are seeking to develop, but also products that you might end up developing, once the product is optimised and any kinks ironed out, as well as similar products that competitors might seek to market to take advantage of the same underlying inventive concept. The scope of the protection that the granted patent will provide will depend on a few factors, some of which will not be fully within your control, such as what other people have previously published in the field of your concept and how the patent offices will consider your concept in comparison. A carefully drafted complete application will have the best chance of having the ammunition you need built into it that will enable you and your patent attorney to defend the application and subsequent patent from the impact of those factors.
Most companies in the Biotech space appreciate the need for patent protection; after all, no company wants to bring a product to market after years of hard work, only to have a competitor copy it and steal sales whilst by-passing all the time, money and effort they have put into bringing their innovative product to market. However, using a patent to stop such copying is only the most obvious way in which Intellectual Property can add value to your company. Are you making the most of the opportunities you have in Intellectual Property? Is your Intellectual Property aligned with your company’s strategy, both immediate and longterm? This article will explain the importance of a strong Intellectual Property strategy and how it can add value to your company. Generally speaking, a Biotech company will be created to develop and commercialise a particular discovery or concept. Hopefully, at least one patent application will be filed to cover that discovery or concept. This application will be important. It could ultimately provide protection in many countries throughout the world, for up to 20 years. The extent of that protection, i.e. the extent to which it will allow you to stop competitor activities, will be dependent on the information in that application when it is filed, and how well the application is written. It can be tempting to spend minimal resources on preparing and filing that application, since by its nature it is filed at a time when money may be tight. But that can be a false economy when the exclusivity value of the eventual product (and, by extension, the value of the company) may be so dependent on the quality of the
That initial application can give you some confidence that the company may be able to eventually provide a fair return on the investment required to develop your product and bring it to market; by virtue of the fact that you have reason to believe you will be able to bring your product to market in key territories under a monopoly. The initial application may provide the same confidence to investors, and so encourage them to invest in your company. But, the importance of developing an Intellectual Property strategy does not stop there. As work is undertaken to develop the product, opportunities are likely to arise to file further patent applications. For example, there may be optimisations or improvements of the initial concept itself, there may be developments in associated production methods, and employees may even
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| BIOSCIENCE TODAY SUMMER 2018 |
| Intellectual Property |
conceive of innovations that are actually only tangentially related to the development product(s). It is important that procedures are put in place to identify and analyse the commercial importance of these opportunities so that, where appropriate, you can work with your patent attorney to file additional patent applications for them. Following this strategy, a successful company will find that, in due course, they have a portfolio of patent applications. Managing that expansion of the portfolio and keeping it commercially relevant is the next important step in the creation of a suitable Intellectual Property strategy. The costs of such a growing portfolio can quickly escalate as it expands and matures, and so can start to feel like more of a burden than an asset. It can be difficult to keep track of what each aspect of the portfolio is for and so see how the portfolio adds value to the company, particularly if you are a Board member not working on the patent portfolio on a regular basis. There can as a consequence be a temptation to simply leave the responsibility for overseeing the patent portfolio and its strategy to a sole individual in the company, such as the Chief Scientific Officer, with the only input from the other company executives being in the form of a limit on the budget that may be spent on it. Yet a strong and valuable patent portfolio will underpin the whole company, with implications for the decisions made by company management, and not just in terms of how much money is spent on it.
A STRONG AND VALUABLE PATENT PORTFOLIO WILL UNDERPIN THE WHOLE COMPANY, WITH IMPLICATIONS FOR THE DECISIONS MADE BY COMPANY MANAGEMENT
This is why it is important to know exactly why you have a particular application or patent, and what benefits it brings to the company. It should be possible to prioritise the relative importance of each application or patent, and allocate the amount of money and attention it receives, accordingly. Being able to communicate this to the Board of your company, and so being able to ensure that the portfolio best underpins the direction that the Board are taking the company, is vital. Your patent attorney can assist you with this. The most important applications and patents will be those that directly cover your intended commercial products, and these should be identified and given the highest priority, so that you can make sure that solid, valuable protection is obtained in all the relevant countries. The next in order of importance might be those that cover the potential future plans of the company, for example likely future iterations of the products or related products that the company intends to develop as part of a longer-term strategy. Following this, it may be important to pursue applications or patents that,
whilst not directly covering the company’s products or future plans, cover alternative products that competitors might want to market to compete with the company’s product(s), so that they can be used to prevent competitors eroding your market share (or for improving a negotiation position with competitors). Finally, and of probably least importance, will be those applications that do not directly support the business aims of the company, perhaps because the aims have changed since the applications were filed or because the applications, though potentially valuable, have always been tangential to those aims. Once you have mapped your patent portfolio onto your company business aims in this way, you can use this knowledge to more effectively control the portfolio. For example, you may want to prioritise or accelerate prosecution of applications covering your key product(s), particularly if launch of product(s) is imminent, or you may want to match patents that cover potential competitor activity to that competitor activity as it arises, in terms of where the protection is obtained and what it covers. Additionally, you may want to consider the future of the least important applications – how much money are you spending on them, are they worth that much to you, would it make sense to try to leverage those applications as a source of revenue income by selling or licensing them, and if not then should you consider abandoning the applications altogether? Of course, the assessment of your patent portfolio may serve another important function, because it may tell you that there is a gap in the cover it provides, so that one of the current or intended products of the company are not actually covered by any of your Intellectual Property. In this case you will want to see what you can do to strengthen your position, perhaps by seeking to acquire or license patents or applications owned by others, or by seeing if there is anything you can do with your current or future applications to fill the gap. Again, your patent attorney can assist you with this. When discussing Intellectual Property protection in this article, the focus has been on patent protection because this can be so important for supporting value in the company products, particularly in the initial years of company growth. However, other Intellectual Property may also be important. For example, trade marks and design rights might provide protection for your branding and the shape of products and packaging, and there may be some aspects of your business that may benefit from trade secrets protection if reasonable steps can be taken to keep it secret. Together they can form the most robust Intellectual Property strategy for your business. Knowing what Intellectual Property you have, and how it adds value to your company, is vital. It is vital because not only is this information needed to achieve maximum value from the Intellectual Property, and to achieve synergy with your business aims, but also because this is information that investors will want to have before investing in your company. A conscientious investor will want to see that you have strong Intellectual Property rights supporting your business activities and providing protection for the value of your products. Ideally, you will be able to succinctly and clearly explain to any such potential investors exactly what Intellectual Property you have and how it underpins the business. This will help reassure them that you are a savvy company that knows how to protect current and future interests, and that you will be able to protect their investment.
Knowing what Intellectual Property you have, and how it adds value to your company, is vital. It is vital because not only is this information needed to achieve maximum value from the Intellectual Property, and to achieve synergy between the Intellectual Property and business aims, but also because this is information that investors will want to have before investing in your company 39
| Intellectual Property |
| BIOSCIENCE TODAY SUMMER 2018 |
EU-wide IP Expertise is essential to the life science industry post-Brexit The UK is world-renowned for its progressive life science and healthcare sectors, which are at the forefront of technical innovation, research excellence, and pioneering treatments. Life science companies, research and development facilities, scientists and academics working tirelessly across the UK have all helped to strengthen its position among the top three life science hubs in the world. The Secretary of State for International Trade, Dr Liam Fox MP, recently praised the UK’s world-leading status, and reaffirmed his department’s commitment to supporting the sectors’ continued growth and future success. The UK’s ability to flourish as a global leader has so far been enhanced by its membership of the European Union (EU), with businesses enjoying the associated benefits including free trade and free movement of goods allowing them relatively seamlessly access to a market of 500 million people in Europe. One important factor in the success of UK businesses has been the protection provided by Intellectual Property (IP) rights registered across the EU. However, with Brexit set to take place from 29th March 2019, there could be significant implications for the Intellectual Property landscape, particularly in the life science and healthcare sectors, which rely on their ability to market their products and innovations internationally. When it comes to Intellectual Property rights post-Brexit, these could be impacted in a number of ways, says Jim Robertson, partner and patent attorney at Intellectual Property firm Wynne-Jones IP. He said: “Brexit presents a daunting range of challenges to businesses of all kinds. Increasingly important to the value of any business, Intellectual Property (IP) rights will be impacted in a variety of ways.” Here Jim Robertson outlines the main changes for IP rights holders in the life science and healthcare sectors after the UK’s withdrawal from the EU.
REPRESENTATION POST-BREXIT In the lead up to Brexit much of the widespread discussion and focus has centred around securing IP rights such as patents, trade marks and designs in the UK that are currently overseen by European systems. Patents and their protection in the UK post-Brexit is particularly relevant in the life science and healthcare industries, which have seen substantial growth in biotechnology innovation in recent years.
applications and patents granted for biotechnology inventions. There has been concern that after Brexit these patents would cease to provide protection in the UK. However, Mr Robertson said that post-Brexit, “European patents” will still provide protection in the UK. This is because the EPO (European Patent Office) is not an EU institution, and the EPC (European Patent Convention) is not an EU legal instrument. Instead, various non-EU states (such as Norway, Switzerland and Turkey) are parties to the EPC, and the UK will continue to be party to it post-Brexit. The big change in patents is likely to come from the Unified Patent Court (UPC). The UPC is an international court which will have jurisdiction over patent disputes across all major EU member states, which at the present time includes the UK. It will provide a single judgement on matters involving Unitary Patents and European patents, with its ruling having cross-border precedent, and will enable inventors to defend their IP rights across the EU. The only thing blocking the UPC from coming into existence was UK and German ratification to the UPC Agreement. On 26 April 2018, it was announced that the UK had ratified the UPC Agreement. That just leaves Germany to ratify the UPC Agreement. However, a challenge before the German constitutional court is preventing that at the moment. The case is listed for this year, and if the constitutional court finds against the challenge then German ratification might take place very rapidly, in turn bringing into force the Unitary Patent Court and the Unitary Patent. If, and when, the UPC comes into existence, it could play a crucial role in determining how the UK will approach patent disputes after Brexit. Although the UPC may provide simplicity and convenience across Europe, companies in the UK could still face legal complications after Brexit when cases are referred to the Court of Justice of the European Union (CJEU). However, it has been suggested that the Government may accept the jurisdiction of the UPC to help rule over common patent matters in the UK. It could also be argued that being precluded from the ruling of the CJEU may actually place the UK in a position of power, as it will no longer be affected directly by its wide-ranging judgements. With regards to owners of EU trade marks and EU designs, there could be a wider, and more concerning implications for their representation in the EU.
This increase has coincided with rapid rises in patent
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BREXIT PRESENTS A DAUNTING RANGE OF CHALLENGES TO BUSINESSES OF ALL KINDS. INCREASINGLY IMPORTANT TO THE VALUE OF ANY BUSINESS, INTELLECTUAL PROPERTY (IP) RIGHTS WILL BE IMPACTED IN A VARIETY OF WAYS.
| BIOSCIENCE TODAY SUMMER 2018 |
| Intellectual Property |
“Anyone can file IP rights such an EU trade mark application or an EU design application,” explains Jim Robertson, “The real question is what happens after Brexit given that only a national of a European Economic Area member state can represent you subsequently in prosecuting your application or dealing with other matters.” Mr Robertson said: “This is incredibly troubling for large numbers of companies in the UK who wish to continue protecting their IP rights and business interests in both the UK and the EU. “Many could be left searching for new legal representation, who will be unfamiliar with their IP portfolio, lack the necessary knowledge about the company’s area of expertise, and generally are not an adequate fit for their needs. “This could lead to disputes receiving ineffective representation before the European Union Intellectual Property Office (the EUIPO) when they are relying on it the most.” In the event of Brexit, UK IP attorneys could lose the right to represent their clients in disputes before the EUIPO as only a national of a European Economic Area state can prosecute an application or deal with other matters. In order to bypass this technicality, some UK firms plan to divert their EU IPO work to newly-acquired branch offices in the 27 remaining EU states. However, as Mr Robertson points out, many of these offices are best suited to serving local clients which is, after all, why they were originally set up. However simply redistributing the work in this way, could have negative consequences, and businesses in the life science sector may find that the local firm they chose may be inadequate for their needs. “The challenge is to retain links between IP owners and their existing contacts in the UK, those attorneys they already know and trust, while minimising problems caused by differences in national laws, languages, cultures and traditions – as well as the tricky question of who can charge the client for the work that’s been carried out,” says Mr Robertson.
As Brexit grinds on and as IP owners and attorneys struggle with these important issues, a Europe-wide IP business is attracting increasing interest. Formed in 2010, AIPEX, the leading European IP law firm, has offices in 13 of 27 EU states. As a Europe-wide operator it offers a tailor-made solution to managing the IP portfolios of pan-regional and international businesses. The firm’s team of more than 500 highly qualified professionals, over 250 of whom are qualified attorneys, means it can work across a company’s entire IP portfolio, including patents, trade marks and design, as well as key areas such as infringement, prosecution, renewals and strategy. Through AIPEX, Wynne-Jones IP, which is a founding member, will be able to continue to represent its clients before the EUIPO. “AIPEX will be the address for service for all the EU designs and EU trade marks on the books of Wynne-Jones IP, so we will retain complete control of all of our clients’ affairs,” says Mr Robertson. “Our clients in the UK will notice no difference from how things work now and there will be no double-charging.” The criteria for one AIPEX client looking to reduce the number of attorneys it was using across Europe, included cost, the quality of work produced and a good professional relationship. “What clinched the deal was AIPEX’s ‘hub-andspoke’ model – a multi-jurisdictional presence in Europe with a single point of contact,” says the client. Brexit presents challenges for many thousands of UK businesses, some of whom haven’t even realised it yet. But, with access to an IP pan-European law firm with expertise in all sectors across all EU states, they can turn that challenge into an opportunity. For more information on Wynne-Jones IP visit: www.wynne-jones.com For more information on AIPEX visit: www.aipex-ip.com
Your team for Life Sciences IP Life Sciences your field? When you need help with intellectual property rights, remember that we’ve been active in this field for decades. Whether you’re a lone inventor, SME or large corporation, you must identify and protect your Crown Jewels®. These are the core technologies, inventions or processes that are critical to your business strategy.
We know our stuff in: Bio-sensors | Diagnostics | Assays | Pharmaceuticals and Drug Synthesis | Small Molecules | Plant Breeders’ Rights | Cosmetics | Supplementary Protection Certificates | Vaccines | Biochemistry | Microbiology | Pharmacology | Biocides | Healthcare Sciences | Proteomics | Biophysics | Veterinary Medicines | Medical Devices
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What are you waiting for? Let’s talk Life Sciences. Jim Robertson, Life Sciences Team Leader T: 01242 267 600 | E: jim.robertson@wynne-jones.com W: www.wynne-jones.com Wynne Jones LifeSciences Advert_133x190.indd 1
21/05/2018 12:56
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| artificial intelligence |
| BIOSCIENCE TODAY SUMMER 2018 |
Discovering a new future through Artificial Intelligence and Machine Learning the Government’s new Industrial Strategy, which is also underpinned by an associated Life Science Sector Deal And life sciences companies are now increasingly recognising the opportunities to apply data in order to optimise drug development activity and address treatment and patient care challenges. As we continue to understand more about our human biology and the biological processes involved in the progress of disease, the opportunities to apply data to progress new developments, treatments and indeed cures, continues to grow.
Malcolm Skingle
Director, Academic Liaison GlaxoSmithKline (GSK) and Science Industry Partnership Chair
A number of industry sectors including aviation, retail and financial services have long applied data and utilised analytics to augment human capabilities, optimise their customer engagement and maximise returns. Indeed the term Artificial Intelligence (AI), incorporating machine learning approaches, is something of an heir apparent to what was once commonly referred to as the utilisation of ‘Big Data’. The Engineering and Physical Science Research Council (EPSRC) has usefully defined AI to reflect the evolution and innovation in Big Data deployments: “Artificial Intelligence technologies aim to reproduce or surpass abilities (in computational systems) that would require ‘intelligence’ if humans were to perform them. These include: learning and adaptation; sensory understanding and interaction; reasoning and planning; optimisation of procedures and parameters; autonomy; creativity; and extracting knowledge and predictions from large, diverse digital data.” Early forms of AI have been in use for several decades, particularly in sectors which have a requirement for somewhat repetitive but critical decision-making, or for the efficient analysis of large volumes of data. However such computing systems – and indeed their operators – did not have the capacity to interpret vast quantities of unstructured data. As computers have become more powerful, it has become possible to analyse those vast quantities of data. And Deep Learning, a subset of Machine Learning, has exploded in the last few years alongside more affordable access to compute capacity. It is this exponential increase in computing hardware performance, together with the increased affordability, that is now driving the rapid growth in the application of AI across many more business sectors, including life sciences. This evolving landscape has been recognised by the UK Government with the recent publication of its Artifical Intelligence Sector Deal to ensure that the UK is at the forefront of AI development. The Deal aims to take “immediate, tangible actions” to advance the UK’s ambitions in AI and the data-driven economy, in line with
For R&D, the ability to analyse large volumes of data to produce deeper insights is enabling us to undertake advanced modelling to produce stronger hypotheses and therefore more targeted research. Other advances, including medical imaging interpretation, genomic profiling and personalised medicines are all set to be revolutionised by the application of Artificial Intelligence.
SPEEDING UP DRUG DISCOVERY Real life deployment of Artificial Intelligence in drug discovery is delivering the future right now. My own company GSK, like other pharmaceutical companies, generates a vast amount of data – and we have recognised that this represents an immense wealth of valuable information. We are using advanced technology and analytics to transform the way we run drug discovery and make decisions. Although we have used “machine learning” – where machines apply knowledge from vast data sets, recognise patterns for themselves and make predictions as a result – for a number of years, we recognised that these techniques could be applied more broadly. In particular, we saw that the type of pattern recognition used in the financial world or for image analysis could also work in drug development. The true value of machine learning in drug discovery will be realised by the integration of the drug discovery domain expert with the data scientist. In response we formed a new Drug Discovery Unit dedicated to exploring and applying AI to drug discovery, under the leadership of John Baldoni, our Senior Vice President of In silico Drug Discovery. Using AI is set to help us and the wider pharmaceuticals industry significantly accelerate our drug development processes.
MY OWN COMPANY GSK, LIKE OTHER PHARMACEUTICAL COMPANIES, GENERATES A VAST AMOUNT OF DATA – AND WE HAVE RECOGNISED THAT THIS REPRESENTS AN IMMENSE WEALTH OF VALUABLE INFORMATION
Drug development is highly resource-intensive and costly, timescales can vary – but typically take 12 years from the initial discovery stage to reach the market; estimates of costs also vary – with the Association of the British Pharmaceutical Industry (ABPI) putting the cost at £1.15bn per drug. With AI, this process could be considerably shortened. In order to harness the power of AI, GSK has recently entered into a range of different collaborations. Last year, we started working with Exscientia, a UK-based AI and machine-learning company. During this collaboration, Exscientia is applying its AI enabled platform and combining this with the expertise of GSK, in order to discover novel and selective small molecules for up to 10 disease-related targets, nominated by GSK across multiple therapeutic areas. Exscientia’s objective is to use this approach to deliver candidate-quality molecules in roughly one-quarter of the
ABOUT THE SCIENCE INDUSTRY PARTNERSHIP SIP members are working with Government to establish the vocational skills needed to build a high value, productive and competent scientific workforce. The SIP’s strategic objectives are: • To have a pipeline of skilled people with the capability, drive and ambition to build a globally competitive science based industry in the UK • To support the development of the workforce to acquire the skills it needs to adopt new technologies and develop innovations and services • To build a more diverse scientific workforce for the future by promoting equality of opportunity in vocational skills
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| BIOSCIENCE TODAY SUMMER 2018 |
| artificial intelligence |
time, and at one-quarter of the cost of traditional approaches. GSK is also working with the Hartree Centre, the UK government-backed research centre, which has some of the most technically advanced computing, data analytics, machine-learning technologies expertise in the UK. GSK is working with Hartree on a supercomputing project that enables scientists to analyse millions of biomedical research publications to identify pattern correlations that might act as the starting point for new treatments. And it is also part of the Accelerating Therapeutics for Opportunities in Medicine (Atom) consortium, a US publicprivate partnership with the Department of Energy and the National Cancer Institute. Atom is developing computing models capable of vetting millions of molecules for efficacy and structural relationships. These models will be able to adapt (without human supervision) as they learn from the huge data sets they go through – a process known as “deep learning”. The value is in reducing the search space for compounds as opposed to finding “the” compound. We still need human interpretation/design. GSK is giving Atom access to more than a million compounds it has screened over the past 15 years, all of which have biological data associated with them.
IMPACT ON SKILLS AI Technologies, Big Data Analytics, Robotic Process Automation and Machine Learning are set to bring a range of unimagined benefits to science-based industries – from drug development and diagnostics to medical devices and monitoring technologies. Practical benefits include new insights into disease, cost reductions, improved productivity and increased speed to market. But it is the benefits to society, including improved treatment outcomes, care management and quality of life that will continue to drive progress. The Science Industry Partnership of employers is now seeking to establish how the continued development of AI-based technologies will impact the skills needs of science industry organisations, highlighting any potential skills gaps, risks to current roles, new opportunities and recommendations for education and training reform that may be required. It began evidence gathering through its Skills Strategy 2025, which immediately identified those areas and occupations requiring urgent action on skills including Bioinformaticians, Cheminformaticians & Health Informaticians. It has also evidenced a shortage of Computational Scientists – and a mismatch of skills in the current workforce, with large portions educated before computational sciences formed a significant part of curricula, and current graduates lacking the type of skills sought by employers. The next step is to further identify the future skills required for the development and deployment of AI technology and secondly the implications for those working in an AI
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environment for sector-specific applications. Working in partnership with be key here – with organisations such as Innovate UK and The Alan Turing Institute. However, the SIP is not waiting to take action on skills and has already made a number of clear recommendations to help the Sector prepare for a technology-enabled future. An early move into formalising vocational skills has been the development of a Masters Level Apprenticeship Standard Bioinformatics Scientist at Level 7. Bioinformaticians are life scientists who use computer and informational techniques, which are applied to a range of problems in the life sciences, for example, in pharmaceutical companies in the process of drug discovery. This vocational training pathway will deliver highly skilled work-ready individuals who will be able to apply their knowledge of computing (including coding), biology, statistics and mathematics while fulfilling a job role in a host company. We’re now looking at other Standards such as Computational Scientist at Level 8/Masters. This development recognises that the sector requires clear, highly specialised, vocational pathways into the jobs of the future. The SIP is also behind moves to build mathematical & statistical skills throughout the education system, and has applauded recent Government investments in this critical area. It is essential that a good grounding in mathematics and statistics is embedded from school age. In addition, training in maths and stats must be available and accessible to address identified weaknesses in the existing scientific workforce. We also need to build practical computing skills across stem education: data handling, computing, programming and software using skills are now touching roles at all levels. The need for these skills is growing and should be core elements of STEM related education. This would provide learners with the skills to work with company specific software and equipment as soon as possible. Finally, we need to facilitate transferability between public and private scientific workforces: facilitating the transfer of staff between industry, NHS and academia has many benefits. These include developing multidisciplinary individuals and teams, increasing cross-sector collaboration, enhancing transfer of ideas and innovation, and creating a more flexible workforce. There is no doubt AI has immense power to deliver improvements in cost, quality, speed, efficiency and outcomes – right across every function in our businesses. The SIP will be seeking collaborations in order to build the skills and capabilities to give our sector the combination or core science and computational skills that will allow to transition from utilising Big Data to Deep Data – high quality, actionable information that will take us to another level of understanding and in turn discovery. For further information on the SIP contact sipmembers@cogentskills.com
| nihr news| |
| |BIOSCIENCE BIOSCIENCETODAY TODAYSUMMER SPRING 2018 |
The Great British
Biosimilar Journey
Attitudes towards biosimilar drugs have rapidly changed in the last 24 months, but there is still work to do. Divya Chadha Manek from the National Institute for Health Research (NIHR) – the research arm of the UK’s National Health Service - takes stock of the British biosimilar journey so far and hints at where we might be heading next. Uptake and access to biosimilars in the UK’s National Health Service (NHS) has improved considerably over the last two years. There has been a shift in attitude towards the rituximab biosimilars, compared to the struggles that etanercept and infliximab biosimilars have endured in terms of winning over clinical confidence. So does the future look bright for upcoming biosimilar medicines that have the NHS in their sights? Without a doubt, there is many a keen eye on the development of biosimilar versions of the blockbuster biologic drug adalimumab, which is expected to hit NHS shelves in 2019. The competition will be lively as there are reported to be between 15 to 20 companies poised to enter the market with an adalimumab biosimilar when the patent expires in October 2018. NHS England continues to do an excellent job of championing the cause by bringing together key players in the biosimilar field: life sciences industry, patient groups, health professionals and NICE. And their efforts seem to be paying off. A significant step-change came with the launch of NHS England’s Commissioning Framework for Biological Medicines (Including Biosimilar Medicines) in autumn 2017. The NHS now has an ambitious target of at least 90% of new patients being prescribed the best value biological medicine within 3 months of launch of a biosimilar medicine, and at least 80% of existing patients being switched within 12 months, or sooner if possible. Yet despite all this work, uptake of biosimilar medicines across the country continues to be varied. In October 2017 the NIHR brought together stakeholders working within the biosimilars arena. Angela McFarlane, Market Development Director for IQVIA, presented data which showed regional variation in NHS trust conversion to biosimilar versions of infliximab, rituximab and etanercept. Angela commented: “There is a lot of work to be done in terms of ironing out variation across England and the NHS England Biologicals Framework will be a key platform for this to happen.”
Indeed, there is still much to do to realise the full cost saving benefits of biosimilar medicines throughout the NHS. And much of it boils down to clinical confidence. Patients and clinicians alike need to feel confident that they will experience the same benefit from a biosimilar medication as from an original biologic drug. One way to develop and build that confidence is by conducting clinical studies - including real-world evidence studies - here in the UK. Clinical studies will provide both clinicians and patients with the opportunity to utilise new biosimilar medicines in highly controlled context and to generate reliable clinical evidence. However, in 2016 it came to light that some global life science companies were overlooking the UK as a destination for biosimilar trials. Conversations revealed that some companies were struggling to generate enough interest from clinicians in the UK - citing that clinicians preferred to work with novel drugs. Further investigations revealed that, in many cases, these companies had been targeting key opinion leaders in larger academic institutions. One global CRO told us:
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| BIOSCIENCE TODAY SPRING SUMMER2018 2018| |
| |news nihr |
“We often find that when a sponsor asks us to run a study in the UK they provide us with a list of sites and investigator contacts. But in some cases those contacts may not prove to be the most fruitful; people may have moved jobs, or it may just be that those investigators are based in big research institutions where there is already a lot of similar research taking place and large demands on some patient populations.” As a result, key opinion leading clinicians decline to participate in the study which could be misinterpreted as apathy for biosimilar medicine trials. However the reality is that the larger NHS/academic institutions, where key opinion leaders tend to be based, make up a fraction of our NHS. The larger portion, made up of multiple types of NHS organisations and NHS service providers, holds enormous potential for biosimilar medicine trials which to date has been largely untapped. To illuminate that potential, in 2016 the NIHR commenced a scoping exercise of clinical interest within indications that are relevant to biosimilar medicines (cancer, gastroenterology, diabetes, dermatology, rheumatology and ophthalmology). We asked all research-active clinicians across the entire NHS in England for a show of hands if they were interested in delivering trials of biosimilar drugs. The list currently runs at over 800 clinicians and continues to grow. This resource has become a useful tool for companies wishing to cast their clinical investigator net beyond their usual little black book of contacts. Armed with this knowledge, the NIHR is actively promoting the UK’s research capacity and capabilities to deliver biosimilar medicine trials to overseas life science companies through its “Focus on Biosimilars campaign” (www.nihr.ac.uk/biosimilars). But this cleverly designed campaign isn’t just aimed at the life sciences industry. It’s also a treasure trove of NHS views and opinions on the benefits of bringing biosimilar medicines into the NHS and is therefore a valuable resource for bolstering clinical confidence. Perhaps hearing it from the horse’s mouth will go some way to easing the concerns of those clinicians who are sitting on the fence. Meanwhile the education efforts continue. The NIHR is planning to introduce a new online training course to raise awareness of biosimilar medicines and their potential benefits to the NHS. Although it will initially be aimed at NIHR staff, this resource is expected to cascade through to research-active NHS professionals who want to know more about biosimilar medicines. This new resource is currently in development and is expected to be launched in summer 2018. Nonetheless, the reality is that biosimilars are the new kids on the block. Clinical confidence will grow with time and experience. Bringing more biosimilar medicine clinical trials to the UK will certainly contribute towards improving clinical confidence where efficacy and similarity are concerned. However, some key opinion leaders feel that the longitudinal piece of the biosimilar jigsaw is still missing. They call for more long-term pharmacovigilance studies of biosimilar medicines similar to BADBIR (British Association of Dermatologist Biologic Interventions Register). BADBIR, led from Manchester, is a UK and Eire observational study seeking to assess the long-term safety of biologic treatments for psoriasis. NICE has recommended that all patients in the UK receiving these new therapies for psoriasis should be registered with BADBIR. Professor Chris Griffiths, Foundation Professor of Dermatology at the University of Manchester and Consultant Dermatologist at Salford Royal NHS Foundation Trust, explains why registries are important:
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“I’m a practising dermatologist and, for example, we know that about 30 per cent of the psoriasis patients in my clinic would not be eligible for clinical trials. This might be because they are either too old, have multiple co-morbidities, or on other drugs which would exclude them from taking part in a trial. Yet these are the patients that we are seeing in the real world when we are using biologic and biosimilar drugs to manage psoriasis. It is this group that probably have the highest risk of adverse events. Thus, real world pharmacovigilance registries, such as the BADBIR study allow us to monitor the longterm safety of these life-changing medications. “This kind of monitoring, and the data it creates, gives both patients and clinicians the added assurance that these drugs are going to perform as well in the real world - as safely and as effectively - as we see in the clinical trials. The BADBIR study has been running for 10 years, and now includes three biosimilar drugs alongside originator drugs. We believe very strongly that the biosimilar drugs should be under the same surveillance as the originator molecules.” The good news is that the UK is a world leader when it comes to real world research. Professor Martin Gibson, Director of the Greater Manchester branch of the NIHR Clinical Research Network, encapsulates the UK’s real world research strengths: “It’s important to define what we mean by real world research. Real world data is routinely collected clinical information. Real world evidence is distilled from analysing the real world data for example in longitudinal observational studies. In the UK we have invented a third category: real world clinical trials. This is where we run an entire trial using routinely collected clinical data, like we did with the Salford Lung Study. “The NHS can do all of the above because we have excellent clinical data systems that are becoming more and more linked through the advent of electronic health records and through organisations such as NHS digital. We can also now explore how user-generated information is collected and added to healthcare data to provide even richer longitudinal outcomes that everyone is interested in. “And the NHS is unique because everybody is in it. This means that results we get are generalisable compared to some other healthcare systems where not everybody has the same equality of access to healthcare that we are fortunate to enjoy. This gives us a significant advantage over many other parts of the world.” Angela McFarlane, IQVIA, agrees: “The UK is the leading real world evidence country in the world. The reason for that is because we have the richest de-identified patient level data set in the world, and of course it’s all in one health system, where every citizen owns a unique NHS number. This is a unique feature which differentiates the UK from the rest of the world in its attractiveness for research and it needs to be capitalised on. Working with the NIHR we hope to bring about a landmark real world evidence study called NHS BioValue which will demonstrate the value of biologics, including biosimilars, in all therapy areas from a patient experience and service impact perspective.” So what does all this mean for biosimilar medicines uptake in the UK? The hope is that clinical confidence will continue to gather momentum as new biosimilar medicines come to the fore. Clinical research has a key role to play. Whether that is using the NHS as a testbed for new biosimilar medicines, or making the most of the NHS capabilities for long-term post-marketing pharmacovigilance surveillance studies of existing biosimilar drugs. The UK is currently leading Europe in uptake of biosimilar medicines and we have even more to offer.
| cell lines |
| BIOSCIENCE TODAY SUMMER 2018 |
The body in
miniature By Craig Brierley at University of Cambridge
The past few years has seen an explosion in the number of studies using organoids – so-called ‘mini organs’. While they can help scientists understand human biology and disease, some in the field have questioned their usefulness. But as the field matures, we could see their increasing use in personalised and regenerative medicine.
Laura Broutier reaches into the incubator and takes out a culture plate with 24 separate wells, each containing a pale pink liquid. “If you look closely, you can see the dots there,” she says, manipulating the plates until specs the size of a full stop catch the light. Broutier is a postdoc in Dr Meritxell Huch’s lab at the Wellcome/ Cancer Research UK Gurdon Institute, and these “dots” are miniature liver tumours that have been regrown from cancer cells taken from patients at nearby Addenbrooke’s Hospital – and they could make it possible to identify cancer drugs personalised for each individual patient. Huch’s latest work builds on her previous research on ‘mini-livers’, part of a growing body of work – no pun
intended – that uses miniature organ-like tissues to understand human biology and in particular why, when it goes wrong, it leads to diseases such as cancer and dementia. In Cambridge alone, aside from Huch’s work on ‘mini-livers’ there are groups growing mini-brains, mini-oesophaguses, mini-bile ducts, mini-lungs, miniintestines, mini-wombs, mini-pancreases… Almost the whole body in miniature, it seems. It’s perhaps a misnomer to call them mini-organs. They certainly look nothing like a miniature organ. Rather, they are ‘organoids’, clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same tissue architecture, gene expression and genetic functions as the part of the organ being studied.
The technique that Huch uses involves taking cells from primary tissue – either from the liver or, in the case of her latest work, liver tumours – and growing these in culture. Her early work involved growing mini-livers from mouse stem cells, but she is now working with human tissue. “Before, we could only do this work in mice or in cell lines, but organoids have opened up a lot of possibilities for us,” says Huch. “They’re not 100% identical to the tissue, but they recapitulate many more functions of the tissue of origin, so we can use them to study adult tissue in a way that wasn’t previously possible.” This ability to use organoids in place of in vivo animal models has attracted the interest of the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), who currently support Huch’s work and awarded her a 3Rs Prize in 2014. Organoid research has exploded in recent years. Their application includes modelling tissue, early development and disease, drug discovery, and now regenerative medicine. Little wonder, then, that The Scientist named the technique one of the biggest scientific advancements of 2013; since then the number of organoid-related scientific papers in the PubMed Central repository has more than doubled to over 1,000 per year. But, as with any promising new development in research, we must be careful not to oversell them, says Professor Alfonso Martinez-Arias from the Department of Genetics. In some cases, he argues, the research is little more than doing “safaris on culture plates”.
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| BIOSCIENCE TODAY SUMMER 2018 |
| cell lines |
Last year, he co-wrote an article in the journal Development about the hype surrounding organoids. He is not as dismissive of the field as one might imagine (though in the article, he takes particular exception to claims in a press release that scientists in the USA had made the “most complete human brain model to date”). The problem, he says, is one of reproducibility – the same experimental conditions should yield samples that are almost identical in terms of size, shape and cellular composition. This is currently not the case, he says – organoids often cannot be grown reliably, forcing researchers to ‘cherry pick’ the best ones, and even then (and in contrast with the organism) each one is different. “If you let cells do things in a Petri dish, they will do things – like children in a playground, they’ll arrange themselves into patterns and some of these will make sense to you. But if we want the system to be reproducible and therefore useful for disease modelling, drug screening or understanding basic mechanisms, we need to steer them and ensure that if an experiment starts with one hundred groups of cells, we end up with one hundred almost identical organoids.” Martinez-Arias’s own work is on gastruloids – the same concept as organoids, but to model very early stages of embryonic development. Working closely with physicists and engineers, his team has managed to generate gastruloids using mouse cells that are highly reproducible. In the same edition of Development, Huch co-wrote a counterpoint to Martinez-Arias’s article, about the hope surrounding organoids, but she agrees with MartinezArias that much of research in the field to date has been merely descriptive. “It has been ‘Oh, we can do this and we can grow this’, but little has been shown about what we can learn from this.” This, she says, is how her recent study on liver tumours – “tumoroids” as she calls them – differs. “We’ve shown not only that we can grow them, but what we can do with them.” Huch recently published a proof of principle that it is possible to derive mini-tumours in culture from a patient’s own cells against which drugs can be tested to find the most effective one for that patient – so-called ‘personalised medicine’. Such work can currently only be done by transplanting tumour tissue into mice, growing it over several months and testing the drugs on the mouse – time-consuming
and technically-limiting. Imagine, she says, being able to screen hundreds – even thousands – of drugs at a time on the mini-liver tumours. Clearly this would be neither practical nor ethical in animals. “Whether it can be done economically and practically on an individual patient basis, time will tell,” she says. “Like with everything, once the technology has become cheaper, then I think it will be feasible.” It is tempting to speculate that if scientists can grow organoids in the lab, then they will soon be able to grow fully-functioning organs, too, but we are nowhere near this stage yet, says Huch. More feasible is the idea of using organoids to replace damaged or diseased tissue – or more accurately, to help such tissue ‘regenerate’. This is one area of research being pursued by Professor Ludovic Vallier from the Wellcome-MRC Cambridge Stem Cell Institute (also a winner of a 3Rs prize in 2011). Earlier in 2017, Vallier succeeded in reconstructing the common bile duct using biliary organoids. The common bile duct is a pipe linking the liver to the gut. It carries bile, which contains all the toxin produced by the liver and is also essential for helping us digest food. If the common bile is damaged, for example in the childhood disease biliary atresia, this can lead to accumulation of toxic bile in the liver and ultimately to liver failure. Vallier and colleagues extracted healthy cells from mouse bile ducts and grew these into functioning 3D duct structures known as biliary organoids. But it was the next step that makes this so significant: they then rebuilt a common bile duct with the help of bioengineers Dr Athina Markaki and Alex Justin. When transplanted into mice, the biliary organoids assembled into intricate structures resembling bile ducts and helped the mice to survive without further complications. The next step, Vallier says, is to try this in large animals such as pigs, which are closer in size and physiology to humans than are mice. “In two or three years’ time, we should have the right biomaterials at the right size to use in clinical trials in humans,” he says. Back at the Gurdon Institute, when Broutier slides her culture plate under the microscope, the organoids are still unremarkable to the eye. Looks can clearly be deceptive: these tiny clusters of cells are most definitely not unremarkable.
Image credits: (left) Ludovic Vallier; (right) Meritxell Huch
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| cell lines |
| BIOSCIENCE TODAY SUMMER 2018 |
Colon Cancer Cells Use Mysterious RNA Strands to Avoid Cell Death New study paves way for novel therapeutics
could be exploited as direct drug targets in this and other human diseases.”
Researchers from Case Western Reserve University School of Medicine have discovered how unusually long strands of RNA help colon cancer cells avoid death, allowing unregulated growth. Unlike other RNAs, the intriguing strands do not appear to encode proteins and are termed “long non-coding RNAs” or “lincRNAs.” A new study showed some lincRNAs could be targeted by drug developers to halt colon cancer.
Khalil’s team discovered that depleting lincDUSP restored inherent cell death mechanisms. Colon cancer cells with low levels of lincDUSP became susceptible to cellular checkpoints that keep growth in check. They immediately committed cell suicide— apoptosis—at the first sign of DNA damage. Depleting the single lincRNA also had widespread genetic effects. Khalil’s team discovered that reducing lincDUSP levels affected expression of over 800 other genes. These results, combined with the team’s experiments showing lincDUSP interacting with DNA, add to a growing body of evidence that lincRNAs are central to gene regulation. As such, they could represent an intriguing arena for drug developers.
In a new study published in Scientific Reports, researchers compared lincRNA levels inside tumor cells, to levels inside healthy colon cells. They found over 200 lincRNAs at significantly different levels inside the tumor cells as compared to normal cells. One in particular, called lincDUSP, was overexpressed in 91 percent of the tumor samples. A few tumors had more than fifteen times the normal amount of lincDUSP. The significant increase suggested this mysterious, and previously uncharacterized, RNA could be cancer-causing. “To determine whether lincDUSP shows oncogenic activity in colon cancer, we decided to test the effects of depleting lincDUSP in patient-derived colon tumor cell lines,” wrote the authors. The researchers genetically modified colon cancer cells to deplete lincDUSP, and surprisingly, the cells began replicating at normal rates. They no longer had unrestricted growth associated with colon cancer tumor cells. Small molecules that inhibit lincDUSP, say the researchers, could have similar effects. “Our work demonstrates that not only proteincoding genes but also non-coding genes contribute to colon cancer progression,” says Ahmad Khalil, PhD, senior author, assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center. “LincRNAs
“Not much is known about the role of long noncoding RNAs in colon cancer,” says Khalil. “Using new technologies that target RNA molecules, instead of proteins, adds a new dimension to cancer therapies.” This research was partially supported by the Case Comprehensive Cancer Center Genomics Core and Cytometry and Imaging Core. The researchers also used the Leica DM6000 widefield microscope in the Light Microscopy Imaging Facility at Case Western Reserve University made available through the Office of Research Infrastructure (NIH-ORIP) Shared Instrumentation Grant (S10RR021228). Forrest, ME, et al. "Colorectal Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis." Scientific Reports. For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
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Case Western Reserve University School of Medicine Researchers Create First Artificial Human Prion Finding May Shed Added Light On, Offer Treatment Hope for Brain-Wasting Diseases Case Western Reserve University School of Medicine researchers have synthesized the first artificial human prion, a dramatic development in efforts to combat a devastating form of brain disease that has so far eluded treatment and a cure. The new findings are published in Nature Communications. Prions are proteins that have folded incorrectly. They can bind to neighboring normal proteins in the brain, triggering a domino effect that causes microscopic holes, turning brains into sponge, resulting in progressive deterioration, dementia, and certain death. There are numerous types of prion diseases in humans; the most common being CreutzfeldtJakob disease (CJD). Why and how human prion mis-folding occurs has been a mystery that the Case Western Reserve investigative team may have solved with its new findings.
RESEARCHERS ALREADY KNOW HOW TO MAKE SOME FORMS OF LABORATORYRODENT PRIONS, BUT UNTIL NOW, NONE OF THESE WAS INFECTIOUS TO HUMANS AS JUDGED IN EXPERIMENTS WITH HUMANIZED MICE MODELS.
“This accomplishment represents a watershed,” said Jiri G. Safar, MD, professor of pathology and neurology at Case Western Reserve School of Medicine and the study’s lead author. “Until now our understanding of prions in the brain has been limited. Being able to generate synthetic human prions in a test tube as we have done will enable us to achieve a much richer understanding of prion structure and replication. This is crucial for developing inhibitors of their replication and propagation throughout the brain, which is essential for halting prion-based brain disease.” Researchers already know how to make some forms of laboratory-rodent prions, but until now, none of these was infectious to humans as judged in experiments with humanized mice models. In their new paper, the researchers describe their success in synthesizing a new, highly destructive human prion from a genetically engineered human prion protein expressed in E. coli bacteria. They also discovered an essential cofactor known as Ganglioside GM1—a cell molecule which modulates cell-to-cell signaling—in triggering infectious replication and transmission of prion-based disease. This finding raises the hope for new therapeutic strategies using analog medications with inhibitory or blocking effect on human prion replication. The CWRU researchers also demonstrated that the replication rate, infectivity, and targeting of specific brain structures
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by synthetic and naturally occurring prions is determined not by the presence of mis-folded prions per se but by particular variations and modifications in the molecule’s structure—specifically in an area known as the C terminal domain—which control the growth rate of infectious prions. “Our findings explain at the structural level the emergence of new human prions and provide a basis for understanding how seemingly subtle differences in mis-folded protein structure and modifications affect their transmissibility, cellular targeting, and thus manifestation in humans,” said Safar. Currently, there is no treatment or cure for CJD. Symptoms are similar to those of Alzheimer’s disease, sometimes leading to mis-diagnosis. These include dementia, memory loss, trouble walking, and impaired vision. The occurrence of human prion diseases peaks at ages 60-65, accounting for approximately 1 in 10,000 deaths worldwide. Despite their relative rarity, human prion diseases have gained considerable notoriety and relevance because they display characteristics of neurodegenerative diseases but are infectious. Furthermore, they can spread not only between humans but also from animals to humans by an infectious agent that is highly resistant to inactivation. Previous prion studies were carried out with laboratory nonhuman prions on mouse and hamster models. While this approach was useful for a general understanding of prion-triggered disease, human prions are different from these strains in both structure and mechanism of replication. Several recent therapeutic trials of human prion diseases have failed. Although these disappointing results may have occurred for multiple reasons, they demonstrate that the results from animal or cellular prion models do not automatically apply to human prions. Creating artificial human prions will allow researchers to engage in an apples-to-apples study process, opening the door to more complete insights into how prions unleash their destructive force, potentially resulting in medications that can stop the disease in its tracks. And since Parkinson’s and Alzheimer’s diseases spread through the brain in similar fashion as CJD, new inroads against these conditions are possible as well. Safar was lead author of a pioneering paper on a “prion shape detector” published in Nature Medicine in 1998, which received extensive global coverage and has been highly quoted ever since. The current paper in Nature Communications is a continuation of this ground-breaking research.
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GE Healthcare FlexFactory Helps XPH Scale Up Industrialization of TCR T-Cell Immunotherapy Drugs GE Healthcare will provide Xiangxue Pharmaceutical Co., Ltd. (XPH) with a FlexFactory™ for cell therapy, a semi-automated end-to-end manufacturing platform, to help scale up, digitize and accelerate manufacturing processes for their cell therapy clinical trials and future commercialization. This project marks the first-ever application of FlexFactory for cell immunotherapy drugs based on high-affinity and high-specificity T cell receptors (TCR). XPH aims to deliver a breakthrough for cancer treatment with a new-generation TCR T-cell therapy, and they have become one of the industry-leading companies to roll out related research for this application. Cell therapy is recognized as one of the most promising models for comprehensive and precise cancer treatment. But the manufacturing process is complex and it is a challenge for companies to produce cell therapies at industrial scale. Thus, FlexFactory for cell therapy was developed to help companies achieve stable, safe and scalable manufacturing of cell therapy products. The platform helps shorten the commercialization cycle through accelerated translation from scientific research to clinical trials to industrial-scale production. GE Healthcare will also provide XPH with training services, process development, flexible cell processing equipment and digital connectivity solutions. Yonghui Wang, Chairman of XPH, said: “As a new
breakthrough in cancer treatment, the importance of cell immunotherapy has gained consensus by the global medical industry, offering great hope for humans to combat cancer. As we continue development in precision medicine, we look forward to long-term collaboration with GE Healthcare, using digital and semi-automated technologies as well as comprehensive analytical methods, to help us more efficiently produce treatments for patients.” With a high concentration of healthcare companies and medical resources, Guangzhou is currently implementing the IAB Plan to advance development in information technology, AI, and biotechnology industries. GE Healthcare and XPH are committed to creating a world-leading cell therapy manufacturing platform in the Guangzhou Development Zone. Thus, this close strategic partnership helps establish a new world-leading bioindustry ecosystem in Guangzhou. Qing Li, General Manager, GE Healthcare Life Sciences, Greater China, said: “FlexFactory will help XPH establish a standardized and large-scale manufacturing process for cell immunotherapy in line with requirements for future commercialization. We look forward to continuing to support the overall development and industrialization of China’s cell and gene therapy industry.” The FlexFactory platform is expected to be operational in March 2019.
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New treatment option for ‘wake-up’ stroke patients Detail revealed in MRI brain scans can help doctors accurately deduce when a stroke begins, according to new research, allowing treatment for many patients who currently cannot receive it. The findings could help to better treat stroke patients, particularly those who wake up with stroke symptoms. Currently, those patients who do not know when their stroke began are not routinely eligible for clot-busting treatment, which is only able to be used a few hours after stroke symptoms start. The WAKE-UP trial – a major European study, which was led in the UK by the University of Glasgow – found that doctors were able to select patients who would benefit from clot-busting treatment based on the information from two different MRI scans. The study is published in New England Journal of Medicine and the findings were presented at the European Stroke Organisation Conference (ESOC). Up to 20 percent of stroke patients wake up in the morning with stroke symptoms. This means that the time when their stroke started is unknown and, as a result, they are not routinely eligible for clot-busting treatment (thrombolysis), which is only approved to be used within 4.5 hours after the start of stroke symptoms. Every year there are estimated to be over 100,000 strokes in the UK, including over 20,000 in patients with ‘wakeup stroke’ or who otherwise have an unknown time of symptom onset. Patients were studied using a combination of two different MRI sequences. The first scan, called diffusion weighted imaging (DWI), shows early changes in the brain after stroke, whereas changes take several hours to become obvious in the second type of scan called FLAIR (fluid-attenuated inversion recovery). If changes are visible on one type of scan (DWI) but not the other (FLAIR), then a patient’s stroke is likely to have happened in the preceding 4.5 hours. The trial tested whether people with this pattern benefitted from thrombolysis using the clot-busting drug alteplase. Treatment with alteplase gave a significantly higher rate of full or nearly-full recovery 3 months after the stroke: 53% of patients treated with alteplase made a full or nearlyfull recovery compared to 42% in the placebo group, representing an absolute increase of 11.5%. This means that for every 9 people treated, one extra person made a complete recovery.
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Professor Keith Muir, SINAPSE Chair of Clinical Imaging at the University’s Institute of Neuroscience & Psychology, and Chief Investigator and coordinator of the trial in the UK, said: “Clotbusting drug treatment is effective only in the first few hours after a stroke, so it has not been possible up until now to treat patients when the stroke happens during sleep, for example. This involves as many as 1 in 5 people affected by a stroke. “The WAKE-UP trial proves that we can use MRI scanning effectively as a timer, and that treating people with an MRI pattern indicating likely onset in the preceding few hours is highly beneficial. “The trial should significantly increase the opportunities for treatment in stroke. Around 1 in 3 of the patients enrolled in the trial had the MRI signature of recent onset, and could be expected to be eligible for treatment that they have been unable to receive in the past. This translates into several thousand additional people per year in the UK. “This important advance brings the possibility of treatment to many more stroke patients, but the challenge is to ensure availability of immediate MRI scanning. Unlike other countries, the UK has very poor access to emergency MRI, so it will need the UK to make immediate access to MRI scanning a priority.” Juliet Bouverie, Chief Executive at the Stroke Association, which was a consortium member on the trial, said: "These findings could be a game-changer for the thousands of people who have a stroke in their sleep so can't receive thrombolysis. “Stroke is a medical emergency and there is a only a small window of opportunity to receive treatment that can reduce brain damage. The impact of a stroke means it can affect someone’s mobility, vision, memory and even their personality, robbing them of the life they had. "Everyone who has had a stroke should be given the best chance of recovery. If the use of this new brain scan technique were rolled out across the UK, it has the potential to save thousands of stroke survivors from serious physical and mental disability.” The WAKE-UP trial was conducted at 70 centres in 8 European countries. Nine hospitals across the UK recruited patients to the trial, with funding received from the 7th framework programme of the European Union. The paper is available here: www.nejm.org/doi/full/10.1056/NEJMoa1804355
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Photo Credit: Nottingham Trent University
The rise of biotechnology: How biotechnology is contributing to regional development SMITH, D.J., ROSSITER, W. and MCDONALDJUNOR, D., Nottingham Business School, Nottingham Trent University How a city creates new development paths when faced with declining industries, is one of the most pressing questions of our time. We’ll fasten our colours to the mast and say that as a publisher based in the North East of England, where many of our traditional industries have declined, we were intrigued to find out how one city is forging a new path. You may associate the UK biotechnology sector with the golden triangle of London, Oxford and Cambridge, but in this issue of BioScience Today, we take a look at another city which is making its mark in the sector.
THE CHALLENGE Prior to the millennium, Nottingham showed all the hallmarks of a city region trapped on a path of decline, but read on to find out how the city turned its historic strengths
(and assets) to new purposes. Discover how biotechnology and bioscience more widely, are contributing to a new model for regional development. In order to understand better how this came about, we must first take a step back in time:
THE BACKGROUND Look back to Nottingham in the 1960’s and you’ll find that Boots, Raleigh and Players, were mainstays of the local economy, with each company employing almost 10,000 people in the city. Boots had developed into one of the UK’s leading pharmaceutical companies, having invested heavily in new research facilities and among its major achievements was the discovery of ibuprofen at their Pennyfoot Street laboratory. Move forward a decade or two however, and you’ll find a different story. Nottingham, like other centres of industry was going through a steady process of de-industrialisation, with manufacturing employment contracting and the balance of the economy shifting towards the service sector.
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CHANGES TO INDIVIDUAL FIRMS Secondly, the changing fortunes of individual firms was a contributing factor to the adaptation of the local economy, and in the case of Nottingham, what happened to Boots was crucial. Having become one of the UK’s leading pharmaceutical companies, by the 1990’s, Boots was facing several challenges including leadership changes and regulatory problems, for example, one drug they had developed, manoplax, was withdrawn. By 1995, the decision had been made by Boots to sell their prescription only drug business to BASF, yet within four years BASF themselves were conducting a review and made the decision to sell their Knoll Pharmaceuticals business to Abbott Laboratories in 2001. Abbott wanted the Intellectual Property rights, but not the Nottingham site and around 450 highly-qualified scientific staff were made redundant.
INSTITUTIONAL CHANGES The adaptation of Nottingham’s economy was influenced by a third factor – changes to local institutions – including both scientific and administrative organisations. This was to prove critical in developing the capabilities necessary to take advantage of a window of opportunity when it arose. The opening of the Medical School at the University of Nottingham in 1970, followed in 1977 by the Queens Medical Centre (QMC) – the first purpose-built teaching hospital to be constructed in the UK – both acted to boost the local science-based labour market and stimulate demand for health related bioscience services. Also, contributing to the city’s science-based economy was the development of the two universities. Nottingham University was to become one of the UK’s leading research intensive universities, with major departments in bioscience and healthcare, whilst the former polytechnic was fast developing, gaining university status in 1992 – becoming Nottingham Trent University (NTU). In addition, Nottingham City Council was awarded unitary status in 1998, giving them a greater say in strategic planning, whilst the establishment of regional development agencies (RDAs) across the UK, including the East Midlands Development Agency (EMDA) in Nottingham, was another important factor in the development of the local economy.
A WINDOW OF OPPORTUNITY Raleigh was hit by the growth in car ownership, whilst Players were affected by the growing awareness of the detriment to health posed by smoking, while Boots, as we shall see, also suffered a change in fortunes. Household names once associated with Nottingham were fast restructuring, going out of business or moving out of the city and the future looked bleak. By 2000, Raleigh had ceased their operations in the city, and around the same time, another manufacturing plant, Royal Ordnance – owned by British Aerospace, also closed. What then were the factors that led to Nottingham finding a new development path based on bioscience and health? Drawing on Kingdon’s multiple streams framework, we identify three key streams of activity which ultimately led to a turnaround in Nottingham’s fortunes.
CHANGES IN THE PHARMACEUTICAL INDUSTRY Firstly, changes in the worldwide pharmaceutical industry, saw a succession of high profile mergers in the 1990’s and at the same time, as part of this consolidation, the model of R&D used by many pharmaceutical companies changed due to the inherent cost of drug development. In-house development was being replaced by outsourced and external R&D - leading to a rise in the number of specialist biotechnology companies offering these services. Closed models of innovation were being replaced by more ‘open’ and outward looking models, and these changes in themselves were to prove an opportunity for Nottingham.
It was the convergence of these three streams; industry, firms and institutions, which served to create both a major economic challenge and a means with which to respond. The catalyst or ‘focusing event’ as Zahariadis terms it, which drew attention to the decline Nottingham’s industrial base was the closure of the former Boots research laboratory and the redundancy of the staff in 2000. It soon became clear that selling the site was not an option, for as one former employee noted, “nobody wanted the site when we tried to sell it for its existing purpose – that was clear”. A second option mooted was the development of the site for alternative purposes – but this too was not feasible as much of the land was badly contaminated through earlier industrial activity. A third possibility considered, given its proximity to their campus, was that NTU should take over the site, and turn the space into lecture theatres and classrooms, but both funding difficulties and the reluctance of the former owners to agree to a whole sale conversion of the site, meant that this option also wasn’t feasible. A fourth option soon became apparent when former research scientists from the Boots/BASF site asked to rent space at the facility in order to set up their own companies and an idea took shape that the laboratories should be turned into some form of incubator housing small start-up bioscience businesses.
THE WAY FORWARD In the event, this was the solution that won the day and regional development agency, EMDA, helped the idea to gain traction,
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brokering a deal which saw the city’s universities collaborate on a joint venture with them and BASF to set up a bioscience incubator. It led to BASF announcing in August 2001 that it was gifting the laboratories in Nottingham to NTU. Valued at some £4 million the facility was comprised of more than 100,000 square feet (THE, 2001) of laboratory space. The laboratories are referenced in Hansard in 2008, as comprising the largest corporate donation ever to have been made to a post-1992 university, and it is estimated that they would have cost close to £50 million to build and equip at the then current prices. The laboratories were to be used to house small start-up firms not only in biotechnology but also in healthcare, including several that employed former BASF/Boots staff and others founded by staff from both of the local universities. In return BASF agreed to cover the cost of running the facility until the partners had had an opportunity to, “develop a robust business plan and secure the necessary funding” (Hansard, 2008), and the new operating company was ready to take it over. Thus was borne ‘BioCity Nottingham’, a bioscience incubator designed to facilitate the biomedical research of universities in the region, especially at the technology-transfer stage.
THE GROWTH OF BIOCITY NOTTINGHAM The first phase of the development was opened by the science minister, Lord Sainsbury in September 2003, since then BioCity has gone from strength to strength and now operates over 5 sites, two in Nottingham, two in Glasgow and one in Alderley Park. Developments which have consolidated BioCity’s position as by far the largest bioscience incubator in the UK (McDonald-Junor 2015) and have formed the basis of an embryonic bioscience cluster in Nottingham – centred on but not limited to BioCity. Changes in industry, individual firms and authorities in the late 1990’s and early 2,000’s coalesced to create the conditions that led to a unique window of opportunity in Nottingham. The subsequent interplay and co-operation between firms, administrative and scientific institutions, saw the emergence of the necessary capabilities to take advantage of this opportunity.
A RECIPE FOR REGENERATION? The success of Nottingham in finding a new bioscience development path raises the question as to whether this model could be applied elsewhere and evidence suggests that this may well be the case. Look around the country and you’ll find a few examples where the departure of a major pharmaceutical company has led to the development of a bioscience incubator. BioPark Herts developed at laboratories vacated by the Swiss pharmaceutical giant Roche, BioCity Scotland at Motherwell developed from laboratories vacated by the American pharmaceutical company Merck and BioHub Manchester utilizing the laboratories of the British pharmaceutical company Astra Zeneca. A fourth example, which has come to light since this research was originally published is the re-development of the former Astrazeneca facility at Loughborough as a Life Sciences Opportunity Zone. These projects represent more than the simple reuse of vacated laboratory space, but also show evidence of policy transference/learning between agencies and authorities in different UK localities, in which the local NHS, local Selected bibliography: Chapman, S.D. (2006) Economy, industry and employment, in J.V. Beckett (ed.) A Centenary History of Nottingham, Chichester: Phillimore, 480-512. Department for Business, Energy & Industrial Strategy, 16 May 2018. Available at: https://www. gov.uk/government/news/uk-life-sciences-sector-brings-record-growth-as-new-life-sciencescouncil-meets-for-first-time [Accessed 14th June 2018] Hansard (2008) Memorandum submitted by Oxford Innovation Ltd, Hansard, 1st October 2008. Available at: Source: http://www.parliament.the-stationery-office.co.uk/pa/cm200809/ cmselect/cmberr/89/89we120.htm. [Accessed 18th June 2015] Kingdon, J.W. (1995) Agendas, Alternatives and Public Policies, New York: HarperCollins.
authorities and economic development/enterprise agencies have all played a significant part.
BIOSCIENCE AND REGIONAL DEVELOPMENT The new bioscience cluster in Nottingham is a fraction of the size of clusters in the ‘golden triangle’, such as that at Cambridge, yet it is the largest bioscience incubator in the UK and this in itself is hugely significant both for regional development and the broader economy. Why so? Just last month, the government acknowledged that Health and life sciences are worth over £70 billion to the economy and provide jobs for almost 241,000 people across the country. Even more significant is the fact that SMEs account for 82% of these businesses and 24% of all UK life sciences employment (BEIS 2018). Which just goes to show how important bioscience incubators - like that at Nottingham - are to the economy in supporting these SMEs and helping them to get off the ground. Moreover, these bioscience incubators, are also important in potentially representing a new model for regional development - as we see echoed in a number of similar projects around the UK. This paper, along with the full references and bibliography, was originally published in full as: Adaptive capability and path creation in the post-industrial city: the case of Nottingham’s biotechnology sector. SMITH, D.J., ROSSITER, W. and MCDONALD-JUNOR, D., 2017, Cambridge Journal of Regions, Economy and Society, 10 (3), pp. 491-508. ISSN 1752-1378
Martin, R., (2005). Thinking about regional competitiveness-critical issues. Nottingham: East Midlands Development Agency. McDonald-Junor, D. (2015) From property management to business growth: Business support in UK biotechnology incubators, unpublished PhD thesis, Nottingham: Nottingham Trent University. THE (2001), £4m gift for innovation centre, Times Higher Education, 31st August 2001. Available at: https://www.timeshighereducation.com/news/4m-gift-for-innovation-centre/164624.article [Accessed: 18thJune 2015] Zahariadis, N. (2007) The multiple streams framework: structure, limitations, prospects, in P.A. Sabatier (ed.) Theories of the Policy Process, 2nd edition, Cambridge, MA: West View Press, 65-92.
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Dundee’s global life sciences contribution highlighted at
BIO 2018
The University of Dundee’s contribution to the UK’s strength in the global life sciences sector is has been highlighted by its Drug Discovery Unit at one of the world’s major scientific gatherings, the 2018 BIO International Convention in Boston.
THE UNIVERSITY OF DUNDEE HOSTS ONE OF THE UK’S LARGEST AND MOST HIGHLY RATED RESEARCH COMPLEXES IN LIFE SCIENCES.
The Drug Discovery Unit operates as a standalone ‘biotech style’ small molecule drug discovery organisation and collaborates with partners worldwide to translate worldclass biology research into novel drug targets and candidate drugs across multiple disease indications. This makes it the only DDU of its type in the UK which, in turn, enables it to work in unfashionable areas such as tropical diseases, with one major delivery to date being a clinical candidate for malaria which is now in development with Merck KGaA. The Unit will present its technologies to more than 45 organisations in one-to-one partnering meetings over the course of four days at BIO 2018. Over the past 12 years the DDU has secured more than $142.6million funding from research grant/charitable funders and industry partnerships. This has allowed the Unit to attract management from senior positions in the pharmaceutical industry and build a team of over 95 translational scientists dedicated to the development of innovative medicines The state-of-the-art infrastructure for preclinical small molecule drug discovery has seen the DDU work in partnership with multiple academic institutions and industry
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partners including the University of Oxford, MRC Laboratories of Molecular Biology (LMB), University of Cambridge, GSK, AZ, Pfizer, Bayer and AbbVie amongst others. “Our presence at Bio2018 will allow us to talk to pharma and biotech companies about partnerships and enable us to look for investors, as well as raising awareness generally of the world-leading work that is being done in Dundee,” explained Dr Julie Brady, from the DDU. Life sciences across the UK as a whole is a well-established sector which is making a significant contribution to economic growth in the UK – annual turnover of nearly $64bn, exports around $30bn – from over 5,000 companies employing 233,000 people. The University of Dundee hosts one of the UK’s largest and most highly rated research complexes in life sciences, with around 900 scientists from over 80 countries and was named last year as the world’s most influential pharmaceuticals research institution in a major global survey by Clarivate Analytics. Building on this success the University, with local partners, is currently bidding for millions of pounds through the Tay Cities Deal to further grow the biomedical cluster in the city and surrounding area and expand on its already strong contribution to Scotland’s economy.
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UK Institute to harness disruptive technology to transform drug discovery Business Secretary Greg Clark has announced funding for a series of ambitious technology projects that will transform the way medicines are discovered, enabling the pharmaceutical industry to develop groundbreaking drugs faster, cheaper and better than ever before. The projects are the first wave of major initiatives for the £103m Rosalind Franklin Institute, that has just been launched at the Harwell Campus, Oxfordshire. New drugs are discovered through a slow and painstaking process of trial and error, often taking ten years and billions of pounds to develop. The Rosalind Franklin Institute (RFI) is investing £6M to create: • The World’s most advanced real-time video camera, the key to a new technique that uses light and sound to eradicate some of the most lethal forms of cancer.
• A new project pioneering fully-automated hands-free molecular discovery to produce new drugs up to ten times faster and transform the UK’s pharmaceutical industry. • A ground-breaking new UK facility that will revolutionise the way samples are produced and harness Artificial Intelligence (AI) to generate new drugs for clinical testing within a few weeks. The RFI will harness disruptive new technologies such as AI and robotics to dramatically improve our understanding of biology, leading to new diagnostics, new drugs, and new treatments for millions of patients Worldwide. It will pioneer new ways of working with industry, as part of the UK’s AI and Data Grand Challenge, bridging the gap between university research and pharmaceutical companies or small businesses. This will build on the Government’s modern Industrial Strategy and put the UK at the forefront of the industries of the future. Business Secretary Greg Clark said: “The new Rosalind Franklin Institute will lead a revolution in drug development and diagnosis to improve the lives of millions of patients. And with over 10 million people in Britain alive today expected to live to 100, now more than ever it is vital that the Government invests in the development of new technologies and techniques which will support people to have healthier lives.” Professor Ian Walmsey, Pro-Vice-Chancellor Research & Innovation at the University of Oxford and Chair of the RFI’s Interim Board said: “The RFI will pioneer disruptive technologies and new ways of working to revolutionise our understanding of biology, leading to new diagnostics, new drugs, and new treatments for millions of patients Worldwide. It will bring university researchers together with industry experts in one facility and embrace high-risk, adventurous
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Still Images - Architect’s Renders of the New RFI Building to be located at Harwell Campus, South Oxfordshire - credit: “Courtesy of IBI”
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research, that will transform the way we develop new medicines.” The namesake of the institute, the pioneering X-ray crystallographer Rosalind Franklin, was one of the key figures in the discovery of the structure of DNA, and used a technique with roots in physics and technology to transform life science. The Institute will follow in this spirit, developing unique new techniques and tools and applying them for the first time to biological problems. The Institute is an independent organisation funded by the UK government through the Engineering and Physical Sciences Research Council (EPSRC) and operated by ten UK universities. Professor Philip Nelson, EPSRC’s Executive Chair, said:
THE RFI WILL PIONEER DISRUPTIVE TECHNOLOGIES AND NEW WAYS OF WORKING TO REVOLUTIONISE OUR UNDERSTANDING OF BIOLOGY, LEADING TO NEW DIAGNOSTICS, NEW DRUGS, AND NEW TREATMENTS FOR MILLIONS OF PATIENTS WORLDWIDE.
“As EPSRC is the main delivery partner for the Rosalind Franklin Institute, I am extremely pleased to see the Institute officially launched today. Research here at the Harwell hub, and at the universities that form the spokes of the Institute, will help the UK maintain a leading position in the application of engineering and physical sciences to problems in the life sciences.” UK Research and Innovation chief executive Professor Sir Mark Walport said: “The UK is home to a vibrant life sciences research community. The Rosalind Franklin Institute’s strength is in bringing this together with physical scientists and engineers at the heart of a campus that fosters innovation and collaboration. Through its pioneering interdisciplinary research and the development of new technologies, it will support advances including improved drug discovery and the faster development of effective treatments for chronic conditions. Through partnership with industry, it will help ensure its insights are more rapidly translated into impacts and drive growth across the UK’s important life sciences sector.” It operates on a ‘hub and spokes’ model, with a central hub at the Harwell Campus in Oxfordshire, delivered by the Science and Technology Facilities Council (STFC). The hub, opening in 2020, will house a unique portfolio of scientific tools and researchers from both industry and academia. Equipment and researchers will also be located in spokes distributed throughout the partner network of universities. The hub at Harwell is a four storey, £40m build, which is being project managed and delivered by STFC. With the façade of the building reflecting the iconic work of Rosalind Franklin, the hub will house the majority of the technologies produced for the Institute, and will have world leading capabilities in imaging and drug discovery, creating a globally unique centre of excellence in life science. It will be home to 150 researchers from industry and academia, working closely with neighbouring facilities at Harwell including the Diamond Light Source and STFC’s Central Laser Facility. Professor James Naismith FRS FRSE FMedSci Director of the Research Complex at Harwell, and Professor of Structural Biology at the University of Oxford, has been appointed as the Interim Co-Academic Lead at the Rosalind Franklin Institute. Speaking about the institute he said:
“The institute will produce technologies to fill the gaps slowing down the progress of research in both industry and academia. Identifying these gaps, working with industry and university colleagues, and then working to produce the technologies which will solve them is at the heart of what we will do here. For example, not being able to watch a drug enter a cell in real time holds back our understanding of how they work - this is one of the challenges we seek to solve. “The technologies we will develop will speed up hugely the process of drug discovery, and help us understand disease better at a fundamental level. For the general public, this means getting better, more effective drugs, more quickly.” “Rosalind Franklin was an exemplary interdisciplinary scientist. She took a technique - X-ray crystallography - and through her application of it, transformed utterly our understanding of life. What is often not known about Rosalind Franklin was the breadth of her work, which started looking at coal and graphite, and moved on to DNA, and then later to look at the structure of viruses. This ability to move between disciplines, and look at a universe of scientific problems without boundaries is what we aspire to here at the Institute. “The building at Harwell has a number of features which will make it the perfect place to build new technologies for life science. The building will have exceptional stability and control on the ground floor, making it ideal to develop techniques in EM and mass spec, and spaces designed throughout which are not only ideal for carrying out research, with chemistry and life science labs, but also for groups to work together and collaborate. The design of the building has been put together by scientists for science - it will be a fantastic place to carry out research.” EPSRC and STFC are part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.
“The new Rosalind Franklin Institute will lead a revolution in drug development and diagnosis to improve the lives of millions of patients.” 57
| IATA |
| BIOSCIENCE TODAY SUMMER 2018 |
Can compliance in pharmaceutical logistics by air be reached through industry collaboration? Pharmaceuticals makeup 1.9% of all air cargo and generate revenues of $1.4 billion per year - 2.6% of total air cargo. In the next three years (2018-2020), growth in pharmaceuticals being transported by air is expected to increase 3.7%. Despite lower than overall air cargo volume growth, the higher yield premiums of pharmaceutical shipments mean that they will still contribute to generating an increasing share of air cargo revenues. The transport of temperature controlled pharmaceutical products requires a lot of attention and the air cargo industry is facing multiple challenges. For goods originating from the healthcare sector, the associated risks generate costs for the industry stakeholders. Shippers of specialized drugs, vaccines and emergency aid rely on air cargo to get their products where they are needed quickly while maintaining the products integrity and quality. The air cargo supply chain stakeholders are urged to adopt and embrace quality measures and industry standards as demand for more predictable logistics supply chains continues to grow due to increasing complexity of treatments and pharmaceutical products and a greater focus on patient safety.
BACKGROUND The International Air Transport Association (IATA) is the industry’s global trade association and represents some 290 airlines comprising 82% of global air traffic. Its mission is to represent, lead and serve the air transport industry and its responsibility is to develop and deliver standards and solutions to ensure safe and harmonized air transport. In Cargo, IATA has a long standing tradition of working closely with industry in all its initiatives to address their needs and ensure regulatory compliance and quality services. The aim is to benefit all parties (airlines, forwarders, governments, handlers and shippers).
To address the challenges in transporting and handling pharmaceuticals and healthcare products, IATA adopted a supply chain approach and set up a dedicated working group, the IATA Time and Temperature Task Force (TTTF) now renamed as the IATA Time and Temperature Working Group (TTWG) composed of industry supply chain subject matter experts. The TTWG recommends standards, best practices and requirements in the pharmaceutical/ healthcare areas that are endorsed by the IATA Live Animals and Perishables Board (LAPB), a governance body comprised of 12 airline members. The healthcare standards are then included into the Temperature Control Regulations (TCR), to become industry standards. These Regulations are not only binding to IATA airline members but they mandated requirements down the supply chain all the way to the shipper. The standards that have been developed, such as the Time and Temperature Sensitive Label for Healthcare Products and the Acceptance Checklist for Time and Temperature Sensitive Healthcare Shipments, have been disseminated to the industry but are still not widely complied with. As such the need to continue raising awareness is essential among all stakeholders across the supply chain to ensure compliance with the Regulations.
COMPLIANCE Customers are demanding that adequate facilities, equipment, handling procedures and trained staff are in place to ensure the temperature range is maintained to protect the integrity and quality of their products throughout the journey. Because of the sensitivity nature of the products being shipped, the procedures, practices and requirements of the healthcare industry must be understood and applied by all those involved in the supply chain.
58
THE INTERNATIONAL AIR TRANSPORT ASSOCIATION (IATA) IS THE INDUSTRY’S GLOBAL TRADE ASSOCIATION AND REPRESENTS SOME 290 AIRLINES COMPRISING 82% OF GLOBAL AIR TRAFFIC.
| BIOSCIENCE TODAY SUMMER 2018 |
| IATA |
Understanding the challenging business environment many airlines, freight forwarders and ground handlers have invested heavily in temperature controlled supply chain solutions. Until recently however, there was no global standardized certification for the handling of pharmaceutical products. To recognize the effort made by the industry to address the pharmaceutical manufacturers’ needs and to help foster air cargo’s competitiveness in this growing industry, IATA developed with the industry the Centre of Excellence for Independent Validators in Pharmaceutical Logistics (CEV Pharma). CEIV pharma is a globally consistent, recognized and standardized certification for pharma shipments in air freight. It ensures that the right processes, people and infrastructure are in place to handle and transport of sensitive shipments in compliance with existing international and national regulatory requirements. CEIV pharma was introduced as an example of air cargo’s commitment to certify the high quality transportation of critical commodities and to address the concerns identified in the supply chain, especially those of pharmaceutical shippers. The pharmaceutical industry is heavily regulated and today there is an increasing number of countries issuing their own regulations and guidance around the world to implement and comply with. There are different levels of compliance in the industry depending on the scope of the operation and required regulatory requirements. There is the Wholesale Distribution Authorization (WDA), the Commercial Certificate and CEIV Pharma Certification. Each stakeholder involved in the transport or handling of pharmaceuticals has to implement the regulatory requirements (e.g. internal quality management system, qualified personnel, well designed processes and equipped premises using a risk based approach) but it all depends on the level of recognition desired or required as well as on the activity of the company (e.g. national, international or global) as to which certification is most suited to their needs. Nevertheless, compliance, standardization, accountability and transparency across the supply chain is needed. This is why IATA developed CEIV Pharma - as a standardized global certification program training and assessing organizations against standards and regulations that encompasses various regulations and standards (including e.g. IATA TCR, National GDPs, WHO). CEIV Pharma is one way to address industry’s concern but what is more important to emphasize is that it was developed by the industry for the industry with a greater focus on the operational aspect of the companies’ activities. In addition, supply chain excellence is achieved as a result of applying procedures that are effective, efficient and meet the needs of customers. Training is paramount to effective implementation. The training of staff handling sensitive cargo is crucial to ensure that the integrity of the temperature controlled supply chain is maintained, therefore training for stakeholders involved in the transport by air of temperature controlled healthcare products is a prerequisite of the IATA Temperature Control Regulations. It is essential that each member of the supply chain understands what the specific requirements for compliance are, as well as those of others in the supply chain. This allows for a greater understanding of the entire supply chain process and smoother process integration.
NEXT STEPS The feedback received from the industry is positive. Such a certification is conducted on a voluntary basis, therefore IATA will continue to respond to the industry’s demand to become CEIV certified. There has been a growing expectation to see standardization and transparency across the supply chain. As a result CEIV Pharma is expanding globally. Stakeholders across the supply chain are now embarking on the program. They recognize the added value and benefit brought
59
forward by the certified entities such as being given the means and tools to enhance their quality services and being recognized as meeting the regulatory requirements as well as the standards in term of operations, adequate facilities and trained staff. Today there are more than 200 entities that are certified and more than 70 that are in the progress of certification.
Continuous improvement is also key in such a quality driven strategy therefore, IATA will ensure with the supply chain stakeholders that the program is always up-to-date in terms of standards and regulatory requirements. In addition, IATA will follow and work closely the different industry initiatives such as Pharma.aero that involves CEIV certified entities to seek industry feedback and best practices. The best recognition of the effectiveness of a standard is when it is adopted by the industry. In the framework of continuous improvement aimed at having global certified trade lanes, CEIV Pharma has taken the industry and moved it to another level. Pharma.aero for example is a good example that focuses on improving pharma handling and quality in the air cargo industry worldwide focusing on pharmaceutical shippers and all industry stakeholders who embrace the IATA CEIV program.
POLICY IMPLICATIONS The industry has seen that less costly sensor technology for monitoring cargo shipments has created new possibilities in improving information flow across the supply chain. This offers an opportunity for improving the quality of the air cargo product and by doing so creating new growth prospects. Industry and technology providers are encouraged to work collaboratively on certification processes and data usage. However, risks to growth prospects exist, particularly if seamless flows of high-value pharmaceuticals across borders are impeded, for example, if Brexit arrangements are restrictive. UK and EU governments are encouraged to ensure effective agreements remain in place post Brexit to facilitate this critical health supply chain continuing. Finally regulations and standards, such as EU GDP and IATA CEIV Pharma, have served to shore up confidence among shippers to rely on air cargo. However, further harmonized efforts are needed to diagnose and bridge gaps in capabilities across the logistics supply chain given increasingly specialized shipper needs. Governments and shippers are encouraged to enhance dialogue with operators to ensure continual improvements in air cargo processes align with regulatory and shipper demands. *(The temperature indicated on the lower half of the label must match the approved transportation temperature range, e.g. +15ºC to +25ºC) +15ºC to +25ºC *
europium phospho
cerium sputtering target | news |
| BIOSCIENCE TODAY SUMMER 2018 |
dielectrics catalog:americanelements.com scandium powder
yttrium granules lanthanum rods
holmium disc 1
1
H
3
2 1
Li
Nd:YAG
4
6.941
2 8 1
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
nano ribbons
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
Au
Zn
2 8 18 18 1
48
Cd
Darmstadtium
Rg (280)
2 8 18 2
31
Ga
49
In
112.411
2 8 18 32 18 1
80
Hg
Tl
200.59
2 8 18 32 32 18 1
Roentgenium
112
Cn (285)
2 8 18 3
32
Ge Sn
113
Uut (284)
Copernicium
Eu
64
95
Gd
65
157.25
2 8 18 32 25 8 2
96
Americium
(247)
Curium
Tb
2 8 18 27 8 2
158.92535
Gadolinium
Am Cm (243)
2 8 18 25 9 2
97
Bk (247)
Berkelium
Dy
2 8 18 28 8 2
67
162.5
Terbium
2 8 18 32 25 9 2
66
2 8 18 32 18 3
82
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
2 8 18 18 4
51
Pb
114
Fl (289)
69
Tm
Se
2 8 18 18 5
83
Bi
52
Te
84
2 8 18 32 32 18 5
116
208.9804
115
Uup
2 8 18 31 8 2
(288)
70
alternative energy
35
Br
Yb
53
36
2 8 18 18 7
54
Kr
I
85
2 8 18 32 32 18 6
117
crystal
83.798
Xe
2 8 18 18 8
131.293
Iodine
2 8 18 32 18 6
2 8 18 8
Krypton
126.90447
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
2 8 18 7
niobium
europiu
39.948
Argon
79.904
2 8 18 18 6
2 8 8
Ar
Bromine
(209)
2 8 18 32 8 2
Neon
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
macromolecu
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2 8 18 6
Polonium
Ununpentium
18
35.453
127.6
2 8 18 32 18 5
2 8 7
20.1797
Cl
Tellurium
Bismuth 2 8 18 32 32 18 4
rod
2 8
Ne
Chlorine
78.96
121.76
Flerovium
2 8 18 30 8 2
34
10
Fluorine
Selenium
Sb
207.2
2 8 18 32 32 18 3
2 8 18 5
2 7
18.9984032
S
Antimony 2 8 18 32 18 4
17
32.065
74.9216
Lead
Ununtrium
164.93032
Dysprosium 2 8 18 32 27 8 2
Ho
2 8 18 29 8 2
As
2 8 6
F
Sulfur
Arsenic
Tin
aluminum nanoparticles
2 8 18 25 8 2
33
118.71
Thallium 2 8 18 32 32 18 2
2 8 18 4
9
15.9994
30.973762
72.64
50
16
Phosphorus
Germanium 2 8 18 18 3
2 8 5
O
2 6
Oxygen
P
He Helium
8
14.0067
28.0855
204.3833
Mercury
15
Silicon
114.818
81
2 8 4
N
2
4.002602
2 5
Nitrogen
Si
Indium 2 8 18 32 18 2
7
12.0107
69.723
2 8 18 18 2
2 4
Carbon
Gallium
Cadmium
Gold
111
Al
Zinc
196.966569
2 8 18 32 32 17 1
14
10.811
Boron 13
65.38
Silver
Platinum 2 8 18 32 32 15 2
2 8 18 1
107.8682
2 8 18 32 17 1
2 8 3
C
26.9815386
63.546
2 8 18 18
6
Aluminum
Copper
Palladium
192.217
2 8 18 32 32 14 2
Cu
B
2 3
nanodispersions
TM
advanced polymers
tering targets
2 8 18 16 1
Iridium
single crystal silicon
rbium doped fiber optics
Rh
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
Rhenium 2 8 18 32 32 11 2
Co
Ruthenium 2 8 18 32 13 2
Re
27
Iron
(98.0)
183.84
106
Fe
2 8 14 2
55.845
Technetium
Tungsten 2 8 18 32 32 12 2
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
Rb Sr Y Zr rhodium sponges Rubidium
2 8 10 2
47.867
Scandium 2 8 18 8 2
5
surface functionalized nanoparticles
9.012182
Lithium
11
Be
2 2
2
dysprosium metal
99.999% ruthenium spheres
1.00794
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